Dipyrrinato-Iridium(III) Complexes for Application in Photodynamic Therapy and Antimicrobial Photodynamic Inactivation

Chemistry - A European Journal

10.1002/chem.202004776

FULL PAPER

Dipyrrinato-Iridium(III) Complexes for an Application in

Photodynamic Therapy and Antimicrobial Photodynamic

Inactivation

Benjamin F. Hohlfeld,^[^a^,^b^]Burkhard Gitter, Christopher J. Kingsbury, Keith J. Flanagan, Dorika

[b]

[c]

[b]

[a,d]

Mathias O. Senge*^[^c^,^e^]and Arno Wiehe*^[^a^,^b^]

Steen, Gerhard D. Wieland, Nora Kulak,

Dedicated to Prof. Peter J. Sadler

[

a]

b]

B. F. Hohlfeld, Dr. A. Wiehe

Institut für Chemie u. Biochemie, Freie Universität Berlin

Takustr. 3, 14195 Berlin, Germany

Dr. A. Wiehe, Dr. B. Gitter, D. Steen, Dr. G. D. Wieland

biolitec research GmbH

Otto-Schott-Str. 15, 07745 Jena, Germany

E-mail: arno.wiehe@biolitec.com, https://www.biolitec.de/

Dr. K. J. Flanagan, Dr. C. J. Kingsbury, Prof. Dr. M. O. Senge

[c]

Medicinal Chemistry, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, Trinity College Dublin, The University of Dublin

St James’s Hospital, Dublin 8, Ireland

E-mail: sengem@tcd.ie

[

d]

e]

Prof. Dr. N. Kulak

Institut für Chemie, Otto-von-Guericke-Universität Magdeburg

Universitätsplatz 2, 39106 Magdeburg, Germany

[

Prof. Dr. M. O. Senge

Institute for Advanced Study (TUM-IAS), Technical University of Munich

Lichtenbergstrasse 2a, D-85748 Garching (Germany)

E-mail: sengem@tcd.ie; twitter: @mathiassenge; www: https://chemistry.tcd.ie/staff/people/mos/Home.html

Supporting information for this article is given via a link at the end of the document.

Abstract: The generation of bio-targetable photosensitisers is of

utmost importance to the emerging field of photodynamic therapy and

antimicrobial (photo-)therapy. A synthetic strategy is presented in

which chelating dipyrrin moieties are used to enhance the known

photoactivity of iridium(III) metal complexes. Formed complexes can

thus be functionalized in a facile manner with a range of targeting

groups at their chemically active reaction sites. Dipyrrins with N- and

O-substituents afforded (dipy)iridium(III) complexes via complexation

imaging^[⁶^]or as antibacterial agents.^[⁷^]In this context, iridium(III)

,

complexes have also found interest as chemotherapeutic

agents.^[⁸^]It has been shown that iridium(III) complexes can

interact with specific cellular targets, e.g. mitochondria, DNA,

proteins, and lysosome structures.^[Currently, metal complexes

are also showing increasing promise for an application as

photosensitizers in photodynamic therapy (PDT).^[¹⁰^]PDT is a

medical treatment of cancer and other non-malignant diseases

and can serve as an alternative to classical treatments, such as

surgery, chemotherapy or radiotherapy.^[¹¹^]PDT uses light

sensitive dyes (photosensitizers) for the destruction of cancer

cells. The photosensitizer is activated by light of an appropriate

wavelength in the presence of oxygen, and cytotoxic reactive

oxygen species (ROS) are generated, which results in oxidative

cellular damage and destruction.^[¹¹^a^-^c^,¹²^]In comparison to

traditional chemotherapy or surgery, PDT has a number of

advantages, chiefly that the specific irradiation limits the effect to

the target tissue and side-effects are lessened due to weak dark

toxicity of the photosensitizers and short half-life time of ROS.

Moreover, this modality can be used when other therapeutic

options are exhausted or in case of specific contraindications to

chemotherapy or surgery in vulnerable patient groups.^[¹¹^b^,^c^,¹³^]In

addition, antimicrobial photodynamic inactivation (aPDI) has

9]

with the respective Cp*-iridium(III) and ppy-iridium(III) precursors

5

(

dipy = dipyrrinato, Cp* = pentamethyl-η -cyclopentadienyl, ppy = 2-

III

phenylpyridyl). Similarly, electron-deficient Ir (dipy)(ppy)

2

complexes

could be used for post- functionalization, forming alkenyl, alkynyl and

glyco-appended iridium(III) complexes. The phototoxic activity of

these complexes has been assessed in cellular and bacterial assays

III

with and without light; the Ir (Cl)(Cp*)(dipy) complexes and the glyco-

substituted iridium(III) complexes showing particular promise as

photomedicine candidates. Representative crystal structures of the

complexes are also presented.

Introduction

Metal complexes are widely used as catalysts in diverse

[14]

chemical reactions, e.g., cross-coupling reactions,^[¹^]oxidation

significant potential for an effective inactivation of bacteria, as

well as viruses^[and fungi and other microbiota in vitro and in

vivo.^[¹⁷^]In this context, iridium complexes have also been

evaluated as photosensitizers for aPDI against Gram-positive and

15]

[16]

r

e

a

c

t

i

o

n

s

,

[

2

]

a

l

k

y

l

a

t

i

o

n

,

[

3

]

o

l

e

f

i

n

a

t

i

o

n

o

r

i

n

o

l

e

f

i

n

m

e

t

a

t

h

e

s

i

s

.

[

4

]

Beside the catalytic application, metal complexes are currently

intensively investigated as therapeutically active compounds.

Specifically, metal complexes are well established for

[

18,19]

Gram-negative bacteria,

and have been found to effectively

generate ROS.^[Specifically for metal complexes, however,

18]

[5]

chemotherapeutic treatments , as contrast agents in medical

1

Chemistry - A European Journal

10.1002/chem.202004776

FULL PAPER

other phototoxic mechanisms, e.g. photoinduced ligand exchange, Gram-positive germ S. aureus and the Gram-negative germ P.

may play an additional role.^[²⁰^]

As well, in recent years, dipyrrins (dipyrromethenes) have

caught attention as organic ligands for metal complexes. Dipyrrins

aeruginosa. Moreover, instead of testing the substances in

phosphate-buffered saline (PBS) only, all tests against bacteria

were additionally carried out with the addition of serum, to

are known to coordinate various metals, e.g., zinc, copper, gallium, challenge their activity under more realistic conditions. In these

platinum, palladium, iridium, and ruthenium.^[²¹^]Such complexes

can exclusively consist of dipyrrins (homoleptic complexes);^[²²^]as

well, metal complexes are reported, containing a combination of

dipyrrins and other organic ligands (heteroleptic complexes).

assays, structures with a high phototoxic potential against

bacteria and cancer cells were identified, pointing at structural

elements that favor an application in PDT and aPDI.

5

Typically, p-cymene, η -cyclopentadienyl, 2-phenylpyridyl, or 2,2-

bipyridyl ligands are moieties employed as capping in heteroleptic

dipyrrinato complexes (Fig. 1).^[²¹^b^,²¹^d^,²³^]

Results and Discussion

Synthesis of Target Compounds

Syntheses of heteroleptic metal complexes employing

dipyrrinato ligands based on late-transition metals, e.g.,

ruthenium(II), rhodium(III) and iridium(III), are known in the

literature.^[

21a,23a,b,26a,29]

The synthesis of the dipyrrinato complexes

typically involves reaction of the dipyrrins under basic conditions

with a commercially available (dichlorido-bridged) metal-arene

_p_r_e_c_u_r_s_o_r_._[2a,b,23b,26a,27a,28d,29a,b,30]

In this work, meso-substituted dipyrrins based on the 5-

pentafluorophenyl and the 5-(4-fluoro-3-nitrophenyl) moiety were

tested for the preparation of dipyrrinato iridium(III) complexes.

The pentafluorophenyl group, as well as the 4-fluoro-3-

nitrophenyl group, enable subsequent nucleophilic aromatic

Figure 1. Examples for homo- and heteroleptic dipyrrinato complexes.

substitution reactions (S

N

Ar), introducing, e.g., sugar moieties^[²⁷^a^,

or alkynyl groups, giving access to subsequent 1,3-dipolar

2

8e,31]

Dipyrrinato ligands have found interest as components for the

formation of coordination polymers and supramolecular

cycloaddition reactions for the connection with biomolecules or

polyethylene glycols (“click” chemistry).^[

32]

_a_s_s_e_m_b_l_i_e_s_,[

24]

or light harvesting structures in dye-sensitized

_s_o_l_a_r_c_e_l_l_s_.[²⁵^]Furthermore, dipyrrinato-iridium and -ruthenium

In preparation for the following experiments, the meso-

substituted dipyrromethanes 1 – 15 were synthesized according

to known procedures published by us and others.^[

Dipyrromethanes can then be transformed into the dipyrrins via

oxidation with a suitable oxidation agent.^[²²^b^,²⁷^a^,²⁸^d^,³³^,³⁴^]Here,

dipyrromethanes (1 – 15) served as starting materials for the

required dipyrrins (Scheme 1).

complexes show high potential for an application as

chemotherapeutic agents. Specifically, ferrocene-appended

28a,b,d.e,33]

(

dipyrrinato)(pentamethylcyclopentadienyl)iridium(III)

dipyrrinato)(p-cymene)ruthenium(II) complexes have been

_r_e_p_o_r_t_e_d_t_o_e_x_h_i_b_i_t_a_n_i_n_c_r_e_a_s_e_d_b_i_n_d_i_n_g_a_f_f_i_n_i_t_y_t_o_D_N_A_._[23c,26] Also,

and

dipyrrinato complexes of zinc, ruthenium and gallium show

promising potential for PDT.^[²⁷^]

In

this

work,

the

stepwise

synthesis

of

5

chlorido(dipyrrinato)(pentamethyl-η -cyclopentadienyl)iridium(III)

complexes

and

(dipyrrinato)bis(2-phenylpyridyl)iridium(III)

complexes for use in PDT and aPDI is presented. meso-

Substituted dipyrrins, based on the pentafluorophenyl- and the 4-

fluoro-3-nitrophenyl moiety, are used for the syntheses of these

dipyrrinato iridium complexes. As shown previously, the

pentafluorophenyl and the 4-fluoro-3-nitrophenyl moiety hold

significant potential for subsequent nucleophilic substitutions on

the respective para-fluorine position.^[²⁷^a^,²⁸^]Hence, the p-fluorine

exchange with numerous nucleophiles, e.g. amines and thio-

carbohydrates, is applied to introduce specific functional

structures. Synthesis of cyclometalated iridium complexes is

performed via both the complexation of pre-functionalized

dipyrrins

and

the

post-functionalization

of

and 4-fluoro-3-nitrophenyl-substituted

dipyrrinato complexes. Crystals suitable for X-ray single crystal

structure determination were obtained for five complexes allowing

analysis of molecular structure and conformation in the solid state.

To preliminarily assess the suitability of the complexes for

phototherapy, the iridium complexes were evaluated for their

phototoxic effect with and without light in assays against several

cancer cell lines. The complexes were as well evaluated for their

antibacterial effect (again with and without light) against the

Scheme 1. Synthesis of meso-substituted dipyrrins via oxidation of

dipyrromethanes (dipyrromethanes were synthesized according to the

literature). ^[

28a,b,d,e, 33]

2

Chemistry - A European Journal

10.1002/chem.202004776

FULL PAPER

Previously, the oxidation of some pentafluorophenyl-

substituted dipyrromethanes (namely 1, 3, and 5 – 7) has been

described in the literature using 2,3-dichloro-5,6-dicyano-1,4-

benzoquinone (DDQ).^[²⁷^a^,³⁴^]Analogously, the dipyrromethanes 2

and 4 were oxidized with DDQ. Nevertheless, the observed yields

were quite low (18% and 40%, respectively, for details cf.

Supporting Information, S4.3.1 and S4.3.2). To achieve a higher

conversion into the desired dipyrrins, DDQ was replaced by p-

chloranil which gave better yields for the oxidation of 2 and 4 (73%

and 45%, respectively, for details on these reactions and the

following discussion cf. S.I., S4.1, S4.2, and S4.3). The

dipyrromethanes 1, 3, 5, and 7 were successfully oxidized with p-

chloranil to their corresponding dipyrrins as well, again resulting

_c_h_l_o_r_i_d_o₍_d_i_p_y_r_r_i_n_a_t_o₎₍_p_e_n_t_a_m_e_t_h_y_l_-_η5_-

cyclopentadienyl)iridium(III) complexes with dipyrrins 16 – 22.

Table

1.

Synthesis

of

Entry

Starting

Material

Substituent (R)

Product

Yield [%]

in higher yields for three of the compounds compared to the

literature.^[

27a]

The exception was the pentafluorophenyl-

1

16

17

31

32

91

36

substituted dipyrromethane 1, here, lower yields were observed

with p-chloranil compared to DDQ.^[³⁴^]

2^]

Similarly,

the

meso-(4-amino-3-nitrophenyl)-substituted

dipyrrins 24, 25, 27, 29, and 30 were prepared from the

corresponding dipyrromethanes by oxidation with p-chloranil as

already described in the literature.^[²⁸^d^]Based on this procedure,

the dipyrrins 26 and 28 were prepared with the same oxidation

reagent. Interestingly, a successful oxidation of the unsubstituted

dipyrromethane 8 to dipyrrin 23 with p-chloranil was not possible.

Here, in analogy to the conversion of 1 to 16, DDQ was required

for a successful oxidation to the desired product 23. With DDQ as

oxidizing agent, dipyrrin 23 was obtained in 81% yield. In an

additional set of experiments, DDQ was tested as well for the

oxidation of the other dipyrromethanes 9 – 15. While DDQ could

be used for this reaction it resulted in significantly lower yields

than p-chloranil (see S.I., S4.1, S4.2, and S4.3). Hence, we

recommend the use of p-chloranil for this type of dipyrromethanes.

In the next step, the dipyrrins 16 – 30 were converted to the

₃[a][b]

18

19

33

34

4

36

86

5

20

21

22

35

36

37

6^[^a^]

7^[^a^]^[^b^]

[

a] No product was observed. [b] Evidence for a dealkylation of the propargyl

group was found (see S.I., S5.4 and S5.8).

corresponding

chlorido(dipyrrinato)(pentamethyl-η⁵-

Using

the

same

method,

the

synthesis

of

cyclopentadienyl)iridium(III) complexes 31 – 45 (Table 1 and 2).

The synthesis of the dipyrrinato iridium complexes required a

base for the deprotonation of the dipyrrin and a suitable

dichlorido-bridged iridium(III) _p_r_e_c_u_r_s_o_r_._[21a,b,26a] Hence, the

pentafluorophenyl-substituted dipyrrin 16 and the pre-

functionalized dipyrrins (17 – 22) were reacted with N,N-

5

chlorido(dipyrrinato)(pentamethyl-η -cyclopentadienyl)iridium(III)

complexes, based on the related 3-nitrophenyl-substituted

dipyrrins 23 – 30, was performed. Again, the dipyrrins were

reacted

with

DIPEA

and

the

di-µ-chlorido-

to

5

bis[chlorido(pentamethyl-η -cyclopentadienyl)iridium(III)]

obtain the corresponding complexes 38 – 45. (Table 2). For the

dipyrrins 23, 24, and 27 – 30, the reactions led into the desired

complexes (38, 39, and 42 – 45) in moderate to good yields (Table

diisopropylethylamine

bis[chlorido(pentamethyl-η -cyclopentadienyl)iridium(III)]

obtain the desired complexes 31 – 37 (Table 1). Very high yields

were observed with 16 and with the pre-functionalized dipyrrin 20

(DIPEA)

and

the

di-µ-chlorido-

to

5

2

). With the dipyrrins 40 and 41 – functionalized with an allyl group

or a propargyl group – formation of the corresponding metal

complexes was not observed; instead inseparable mixtures of

multiple products were obtained. Here, no evidence for a

dealkylation of the allyl or the propargyl group could be found. In

order to generate the allyl or propargyl functionalized complexes

(

91% and 86%, respectively); dipyrrins 17 and 19 gave the

corresponding complexes in moderate yields (Table 1). The lack

of formation of compounds 33, 36, and 37 can be explained in

part by the reactivity of the respective dipyrrins 18, 21, and 22, i.e.

those carrying an allyl or a propargyl moiety. We found hints for a

cleavage of the propargyl group, e.g., in the case of dipyrrins 18

and 22, in NMR and mass spectra, and evidence for the formation

of the corresponding 4-amino-2,3,5,6-tetrafluorophenyl- and the

(

namely 33, 36, 37, 40, and 41) the synthetic procedure was

modified. The unfunctionalized complexes 31 and 38 were tested

for possible subsequent nucleophilic substitutions; complex 31

was reacted with amines and alcohols, e.g., propargylamine,

propargyl alcohol, or allyl alcohol (for details on these reactions

and the following discussion cf. the S.I., S6). Similar reactions

were performed with complex 38 except for the reaction with

alcohols, infeasible due to known side reactions of the alkoxide

with the nitro group.^[²⁸^d^]Absorption spectra of selected

4

-hydroxy-2,3,5,6-tetrafluorophenyl moieties (see S.I., S5.4 and

S5.8).

5

chlorido(dipyrrinato)(pentamethyl-η -cyclopentadienyl)iridium(III)

complexes are presented in the S.I. section S13.

3

Chemistry - A European Journal

10.1002/chem.202004776

FULL PAPER

_c_h_l_o_r_i_d_o₍_d_i_p_y_r_r_i_n_a_t_o₎₍_p_e_n_t_a_m_e_t_h_y_l_-_η5_-

cyclopentadienyl)iridium(III) complexes with dipyrrins 23 – 30.

1-,3-,7-, and 9-position. For this, the 5-pentafluorophenyl-1,3,7,9-

tetramethyldipyrrin 48 and the 5-(4-fluoro-3-nitrophenyl)-1,3,7,9-

tetramethyldipyrrin 49 were tested in the synthesis of

cyclometalated iridium complexes. The synthesis of dipyrrin 48

has previously been described in the literature.^[³⁸^]However, 48

was originally prepared in a one-pot multi-step synthesis from 2,4-

dimethylpyrrole and pentafluorobenzaldehyde. In this work we

opted for a stepwise synthesis of the corresponding 1,3,7,9-

tetramethyl dipyrrins 48 and 49. This would also enable future

nucleophilic substitutions already at the dipyrromethane stage

following on from the previous experiments (see above) which

have shown that the use of pre-substituted dipyrrins is more

Table

2.

Synthesis

of

Entry

Starting

Material

Substituent (R)

Product

Yield [%]

effective

in

the

synthesis

of

chlorido(dipyrrinato)(pentamethylcyclopentadienyl) complexes.

The 1,3,7,9-tetramethyl substituted dipyrromethanes 46 and 47

were prepared via trifluoroacetic acid-catalyzed condensation of

1

2

23

24

38

39

43

46

2

,4-dimethylpyrrole and the corresponding benzaldehyde

(

pentafluorobenzaldehyde or 4-fluoro-3-nitrobenzaldehyde). The

respective dipyrromethanes were obtained in almost quantitative

yields (Scheme 2). In the next step, the corresponding dipyrrins

₃_[a]

25

40

4

8 and 49 were formed via oxidation with DDQ and isolated in

6

3% and 90% yield, respectively (Scheme 2). Compared to the

4^[^a^]

26

27

41

42

[38]

literature,

the stepwise synthesis of dipyrrin 48 provided no

significant difference in the overall yield.

Finally, the target dipyrrinato iridium complexes 50 and 51 were

synthesized, employing the method described for the preparation

5

46

of

the

complexes i.e. deprotonation with DIPEA, followed by

complexation with the corresponding metal precursor. Complexes

6

7

28

29

43

44

29

5

0 and 51 could be obtained in 32% and 27% yield, respectively

(

Scheme 2). The low yields may be the result of partial

decomposition of the starting material, as evidenced by the

formation of a large amount of a black precipitate during the

reactions.

8

30

45

52

[a] No product was observed.

A post-functionalization of tris(pentafluorophenyl)dipyrrinato

complexes with amines and alcohols has been described in the

literature.^[

27a]

However, the trial reactions with 31 and 38 were

unsuccessful (see S.I., S6), probably due to ligand exchange

reactions. An exception was the substitution of 38 with n-

butylamine, where the desired complex 39 was isolated with 71%

yield. In the case of the post-functionalization of 31 with allyl

alcohol, the NMR spectrum again provided evidence for the

formation

of

the

corresponding

4-hydroxy-2,3,5,6-

tetrafluorophenyl moiety.

The complications in the syntheses described above occurred

mainly with complexes carrying double and triple bonds. The

observed cleavage of the allyl and propargyl group might be

caused by interactions of the iridium with these multiple bonds.

Such interaction of multiple bonds and metal complexes typically

occurs in metathesis reactions or alkene and alkyne

rearrangements, both reactions where iridium-based catalysts

have been employed.^[³⁵^,³⁶^]

Scheme 2. Synthesis of chlorido(pentamethylcyclopendadienyl)(1,3,6,9-

tetramethyldipyrrinato)iridium(III) complexes.

Another type of heteroleptic dipyrrinato iridium(III) complexes is

The introduction of additional functional groups to the pyrrole

units of the dipyrrin chelate is a further means to modulate the

represented

by

(dipyrrinato)bis(2-phenylpyridyl)iridium(III)

systems.^[

23a,29b,30]

bis(2,2’-

have been

(

photo)chemical characteristics of the resulting metal

bipyridyl)(dipyrrinato)ruthenium(II)

synthesized previously via the ligand exchange of corresponding

chlorido(p-cymene)(dipyrrinato)ruthenium(II) complexes with

complex.^[

27b,37]

Hence, we investigated the synthesis of

chlorido(dipyrrinato)(pentamethylcyclopentadienyl)iridium(III)

complexes with dipyrrins carrying additional methyl groups at the

4

Chemistry - A European Journal

10.1002/chem.202004776

FULL PAPER

2

,2’-bipyridine.^[²⁷^a^,²⁸^d^]Analogously, complexes 31 and 43 were

In the next step, the 3-nitrophenyl-substituted dipyrrins 23 – 30

were tested in the synthesis of the cyclometalated iridium

complexes (53, 60 – 66, Table 4). Reactions with the dipyrrins 23,

24 and 27 – 30 led to the desired complexes (53, 60, 61, and 64

– 66) in moderate to good yields (Table 4). Using 25 - the dipyrrin

carrying the allyl group - the desired complex 62 was obtained

only in low yields (Table 4). In the case of complex 63, formation

of the corresponding metal complexes was not observed instead

inseparable mixtures of compounds were obtained again.

tested in ligand exchange reactions with 2-phenylpyridine.

Complex 31 was dissolved together with 2-phenylpyridine in

ethanol and was reacted under reflux. Alternatively, the ligand

exchange of 43 was performed in a 1-methoxyethanol/water

mixture, to increase the reaction temperature. However, in both

cases the desired products (52 and 53) could not be obtained and

the starting materials were recovered (see S.I., S7.1 and S7.2).

Thus,

to

obtain

the

desired

(dipyrrinato)bis(2-

phenylpyridyl)iridium(III) complexes the synthetic procedure had

to be modified. The synthesis of the target systems was

performed via the complexation of dipyrrins with bis(µ-

chlorido)tetrakis(2-phenylpyridyl)diiridium(III).^[²³^a^,²⁹^b^,^c^,³⁰^]For this,

the dipyrrins (16 – 22) were reacted with DIPEA and bis(µ-

chlorido)tetrakis(2-phenylpyridyl)diiridium(III) in THF to obtain the

corresponding complexes (52, 54 – 59, Table 3). The highest yield,

Table 4. Synthesis of (dipyrrinato)bis(2-phenylpyridyl)iridium(III) complexes

with dipyrrins 23 – 30.

6

5%, was achieved with dipyrrin 16. The reactions with pre-

functionalized dipyrrins (17, 19 – 21) also gave the desired

complexes (52, 54, 56, and 57) in good yields (Table 3). Again,

for dipyrrins with the propargyl moieties (18 and 22) no product

was obtained. Also, the allyl-substituted complex 58 could only be

isolated in 8% yield (Table 3) via the complexation with dipyrrin

2

1. In the case of complex 55, the NMR spectrum provided

evidence for a dealkylation of the propargylamino group (see S.I.,

S8.4).

Entry

Starting

Material

Substituent (R)

Product

Yield

[%]

1

2

23

24

60

61

29

36

Table 3. Synthesis of (dipyrrinato)bis(2-phenylpyridyl)iridium(III) complexes

with dipyrrins 16 – 22.

3

25

62

11

4^[^a^]

26

27

63

64

5

44

6

7

28

29

53

65

49

26

Entry

Starting

Material

Substituent (R)

Product

Yield [%]

1

2

16

17

52

54

65

33

8

30

66

43

3^[^a^]^[^b^]

18

19

55

56

[

a] No product could be observed.

4

35

In

order

to

finally

generate

(dipyrrinato)bis(2-

phenylpyridyl)iridium(III) complexes functionalized with an allyl

group or a propargyl group, a post-functionalization approach was

investigated (Scheme 3 and 4). Amines and alcohols were tested

for the nucleophilic substitution of 52, e.g., allylamine,

propargylamine, allyl alcohol, and propargyl alcohol. First,

complex 52 was dissolved with the corresponding amine in DMSO

and stirred for 24 h at 80 °C. The desired complexes 56 and 67

could be obtained in 89% and 64% yield, respectively (Scheme

5

20

21

22

57

58

59

48

8

6

7^[^a^]

3

). Substitution of 52 with allyl alcohol and propargyl alcohol was

[

a] No product was observed. [b] Evidence for a dealkylation of the propargyl

possible as well: Compound 52 was reacted with the

corresponding alcohols and potassium hydroxide for the

group was found (see S.I., S8.4).

5

Chemistry - A European Journal

10.1002/chem.202004776

FULL PAPER

deprotonation of the alcohol to give the target systems 58 and 59

in high yields (84% and 87%, respectively, Scheme 3).

Finally, the unsubstituted iridium complexes 52 and 60 were

tested for the glycosylation with thio-carbohydrates. Glycosylation

is a straightforward method to improve solubility, biological activity

and bioavailability of therapeutically interesting molecules.^[³⁹^]Also

for iridium(III) complexes certain glycosylated derivates have

been reported.^[⁴⁰^]Different concepts for the introduction of

carbohydrates have been described in the literature. On one hand,

linker groups are often used for coupling carbohydrates with

therapeutically interesting molecules, e.g., BODIPY-carbohydrate

conjugates, glycopeptides, or multivalent glycoconjugates.^[

Alternatively, a fast and effective method for direct glycosylation

41]

N

of porphyrins, corroles, and metal complexes employs an S Ar

strategy.^[³¹^,⁴²^]Notably, this type of glycosylation is feasible with

unprotected thio-carbohydrates, as shown for porphyrinoids,

metal complexes, and BODIPYs.^[

27a,28e,42a,43]

In analogy to earlier studies,^[¹⁴^a^,²⁸^e^,⁴²^a^,⁴³^]the glycosylation was

tested directly with unprotected thio-carbohydrates and the

complexes 52 and 60. The respective complex was dissolved in

DMF together with the corresponding sodium 1’-thio-β-D-

carbohydrate (glucose or galactose). Starting with 52, within a

short reaction time the corresponding glycosylated complexes (68

and 69) were formed (Scheme 5). The glucosyl conjugate 68 was

obtained in almost quantitative and the galactosyl conjugate 69 in

9

2% yield. Analogous reactions of complex 60 gave the

corresponding glycosylated conjugates 70 and 71 in very high

yields of 92% and 90%, respectively (Scheme 5).

Scheme 3. Nucleophilic substitutions of complex 52 with amines und alcohols.

Next, complex 60 was functionalized with allylamine and

propargylamine. This entailed dissolving complex 60 with the

corresponding amine in DCM and gave 62 and 63 in high yields

(

Scheme 4). The results clearly show that the synthesis of the

complexes carrying propargyl groups and allyl groups which was

not possible using pre-functionalized ligands or complexes is

easily viable via a post-functionalization of the unsubstituted

complexes 62 and 63. In this case, the metal center is shielded

by the ligand and possible interactions with the propargyl group

and allyl group are suppressed. This post-functionalization of the

metal complex is thus an effective strategy circumventing the

reactivity associated with ligand exchange. Absorption spectra of

selected (dipyrrinato)bis(2-phenylpyridyl)iridium(III) complexes

are presented in the S.I. section S13.

Scheme 5. Glycosylation of 52 and 60.

Conjugates of iridium(III) complexes and BODIPYs with

promising photochemical properties have already been described

in the literature; in this context, iridium(III)-BODIPY conjugates

exhibited potential for an application as photosensitizers.^[⁴⁴^]

Scheme 4. Nucleophilic substitution of complex 60 with amines.

6

Chemistry - A European Journal

10.1002/chem.202004776

FULL PAPER

However, thus far, (dipyrrinato)iridium(III)-BODIPY conjugates

The dipyrrin ligand is coordinated in an off-axis manner, as

demonstrated in Fig. 2b, such that the metal center is deviated

are unknown. Here,

a

coupling of

a BODIPY with a

(

dipyrrinato)iridium(III) complex was performed via the copper-

3

from the mean plane of the N-C -N chelate by 0.600(4) Å.

catalyzed

1,3-diploar

cycloaddition.

Alkynyl-substituted

Discounting the 5-aryl substituent, the ligand-metal 10-atom unit

has an approximate mirror plane which relates the two pyrrole

subunits, with bond distances indicative of charge delocalization

nearly evenly across these two pyrroles. The torsion angles

compounds are suitable building blocks in this reaction, e.g., for

coupling porphyrins or BODIPYs to other compounds or

surfaces.^[

28a,32c,45]

Therefore, after finally having alkynyl-

substituted iridium(III) complexes at hand, the 4-propargyloxy-

substituted complex 59 was tested in the copper-catalyzed

cycloaddition. The 4-azido substituted BODIPY 72 and the

α

around the C -Cmeso bonds linking these pyrrole units (i.e. N1-C4-

C5-C6 and C4-C5-C6-N2) are -0.8(6)° and 6.5(6)°, indicating a

small rotational perturbation of the individual pyrrole units towards

complex 59 were dissolved in DMF and reacted with CuSO

4

and

6 5

coplanarity with the Ir center. The C F ring at the sole meso-

sodium ascorbate and gave the desired (dipyrrinato)iridium(III)-

BODIPY conjugate 73 in 21% yield (Scheme 6).

position is inclined at 74.13(10)° to the mean plane of the ligand

– this angle has been shown to be important in fine-tuning of the

related BODIPY photochemistry.^[²⁸^e^,⁴⁸^]

Scheme 6. Synthesis of the (dipyrrinato)iridium(III)-BODIPY conjugate 73.

Crystal/Molecular structures

complexes

of dipyrrinato iridium

Diffraction data for the crystal structure determinations of

representative compounds of each of the classes of iridium(III)

complexes were collected and refined. Two examples of the Cp*-

ligand complexes are demonstrated, compounds 31 and 51, as

well as three examples of the bis(2-phenylpyridinyl) complexes 54,

Figure 2. a) View of the structure of the asymmetric unit of compound 31 in the

crystal. H atoms are represented as spheres of fixed radius, thermal ellipsoids

for non-H atoms are presented at 50% probability. b) A side-on view of

compound 31, showing the off-axis coordination mode.

6

0and 66.

Compound 31 crystallized in a triclinic cell setting, and the

The crystal structure of the related compound 51 is shown in

Fig. 3 and S1.2.2 and shows an iridium(III) metal center in a

similar piano-stool half-sandwich coordination environment as

that for 31. Four methyl groups present on the dipyrrin moiety can

be implicated in an increased distortional profile – the planar

solution to the diffraction pattern in P-1 is shown in Fig. 2 and

S1.2.1. In this complex, a lone iridium(III) metal center is

coordinated by a 5-pentafluorophenyl-2,2’-dipyrrinato (N^N)-

chelate, by the η⁵Cp* ligand and a single chloride. The

coordination environment is the expected piano-stool

geometry,^[and approximates the Cl and N,N occupying three

adjacent corners of an octahedron with interior angles of

deviation (NC

and torsion angles (C

3

N⋯Ir, 0.935(5) Å), Ir⋯Cp* distance (1.840(2) Å)

-Cmeso, 2.6(5)° and 9.7(7)°) are exaggerated

46]

α

from the unsubstituted dipyrrin parent, with the N⋯N distance of

the dipyrrinato chelate reduced to 2.767(5) Å, and the N-Ir

distances shortened to 2.065(4) and 2.081(4) Å. The angle of the

dipyrrinato mean plane to the meso-appended aryl unit is

approximately equal to that in 31, at 74.47(13)°. The increased

steric bulk of the tetramethyl groups is sufficient to explain the

distortion patterns – a pincer-like convergence of the two pyrrole

units around the C ‘pivot’ upon increased steric bulk has a direct

m

effect on the coordination environment provided by the ligand.

This concerted movement of the pyrrole units towards each other

8

7.14(8)°, 87.96(8)° and 85.35(12)°; the Cp* occupies the center

of the opposing face.

The measured Ir-Cp* 5-atom centroid distance, at 1.7942(15)

Å, is typical of iridium(III) compounds with the Cp-Cl-N²

[47]

5

coordination environment (1.789(17) Å, n = 252). The C ring

atoms within the Cp* ligand have a pattern of alternating longer

and shorter bonds, indicating that the anionic charge is partially

localized to the three carbon atoms sharing the dipyrrinato-Ir

coordination plane (C17 – C19).

7

Chemistry - A European Journal

10.1002/chem.202004776

FULL PAPER

similarly engenders increased non-planar distortion of the dipyrrin

attempting to satisfy the idealized coordination environment of the

metal center.

approximately coplanar with the iridium(III) metal center in 54, 60

and 66, as distinct from the off-axis coordination mode observed

for the piano-stool compounds 31 and 51.

Compound 60 is shown in Fig. 4b and S1.2.4; the

phenylpyridine ligands and metal center exhibit the expected

geometry, however, a small deviation from the idealized C2v

symmetry can be observed for the dipyrrin fragment indicative of

contribution of partial charge localization. The aryl unit at the 5-

position of the dipyrrin is inclined at 69.0°, in line with

unsubstituted 5-aryl-dipyrromethene chelates (median 62.8°, IQR

5

5-71°, n = 430).

Figure 3. A view of the main molecular fragment within the crystal structure of

compound 51; thermal ellipsoids are presented at the 50% probability level. H

atoms have been omitted for clarity.

Three previously structurally characterized examples of

III

Ir (Cl)(Cp*) dipyrrin complexes have been reported; with a

mononuclear dipyrrin,^[⁴⁹^]a dinuclear bis-bidentate dipyrrin and

a macrocylic tetrakis(perfluorophenyl)rubyrin derivative.^[Each

of these structures indicated a significant non-planarity of the

iridium(III) to the dipyrrin subunit, localized piano-stool Cp* ligand

atom positions and delocalization of the dipyrrin ligand electron

density, in line with the two structures reported here. As has been

previously reported, the coordination geometry of the iridium(III)

center is particularly important for anticancer activity – presence

of an exocyclic linkage of the Cp* ligand led to increased

[50]

51]

[52]

anticancer activity. This ‘tethering’ approach inhibits hydrolysis

and induces a strained coordination environment; steric conflict

between α-methyl groups and the Cp* ligand strains this

coordination environment in a similar manner, and is a useful tool

for microstructure manipulation. We can reasonably extrapolate

that each of the compounds reported herein for which a crystal

structure has not been reported should adopt a similar geometry,

given the limited electronic or steric influence of alteration of the

terminal aryl C-F unit in each of the examples, and consistency

between examples. Preliminary investigation of a crystal of

compound 35 from toluene (oP, a 13.947(6) b 22.654(9) c

Figure 4. The main molecular units of complexes [Ir(ppy)

2,3,5,6-F -4-NHBu-Ph; (b) 60, 4-F-3-NO -Ph (c) 66,

NHPentCO Me-3-NO -Ph. C-bound H atoms have been omitted, and thermal

2

(R-dipyrrin)] (a) 54, R

1

6.534(6)) has indicated a similar coordination environment is

=

4

R

=

2

R =

4-

present in this example, however, data were not satisfactory for

publication.

2

ellipsoids are shown at the 50% probability level.

Three crystal structure models, 54, 60·½(DCM) and 66·½(Tol),

2

could be identified containing the second PDT motif, that of bis(κ -

III

2

-phenylpyridinyl)Ir with a substituted 5-phenyldipyrrin. Each of

The presence of long-chain alkyl groups at the aryl 4-position

in compounds 54 and 66 introduces these additional chemical

motifs with retention of the metal chelate structure, as shown in

Fig. 4(a,c), S1.2.3 and 1.2.5. The terminal alkyl chain at the aryl

4-position in 54 has higher thermal displacement as atoms

process further from the aryl ring. The 4-alkylamino-substituted

compound 66 exhibits an intramolecular hydrogen bond between

the amine and ortho-nitro unit on the 5-aryl substituent, at

2.642(3) Å N⋯O and 129(3)° N-H⋯O, consistent with 2-

nitroanilines generally.^[⁵⁴^]This H-bond, expected to be present in

each compound with the o-NH moiety is presumably responsible

for the decreased thermal displacement associated with rotational

averaging of the nitro unit in 60. Previously characterized

2

these structures shows the iridium(III) metal center in an

octahedral C coordination environment, with the C atoms of

2

N

4

the coordination environment occupying the octahedral sites trans

to the dipyrrin. These tris-chelate compounds exhibit the expected

Δ and Λ stereoisomerism, however, each was modelled as a

racemate in an achiral space-group; these crystals demonstrate

equal appearance of the two enantiomeric forms, in contrast to

the achiral piano-stool complexes. The exclusive formation of the

trans-pyridyl isomer is as expected for iridium compounds with the

(

2

C^N) (N^N) coordination geometry, and unaltered from the

[

53]

presumptive geometry of the starting material; the metal center

geometry and bond distances are approximately equal between

each of the three examples. The dipyrromethene ligand is

examples of Ir(ppy) (5-aryl-dipyrrin) complexes include aryl =

8

Chemistry - A European Journal

10.1002/chem.202004776

FULL PAPER

phenyl,^[⁵⁵^]4-pyridyl (and derivatives thereof),^[⁵⁶^]4-benzoic acid

In the cellular assays, cells were incubated with cell medium

containig 10% fetal calf serum (FCS) and with 2 or 10 µM of

the corresponding iridium complex for 24 h before irridiation.

After exchange of the medium to remove any complex not

taken up by the cells, a white light source at a dose rate of

(

and

derivatives

thereof),^[⁵⁷^]

4-(3,5-lutidinyl),

and 4-(dimesitylborophenyl).

4-(N,N-

Each

[55]

[55,58]

diphenylamino)phenyl

exhibited a similar coordination mode and metal-ligand distances

as the structures presented above, unperturbed by peripheral

modification of the aryl unit..

2

approximately 50 J/cm was used for irradiation. Afterwards, cells

were incubated in a humidified incubator (5 % CO

°C) for 24 h until cell viability assay.

2

in air at 37

Evaluation in assays against bacteria and cells

The

biological

activity

of

the

iridium(III)

As can be seen in Fig. 5 (see also S.I., S3.3) the

chlorido(dipyrrinato)(pentamethylcyclopentadienyl)iridium(III)

complexes (31, 32, 34, 35, 38, 39, 42 – 45, 50, and 51) in general

showed no or only a low toxic effect without illumination,

except for 31 and 39 in two cell lines (A431, for A253 see S.I,

S3.3). Under irradation with light, however, several complexes

with a signifcant phototoxicity could be identified. Especially,

complexes substituted with a butylamino, a butyloxy, or the

dibutylamino group (32, 35, 39, and 43) exhibited a high

phototoxic effect. Also, the unfunctionalized complex 31

exhibited a high phototoxic effect on the cells, but also dark

toxicity in the highest concentration. In the case of the 2,3,5,6-

tetrafluorophenyl-based complexes 32 and 35, already at a

concentration of 2 µM a significant decrase of the cell viability

was observed.

chlorido(dipyrrinato)(pentamethylcyclopentadienyl)

complexes (31, 32, 34, 35, 38, 39, 42 – 45, 50, and 51) and the

dipyrrinato)bis(2-phenylpyridyl) iridium(III) complexes (52 – 71)

(

was evaluated with and without illumination in cellular assays in

four cancer cell lines. In the cellular assays the following cell lines

were used: human colorectal adenocarcinoma (HT29), human

epidermoid carcinoma (A431), submaxillary salivary gland

epidermoid carcinoma (A253), human epithelial tongue

squamous cell carcinoma (CAL27). Results for the A431 and

HT29 cell lines can be seen in Fig. 5 – 7 (for CAL27 and A253,

see S.I., S3.3, and S3.4). As well, the antimicrobial properties of

the synthesized complexes with and without light were studied

against the Gram-positive germ S. aureus and the Gram-negative

germ P. aeruginosa (Fig. 8 – 10, and S.I., S3.5, S3.6).

Figure 5. Dark and phototoxicity of chlorido(dipyrrinato)(pentamethylcyclopentadienyl)iridium(III) complexes in cellular assays with the A431 cell line (a) and the

cell line HT29 (b). Blue colored structures 50 and 51 represent the two (pentamethylcyclopentadienyl)(1,3,7,9-tetramethyl-dipyrrinato)iridium(III) complexes.*

indicates significant values with p < 0.005.

9

Chemistry - A European Journal

10.1002/chem.202004776

FULL PAPER

In comparison, the 3-nitrophenyl-substituted dipyrrinato

complexes 39 and 43 showed a lower phototoxic activity.

However, complex 43 still showed a phototoxic effect against

all cell lines at the highest concentration; while complex 39

only exhibits phototoxicity against the cell line A253 at the

highest concentration. Moreover, complex 39 showed

significant dark toxicity at 10 µM against the cell line A253 (see

S.I., S3.3).

for A253 see S3.3). Whereas the corresponding 1,3,7,9-

tetramethyl-5-(4-fluoro-3-nitrophenyl)-substituted complex 51

(substituent in blue color in Fig. 5 and S3.3) exhibited no

significant phototoxicity. There is

tetrafluorophenyl-substituted complexes to have

a

tendency for the

higher

a

phototoxic activity than the corresponding 3-nitrophenyl-

substituted compounds. This has also been observed for boron-

dipyrromethene complexes with these substitutions.^[²⁸^e^]In

Interestingly, the complexes 32, 42, and 44, functionalized

with polar groups, generally showed only a limited phototoxic

activity. Only complex 42 showed a higher phototoxic effect on

specific cell lines (A431, for CAL27 see S3.3) at the highest

concentration (10 µM). As well, complex 45 exhibited a limited

phototoxicity againt certain cell lines (A431, for A253 and

CAL27 see S3.3). This lower phototoxicity of the complexes

with polar substituents is a little bit counter-intuitive as often

polar substitution, like OH groups, increases the PDT effect,

as it increases the solubility in the cellular surrounding.^[³¹^,⁵⁹^]

other

cases,

(pentamethylcyclopentadienyl)iridium(III)

complexes have also shown a high potential as anticancer

agents.^[

(pentamethylcyclopentadienyl)iridium(III) complexes showed

a significant phototoxic activity against cell lines.^[¹⁸^e^,⁶¹^]

8b,60]

However, only a limited number of these

Next,

the

(dipyrrinato)bis(2-phenylpyridyl)iridium(III)

complexes (52 – 71) were as well tested against the cell lines

(Fig. 6, 7, and S3.4). Again, the complexes tested showed no

significant dark toxicity, except for the glycosylated conjugates

68

– 71 in the high concentration of 10 µM. The

The

1,3,7,9-tetramethyl-5-pentafluorophenyl-substituted

(dipyrrinato)bis(2-phenylpyridyl)iridium(III) compounds with

complex 50 (substituent in blue color in Fig. 5, and S3.3)

exhibited a high phototoxic activity against all cell lines at the

concentration of 10 µM. Moreover, complex 50 exhibited a

high phototoxicity already at 2 µM for specific cell lines (A431,

polar substituents (56, 64, and 65), specifically the

glycosylated conjugates 68

– 71 exhibited a very high

phototoxicity even at a concentration of 2 µM.

Figure 6. Dark and phototoxicity against the A431 cell line in cellular assay with bis(2-phenypyridyl)(tetrafluorophenyl-dipyrrinato)iridium(III) complexes (a) and (3-

nitrophenyl-dipyrrinato)bis(2-phenypyridyl)iridium(III) complexes (b).* indicates significant values with p < 0.005.

1

0

Chemistry - A European Journal

10.1002/chem.202004776

FULL PAPER

Figure 7. Dark and phototoxicity against the HT29 cell line in cellular assay with bis(2-phenypyridyl)(tetrafluorophenyl-dipyrrinato)iridium(III) complexes (a) and (3-

nitrophenyl-dipyrrinato)bis(2-phenypyridyl)iridium(III) complexes (b).* indicates significant values with p < 0.005.

A high phototoxic activity against cells has also been

environments. In addition, protein-rich environments can

significantly influence the effectiveness of photosensitizers.^[

Therefore, to establish a more realistic model of the environment

additional bacterial tests were performed in PBS supported with

horse serum (10%). The bacterial assays included different

conditions (blank: no complex and without illumination;

identification of dark toxicity with 100 µM of the complex; and

using different concentrations of 1, 10, and 100 μM, with and

without addition of serum). To study the phototoxic activity against

the bacteria, the corresponding complexes were incubated with

cultures of S. aureus and P. aeruginosa (in the three different

concentrations) for 30 min in PBS and in PBS supported with

serum. Afterwards, the samples were exposed to white light with

a power density and irradiation time resulting in an energy

fluence of about 100 J/cm². The control experiment with both

bacterial strains treated only with this light dose can be found in

the S.I. (S3.7). For the bacterial assays, an incubation time of 30

min was chosen. This short incubation time – compared to the

incubation time for the investigations of the phototoxicity against

the tumor cells (24 h) – was selected with respect to the specific

recommendations of antibacterial therapy: Typically, bacterial

reproduction is more rapid than that of cells, therefore, activity is

66]

reported for some other types of (2-phenylpyridyl)iridium(III)

complexes.^[

18d,62]

No significant phototoxic activity was

observed for the unfunctionalized complex 52 and the 3-

nitrophenyl-substituted complexes 61, 53, and 66, the other

complexes exhibited a limited phototoxicity in some cell lines.

Again, there is a tendency for the tetrafluorophenyl-substituted

complexes to have

a higher phototoxic activity than the

corresponding 3-nitrophenyl-substituted compounds.

In order to evaluate the antimicrobial activity of the synthesized

heteroleptic (dipyrrinato)iridium(III) complexes, bacterial assays

against S. aureus and P. aeruginosa were performed with and

without irradiation. The Gram-positive germ S. aureus is an

important target as it is a typical member of the microflora of

chronically infected wounds with a high tendency to develop

antibiotic resistance.^[⁶³^]Wound healing and treatment are

prospective fields where aPDI has already shown potential.^[⁶⁴^]

The Gram-negative germ P. aeruginosa also has a high tendency

to develop antibiotic resistance and is a major threat in

nosocomial infections.^[⁶⁵^]A critical aspect of the use of new

antimicrobials in the clinical practice is that the drug candidates

must be active in the presence of body fluids in complex biological

1

Chemistry - A European Journal

10.1002/chem.202004776

FULL PAPER

needed after shorter residence times.^[⁶⁷^]The antimicrobial activity

of the (dipyrrinato)iridium(III) complexes is presented in Fig. 8 –

culture plates. Most likely, a light-independent antibacterial effect

contributes to this as all compounds, except 50 and 51, with the

1,3,7,9-tetramethyl-dipyrrinato ligand, exhibited strong dark

toxicity in the control experiment with incubation of 100 μM of the

complex. Such an antibacterial activity without irradiation, i.e. an

antibiotic effect, has also been observed for other selected

iridium(III) complexes.^[The complexes tested (31, 32, 34, 35,

1

0 (see also S.I., S3.5, and S3.6) and the bacterial inactivation is

given as the logarithm of the number of colony-forming units, lg

-1

(

CFU mL ). In this context it should be taken into account that

only a reduction of bacterial growth of at least 99.9% (≥ 3 log

stages) is considered relevant with respect to bactericidal activity

and a reduction by 4 and 5 log stages, respectively, is usually

required for disinfectants in standard testing.^[⁶⁷^c^-^f^]Results for the

68]

38, 39, and 42

– 45), whether based on the 2,3,4,5-

tetrafluorophenyl or the 3-nitrophenyl moiety, gave complete

inactivation of S. aureus already at a concentration of 1 μM under

light. Compounds 50 and 51 which showed no dark toxicity had

nevertheless a strong phototoxic effect. A complete inactivation of

bacteria was observed with 50 already at a concentration of 1 μM

under light, while the corresponding complex 51 showed a

complete photoinactivation of bacteria at a concentration of 10 μM.

series

of

chlorido(dipyrrinato)(pentamethylcyclopentadienyl)iridium(III)

against S. aureus are presented in Fig. 8. Almost all tested

complexes suppressed bacterial growth below the detection limit

at all three concentrations, i.e. the number of bacteria becoming

so low that no colonies were detected after incubation on the

Figure 8. Photoinactivation of S. aureus by chlorido(dipyrrinato)(pentamethylcyclopentadienyl)iridium(III) complexes (30 min incubation and irradiation with white

light) in phosphate-buffered saline (PBS) (a) and in PBS + 10% serum (b). The antibacterial toxicity is expressed as logarithm of the number of colony-forming units,

-

1

lg (CFU mL ). Arrows indicate

a suppression of bacterial growth below the detection limit. Blue colored structures 50 and 51 represent the two

(pentamethylcyclopentadienyl(1,3,7,9-tetramethyl-dipyrrinato)iridium(III) complexes.

1

2

Chemistry - A European Journal

10.1002/chem.202004776

FULL PAPER

Next, these highly effective complexes were challenged in

antibacterial tests in the presence of 10% serum (Fig. 8b). Not

unexpectedly, the effectiveness of the tested complexes

decreased in the presence of serum. Nevertheless, in the

presence of serum some complexes still exhibited strong dark and

phototoxic effects against S. aureus. Complexes 31, 32, 35, and

inactivation of the bacteria at the highest concentration (100 µM)

under irradiation. In the case of the tetramethyldipyrrinato

complexes 50 and 51, only 50 still exhibited its phototoxic activity.

Here, an effective inactivation of the bacteria was observed at 10

µM. This combined cytotoxic and phototoxic activity against

bacteria has also been reported in some other cases for

iridium(III) complexes.^[

18c,19]

Again, there is a tendency for the

higher

4

3

3 showed no change in their dark toxicity. For complexes 32 and

5 no differences in their activity against S. aureus were found in

tetrafluorophenyl-substituted complexes to have

a

the presence of serum and in PBS alone, in both cases a

complete inactivation even at the lowest concentration (1 µM) is

observed. Notably, compounds 31 and 45 exhibited a phototoxic

activity at the medium concentration (10 µM). As well, the 3-

nitrophenyl-substituted complexes 39 and 43 showed a complete

phototoxic activity than the corresponding 3-nitrophenyl-

substituted compounds in the presence of serum, as it was also

observed in the cellular assays. Fig. 9 shows the results of the

chlorido(dipyrrinato)(pentamethylcyclopentadienyl)iridium(III)

complexes against the Gram-negative Germ P. aeruginosa.

Figure 9. Photoinactivation of P. aeruginosa by chlorido(dipyrrinato)(pentamethylcyclopentadienyl)iridium(III) complexes (30 min incubation and irradiation with

white light) in phosphate-buffered saline (PBS) (a) and in PBS + 10% serum (b). The antibacterial toxicity is expressed as logarithm of the number of colony-forming

-

1

units, lg (CFU mL ). Arrows indicate a suppression of bacterial growth below the detection limit. Blue colored structures 50 and 51 represent the two

pentamethylcyclopentadienyl) (1,3,7,9-tetramethyl-dipyrrinato)iridium(III) complexes.

(

1

3

Chemistry - A European Journal

10.1002/chem.202004776

FULL PAPER

Compared to the results with S. aureus, the phototoxicity is

significantly lower against P. aeruginosa. However, a reduction of

bacterial growth of about 1.5 to 2 log stages was already achieved

without light (100 µM) with the complexes 31, 32, 35, 39, 42, and

The tests with the (dipyrrinato)bis(2-phenylpyridyl)iridium(III)

complexes on S. aureus were then repeated in the presence of

serum. In most cases the antibacterial activity greatly decreased

or vanished completely. In the case of the complexes with ligands

carrying polar substituents polar-substituted complexes (56, 64,

and 65) and complexes with glycosylated ligands (70 and 71), a

reduction of bacterial growth of about one log stage was observed.

Only the glycosylated 2,3,5,6-tetrafluorophenyl-substituted

complexes, 68 and 69, gave a significant reduction of the bacterial

growth, with 69 being the most effective compound able to

suppress bacterial growth below the detection limit.

4

5. Such an antibacterial activity without irradiation has as well

been observed for some other iridium(III) complexes.^[⁹^b^,⁶⁹^]Here,

however, a phototoxic reduction of bacterial growth below the

detection limit was achieved with several complexes. A complete

inactivation of P. aeruginosa was observed with the complexes

3

1, 35, 38, 39, and 45 already at a concentration of 10 µM under

irradiation with light. In addition, the complexes 32, 42, and 44

showed a complete photoinactivation of P. aeruginosa at the

highest concentration (100 µM). The 1,3,7,9-tetramethyl-

dipyrrinato complexes 50 and 51 exhibited no dark or

phototoxicity against P. aeruginosa. The lower antibacterial

activity of the complexes against P. aeruginosa is not unexpected

because Gram-negative germs are generally more difficult to be

inactivated than Gram-positive ones. This is i.a. due to the

pronounced differences in their cell wall composition.^[⁶⁶^b^,⁷⁰^]In fact,

Tests

of

the

(dipyrrinato)bis(2-phenylpyridyl)iridium(III)

complexes against P. aeruginosa revealed no significant

phototoxicity or dark toxicity (see S.I., S3.6).

Conclusion

In this work synthetic strategies to (dipyrrinato)iridium(III)

complexes carrying a multitude of functional groups were

presented. Their potential for antitumor and antibacterial

phototherapy has been preliminarily assessed in assays with four

tumor cell lines, and two bacterial strains known to pose one

major problem in nosocomial infections, the Gram-positive germ

S. aureus and the Gram-negative germ P. aeruginosa. Starting

it

is

somewhat

remarkable

that

some

of

the

(

dipyrrinato)(pentamethylcyclopentadienyl) complexes show

such a pronounced activity against P. aeruginosa in PBS though

they are not cationic, which is a typical feature found in

photosensitizers active against Gram-negative bacteria.^[⁷⁰^,⁷¹^]

However, this also gives cationic photosensitizers a higher affinity

towards DNA rendering some of them potentially mutagenic.^[⁷²^]

Hence, compounds active against Gram-negative bacteria

lacking cationic charges are desirable. Similar to the investigation

with S. aureus the (dipyrrinato)(pentamethylcyclopentadienyl)

complexes were finally challenged in their antibacterial activity

against P. aeruginosa by performing the test in the presence of

serum (Fig. 9b). In many cases this antibacterial activity greatly

decreased or vanished completely in the presence of serum.

However, some complexes still exhibited a phototoxic effect on P.

aeruginosa in the presence of serum. Complex 42 still showed a

phototoxic effect with a reduction of about 2 log stages with light.

While 31, 35, and 44 reduced the bacterial growth by about 1 log

stage. Nevertheless, the observed antibacterial activities of the

point

for

the

stepwise

synthesis

of

the

5

chlorido(dipyrrinato)(pentamethyl-η -cyclopentadienyl)iridium(III)

complexes and the (dipyrrinato)bis(2-phenylpyridyl)iridium(III)

complexes were meso-substituted dipyrrins, based on the

pentafluorophenyl and the 4-fluoro-3-nitrophenyl moiety. As

shown previously, the pentafluorophenyl and the 4-fluoro-3-

nitrophenyl group can easily be modified by subsequent

nucleophilic substitutions on their respective para-fluorine

positions. Hence, the p-fluorine exchange with amines, alcohols

and thio-carbohydrates was used to introduce specific functional

structures. In addition to the synthesis of the cyclometalated

iridium complexes via the complexation of pre-functionalized

dipyrrins,

the

post-functionalization

of

the

dipyrrinato)(pentamethylcyclopentadienyl) complexes against S.

pentafluorophenyl-

and 4-fluoro-3-nitrophenyl-substituted

aureus and P. aeruginosa with and without illumination suggest

that these compounds are valuable targets for more detailed

QSAR studies on their (photo)antibiotic properties.

dipyrrinato complexes was performed as well. This post-

functionalization route proved to be especially suitable for

introducing alkenyl and alkynyl as well as glyco-substituents,

which are not accessible using the pre-functionalized dipyrrins.

For several complexes, crystals suitable for X-ray crystal structure

determination were obtained allowing to unequivocally determine

their structure. These studies indicated that the molecular

geometry of the dipyrrin ligand and immediate metal coordination

environment was consistent between the phenylpyridine

examples irrespective of the modification of the dipyrrin aryl unit.

Flexion of the dipyrrin unit was observed when paired with the Cp*

ligand complex, to accommodate the sterics of this ligand,

increasing with additional steric bulk on the dipyrrin moiety.

In the preliminary assessment of their suitability for tumor

The (dipyrrinato)bis(2-phenylpyridyl)iridium(III) complexes

were also tested against S. aureus and P. aeruginosa (Fig. 10 and

S3.5). The glycosylated conjugates 68 – 71 and the polar

substituted complexes 56, 64, and 65 showed a very effective

inactivation of S. aureus in PBS with a suppression of bacterial

growth below the detection limit already at a concentration of 1

μM under light.

However, the tetrafluorophenyl-based complexes 56, 68, and 69

did exhibit a strong dark toxicity with a complete inactivation of

bacteria already at a concentration of 100 μM.

The complexes 57, 60, and 66 exhibited a phototoxic activity, with

complete inactivation of S. aureus at the highest concentration

(

photo)therapy in assays against four cancer cell lines the non-

functionalized

(

100 µM) under light irradiation. The other 2,3,5,6-

chlorido(dipyrrinato)(pentamethylcyclopentadienyl)iridium(III) and

the respective complexes carrying simple alkyl chains proved to

be most effective.

tertrafluorophenyl-based complexes (52, 55, 58, and 59) provided

an inactivation of S. aureus of at least 2 log stages at the highest

concentration. While the other 3-nitrophenyl-based complexes

(

53, and 61 – 63) showed no significant effect on S. aureus.

1

4

Chemistry - A European Journal

10.1002/chem.202004776

FULL PAPER

Figure 10. Photoinactivation of S. aureus (30 min incubation and irradiation with white light) by bis(2-phenylpyridyl)(tetrafluorophenyldipyrrinato)iridium(III)

complexes in phosphate-buffered saline (PBS) (a), (3-nitrophenyldipyrrinato)bis(2-phenylpyridyl)iridium(III) complexes in PBS (b), and glycosylated

(

dipyrrinato)bis(2-phenylpyridyl)iridium(III) complexes in PBS + 10% serum (c). The antibacterial toxicity is expressed as logarithm of the number of colony-forming

-

1

units, lg (CFU mL ). Arrows indicate a suppression of bacterial growth below the detection limit.

1

5

Chemistry - A European Journal

10.1002/chem.202004776

FULL PAPER

In the tests with the (dipyrrinato)(2-phenylpyridyl)iridium(III)

complexes the compounds having alkenyl, alkynyl, and polar

the signals was assigned as follows: s = singlet, br s = broad

singlet, d = doublet, t = triplet, dd = doublet of doublets, dt =

doublet of triplets, td = triplet of doublets, ddd = doublet of

doublets of doublets, ddt = doublet of doublets of triplets, m =

(

hydroxyl) substituents showed the strongest reduction of tumor

cell viability, with the glyco-substituted complexes being most

effective. In the evaluation of their antibacterial effect with and

without light against the Gram-positive germ S. aureus the

chlorido(dipyrrinato)(pentamethylcyclopentadienyl)iridium(III)

complexes exhibited an exceptionally high toxicity with but also

without illumination, regardless of the substitution.

On repetition of the test in the presence of serum strong dark

and phototoxic effects were found for some compounds, namely

the non-substituted and the simple alkyl-substituted ones. When

testing the (dipyrrinato)(2-phenylpyridyl)iridium(III) complexes

against S. aureus a high antibacterial activity was observed with

the polar (hydroxyl) substituted compounds, specifically the glyco-

modified complexes. Of these, the galactosyl-substituted complex

c

multiplet, m = centered multiplet. Chemical shifts are reported

1

13

relative to CDCl

3

( H: δ = 7.26 ppm, C: δ = 77.2 ppm), CD

2

Cl

2

( H: δ = 5.32 ppm, ¹³C: δ = 53.8 ppm), THF-d

¹³C: δ = 67.6 ppm), DMSO-d (¹H: δ = 2.50 ppm, ¹³C: δ = 39.5

1

( H: δ = 3.58 ppm,

1

8

6

ppm). All ¹³C NMR spectra are proton-decoupled and coupling

constants are given in hertz (Hz). 2D spectra were measured for

detailed peak assignments (COSY, HMBC, and HMQC). HRMS

analyses were carried out on an Agilent Technologies 6210 ESI-

TOF (electrospray ionization, time of flight) instrument. IR spectra

were measured with a JASCO FT/IR 4100 spectrometer equipped

TM

with a PIKE MIRacle ATR instrument. UV/Vis spectra were

recorded on a SPECORD S300 UV/Vis spectrometer (Analytic

Jena) in quartz cuvettes (1 cm length). Absorption spectra of

selected heteroleptic (dipyrrinato)iridium(III) are given in the S.I.

section S13. Specified melting points were recorded on a Reichert

Thermovar Apparatus and are not corrected.

(

compound 69) was also the only compound showing a bacterial

reduction below the detection limit even in the presence of serum.

In the tests with the Gram-negative germ P. aeruginosa, again

some

of

the

chlorido(dipyrrinato)(pentamethylcyclopentadienyl)iridium(III)co

mplexes were able to reduce bacterial growth to the limit of

detection. And even in the presence of serum these complexes

exerted a significant effect by reducing bacterial growth by one or

two log stages. With the (dipyrrinato)(2-phenylpyridyl)iridium(III)

complexes no significant antibacterial activity towards P.

aeruginosa was found.

Compounds 1 – 15^[²⁸^a^,^b^,^d^,^e^,³³^], 16^[³⁴^], 18^[²⁷^a^], 20 – 22^[²⁷^a^], 24^[²⁸^d^]

,

25^[³³^], 29^[²⁸^d^], 30^[²⁸^d^], and 72^[²⁸^b^]were prepared according to the

literature. Dipyrrins 16, 18, and 20 – 22 were previously

synthesized via oxidation with DDQ.^[²⁷^a^,³⁴^]In this work the

oxidation was performed with p-chloranil to increase the yield of

the corresponding dipyrrins 16, 18, and 20 – 22. Previously,

dipyrrin 48 was described in the literature via one pot-multi-step

synthesis,^[³⁸^]herein, a stepwise synthesis of 48 is presented.

In summary, the synthetic tools provided herein, specifically the

post-functionalization of fluorophenyl-substituted dipyrrinato-

iridium complexes allow

a

convenient access to various

General synthetic procedure for the oxidation of

dipyrromethanes (16 – 30). The corresponding dipyrromethane

(1 – 15, 1 equiv.) was dissolved in THF and p-chloranil or DDQ (1

equiv., suspended in THF) was added. The reaction mixture was

stirred for the indicated time at room temperature. Afterwards, the

solvent was evaporated at reduced pressure, the remaining solid

was dissolved and filtered over a silica gel filled glass frit. The

filtrate was evaporated to dryness and purified by column

chromatography.

functionalized cyclometalated iridium complexes. Some of these

complexes are found to show a high phototoxicity against tumor

cells and a strong antibacterial activity, often even without

illumination. Of specific interest is the strong antibacterial activity

of

the

chlorido(dipyrrinato)(pentamethylcyclopentadienyl)iridium(III)

complexes against the Gram-positive germ S. aureus and the

Gram-negative P. aeruginosa and the high activity of the glyco-

substituted iridium complexes against tumor cells and bacteria,

underlining the potential that such complexes hold for

General

synthetic

procedure

for

the

5

(

photo)medical applications. The observed antibacterial activities

chlorido(dipyrrinato)(pentamethyl-η -cyclopentadienyl)-

of the (dipyrrinato)(pentamethylcyclopentadienyl) complexes with

and without illumination value more detailed structure-activity

investigations including modified glyco-substitutions on the way to

new (photo)antimicrobials.

iridium(III) complexes (31 – 45). The corresponding dipyrrin (16

– 30, 1 equiv.) and the [IrCl Cp*] (0.5 equiv.) were dissolved in

2

DCM or THF. DIPEA (14 equiv.) was added and the mixture was

stirred for 24 h at room temperature. The flask was shielded from

ambient light with aluminum foil. After the indicated time,

saturated NaCl solution was added and extracted with DCM

several times. The combined organic layers were dried with

Experimental Section

Na

2 4

SO , filtered, and evaporated to dryness. The crude product

was purified by column chromatography and recrystallized.

General Remarks. All reactions were performed in standard

round bottom flasks. Air sensitive reactions were carried out under

an argon gas protecting atmosphere. Solvents DCM, n-pentane,

and methanol were purchased and used as received. Other

solvents were purchased and distilled at reduced pressure.

Purchased chemicals were used as received without further

purification. All liquid reagents were added through syringes.

Reactions were monitored by thin-layer chromatography (Merck,

TLC Silica gel 60 F254. Flash column chromatography was

performed on silica gel (Fluka silica gel 60M, 40-63μm). NMR

spectra were recorded with JEOL ECX400, JEOL ECP500,

Bruker Avance500, and JEOL ECZ600 Instruments. Multiplicity of

Preparation

of

chlorido(5-pentafluorophenyl-1,3,7,9-

5

tetramethyldipyrrinato)(pentamethyl-η -cyclopentadienyl)-

2 2

iridium(III) (50). Dipyrrin 48 (250 mg, 0.68 mmol), [IrCl Cp*] (272

mg, 0.34 mmol) and DIPEA (1.62 mL, 9.55 mmol) were dissolved

in 10 mL of THF. The mixture was stirred for 24 h at room

temperature. The flask was shielded from ambient light with

aluminum foil. After the indicated time, saturated NaCl solution

was added and extracted with DCM several times. The combined

organic layers were dried with Na

2 4

SO , filtered, and evaporated

to dryness. After column chromatography (silica gel, EtOAc/n-

1

6

Chemistry - A European Journal

10.1002/chem.202004776

FULL PAPER

hexane = 1/1, v/v) and recrystallization (DCM/n-hexane) complex

organic layer was dried with Na

2

SO

4

, filtered, and evaporated to

5

3

0 was obtained as an orange-green solid (161 mg, 0.22 mmol,

dryness. The crude product was purified by column

chromatography and recrystallization.

1

2%). M.p. >250 °C. H NMR (500 MHz, CD

2

Cl

2

): δ (ppm) = 1.40

(

H

(

1

s, 15H, MeCp*), 1.68 (s, 6H, Me), 2.62 (s, 6H, Me), 6.16 (s, 2H,

pyrrole). ¹³C NMR (126 MHz, CD

Cl ): δ (ppm) = 8.6 (MeCp*), 15.1

Me), 18.9 (Me), 86.8 (CCp*), 123.4 (CHpyrrole), 130.6 (Cmeso), 142.1

pyrrole), 162.9 (Cpyrrole). ¹⁹F NMR (376 MHz, CD

Cl ): δ (ppm) = -

62.07 – -161.89 (m, 2F, CFortho), -153.99 (t, J = 20.9 Hz, 1F,

CFpara), -139.87 (dd, J = 24.3, 8.5 Hz, 1F, CFpara), -140.38 (dd, J

2

General synthetic procedure for nucleophilic substitution of

52 with alcohols. Complex 52 (1 equiv.) was dissolved in THF,

freshly powdered potassium hydroxide (5 equiv.), and the

corresponding alcohol (10 equiv.) were added. The mixture was

stirred for 24 h at room temperature. Afterwards, the mixture was

diluted with DCM and washed several times with water. The

organic layer was dried with Na SO , filtered, and evaporated to

2 4

dryness. The crude product was purified by column

chromatography.

C

2

=

51.5, 22.8 Hz, 2F, CFmeta). HRMS (ESI-TOF): m/z calcd. for

+

C

29

H

29

F

5

IrN

2

[M-Cl] : 693.1875, found: 693.1857, m/z calcd. for

+

58

58ClF10Ir

2

N

4

[2M-Cl] : 1421.3443, found: 1421.3393. UV/Vis

DCM): λmax (nm) [log (ε/L mol^-cm )] = 518 [4.62].

1

-1

(

Preparation

of

chlorido(4-fluoro-3-nitrophenyl-1,3,7,9-

General synthetic procedure for nucleophilic substitution of

60 with amines. Complex 60 (1 equiv.) and the corresponding

amine (20 equiv.) were dissolved in DCM. The mixture was stirred

for 2 h at room temperature. After the indicated time, the mixture

was diluted with EtOAc and washed with water several times. The

organic layer was dried with Na SO , filtered, and evaporated to

2 4

dryness. The crude product was purified by column

chromatography.

5

tetramethyldipyrrinato)(pentamethyl-η -cyclopentadienyl)-

iridium(III) (51). Dipyrrin 49 (250 mg, 0.74 mmol), [IrCl Cp*] (293

2 2

mg, 0.37 mmol) and DIPEA (1.75 mL, 10.31 mmol) were

dissolved in 10 mL of THF. The mixture was stirred for 24 h at

room temperature. The flask was shielded from ambient light with

aluminum foil. After the indicated time, saturated NaCl solution

was added and extracted with DCM several times. The combined

organic layers were dried with Na

to dryness. After column chromatography (silica gel, DCM/EtOAc

1/1, v/v) and recrystallization (DCM/n-hexane) complex 51 was

2 4

SO , filtered, and evaporated

General synthetic procedure for glycosylation of 52 and 60.

The complex 52 or 60 (1 equiv.) and the corresponding thio-

carbohydrate sodium salt (1.2 equiv.) were dissolved DMF. The

mixture was stirred for the indicated time at room temperature.

Afterwards, 5 ml of water was added and stirred for additional 5

min at room temperature. Due to the high polarity of the product,

the mixture was directly evaporated to dryness with a rotary

evaporator. The crude product was purified by column

chromatography and recrystallization.

=

obtained as a red-orange solid (137 mg, 0.20 mmol, 27%). M.p.

1

>

250 °C. H NMR (500 MHz, CD

2

Cl

2

): δ (ppm) = 1.41 (d, J = 5.4

Hz, 15H, MeCp*), 1.48 (d, J = 2.3 Hz, 6H, Me), 2.60 (s, 6H, Me),

6

1

.14 (d, J = 2.6 Hz, 2H, Hpyrrole), 7.43 (ddd, J = 24.4, 10.8, 8.5 Hz,

H, Ar-Hmeta), 7.57 (ddd, J = 8.4, 4.2, 2.1 Hz, 1H, Ar-Hortho), 7.97

1

3

(

td, J = 7.7, 7.2, 2.2 Hz, 1H, Ar-Hortho). C NMR (126 MHz,

CD Cl ): δ (ppm) = 9.0 (MeCp*), 16.9 (Me), 18.7 (Me), 86.6 (CCp*),

2

1

2

C

1

19.20 (d, J = 24.2 Hz, Ar-Cmeta), 123.2 (CHpyrrole), 126.50* (d, J =

.4 Hz, Ar-Cortho), 129.10 (d, J = 2.6 Hz, ), 131.34 (d, J = 5.0 Hz,

pyrrole), 136.14* (d, J = 8.6 Hz), 137.9 (Ar-Cortho), 139.0 (Cmeso),

43.40 (d, J = 5.7 Hz, Cpyrrole), 155.90 (d, J = 265.6 Hz, Ar-Cpara),

62.0 (Cpyrrole). *These signals could not be assigned exactly to

X-ray Crystallography. The compounds 31, 51, 54, 60 and 66

were each crystallized by slow evaporation of a solution of the

target compound in dichloromethane (31, 60), layered

dichloromethane/hexane (54) or toluene (51, 66) following the

concept developed by Hope,^[⁷³^]and the crystal structure obtained

from patterns collected on a Bruker APEX-II Duo diffractometer

with CuKα or MoKα as indicated in Table S1.1.1 Data reduction and

multi-scan absorption corrections were applied with the Bruker

APEX3 package.^[⁷⁴^]Structures were solved using SHELXT,

corresponding carbon atoms. They belong to the Ar-Cipso and the

Ar-Cnitro of the aryl moiety. F NMR (376 MHz, CD

=

C

1

9

2

Cl

2

): δ (ppm)

-119.25 – -118.56 (m, 1F, CF). HRMS (ESI-TOF): m/z calcd. for

+

29 2 2

H32FIrN O [M-Cl] : 666.2102, found: 666.2124. IR (ATR): 휈̃

-1

[75]

(

cm ) = 3052 [ν(Ar-H)], 2960 and 2916 [ν(Me)], 1616 and 1580

2

[

(

ν(C=C), ν(C=N-)], 1532 [νas(NO )], 1441 [δ(CH )], 1339

2

and refinements were performed against |F | using SHELXL in the

ν

sym(NO

2

)], 1087 [ν(C=CF)], 732 [δ(HC=CH)]. UV/Vis (DCM): λmax

ShelXle^[⁷⁶^]GUI. All non-H atoms were refined with anisotropic

thermal parameters, with H atoms as riding isotropic thermal

parameters. C-bound H-positions were constrained to

geometrically optimized positions, N-bound H atoms were

positionally refined. Additional refinement details are presented in

S.I. section S1.1.2.

nm) [log (ε/L mol^-¹cm )] = 509 [4.54].

-1

General synthetic procedure for the (dipyrrinato)bis(2-

phenylpyridyl)iridium(III) complexes (52 66). The

corresponding dipyrrin (16 – 30, 1 equiv.) and DIPEA (14 equiv.)

–

were dissolved in THF. Under an argon atmosphere the

CCDC

2035034-2035038

contain

the

supplementary

[

IrCl(ppy)

2

]

2

(0.5 equiv.) was added and the mixture was stirred

crystallographic data for this paper. These data can be obtained

free of charge from The Cambridge Crystallographic Data Centre.

for 24 h at reflux. After the indicated time, DCM was added and

washed with water several times. The organic layer was dried with

2 4

Na SO , filtered, and evaporated to dryness. The crude product

was purified by column chromatography and recrystallized.

Acknowledgements

General synthetic procedure for nucleophilic substitution of

The biolitec research GmbH gratefully acknowledges financial

support by the German Bundesministerium für Bildung und

Forschung (BMBF) (03ZZ0927B). This work has received funding

from the European Union's Horizon 2020 research and innovation

5

2 with amines. Complex 52 (1 equiv.) and the corresponding

amine (20 equiv.) were dissolved in DMSO. The mixture was

stirred for 24 h at 80 °C. After the indicated time, the mixture was

diluted with DCM and washed with water several times. The

1

7

Chemistry - A European Journal

10.1002/chem.202004776

FULL PAPER

2

55–261; e) S. B. Brown, E. A. Brown, I. Walker, Lancet Oncol. 2004, 5,

97–508.

programme under the Marie Skłodowska-Curie Grant Agreement

4

No. 764837 and through a grant from Science Foundation Ireland

[

12] C. A. Robertson, D. Hawkins, E. H. Abrahamse, J. Photochem.

(

IvP 13/IA/1894). It was prepared with the support of the Technical

Photobiol., B 2009, 96, 1–8.

University of Munich – Institute for Advanced Study through a

[13] H. Huang, S. Banerjee, P. J. Sadler, ChemBioChem 2018, 19, 1574–

589.

14] a) N. Kashef, Y.-Y. Huang, M. R. Hamblin, Nanophotonics 2017, 6, 853–

79; b) T. Maisch, J. Photochem. Photobiol., B 2015, 150, 2–10; c) Y.

1

Hans Fischer Senior Fellowship for M.O.S.

[

8

Keywords: Dipyrrins • (Dipyrrinato)iridium(III) Complexes •

Glycosylation • Photodynamic Therapy • Antimicrobial

Photodynamic Inactivation

Liu, R. Qin, S. A. J. Zaat, E. Breukink, M. Heger, J. Clin. Transl. Res.

2015, 1, 140–167; d) T. Maisch, Mini-Rev. Med. Chem. 2009, 9, 974–

983.

15] a) L. Costa, M. A. F. Faustino, M. G. P. M. S. Neves, Â. Cunha, A.

Almeida, Viruses 2012, 4, 1034–1074; b) L. Sobotta, P. Skupin-

Mrugalska, J. Mielcarek, T. Goslinski, J. Balzarini, Mini-Rev. Med. Chem.

[

1]

a) M. Ohff, A. Ohff, M. E. van der Boom, D. Milstein, J. Am. Chem. Soc.

997, 119, 11687–11688; b) M. Ohff, A. Ohff, D. Milstein, Chem.

1

2015, 15, 503–521; c) A. Wiehe, J. M. O’Brien, M. O. Senge, Photochem.

Commun. 1999, 357–358; c) R. B. Bedford, S. M. Draper, P. N. Scully,

S. L. Welch, New J. Chem. 2000, 24, 745–747.

Photobiol. Sci. 2019, 18, 2565–2612.

[16] R. F. Donnely, P. A. McCarron, M. M. Tunney, Microbiol. Res. 2008, 163,

[

2]

3]

a) K.-C. Cheung, W.-L. Wong, D.-L. Ma, T.-S. Lai, K.-Y. Wong, Coord.

Chem. Rev. 2007, 251, 2367–2385; b) C. Parmeggiani, F. Cardona,

Green Chem. 2012, 14, 547–564.

1–12.

[

17] a) M. S. Baptista, M. Wainwright, Braz. J. Med. Res. 2011, 44, 1–10; b)

K. Page, M. Wilson, I. P. Parkin, J. Mater. Chem. 2009, 19, 3819–3831;

c) K. Aponiene, E. Paskeviciute, I. Reklaitis, Z. Luksiene, J. Food Eng.

a) S. Elangovan, J. Neumann, J.-B. Sortais, K. Junge, C. Darcel, M.

Beller, Nat. Commun. 2016, 7, 12641; b) J. J. Van Veldhuizen, J. E.

Campbell, R. E. Giudici, A. H. Hoveyda, J. Am. Chem. Soc. 2005, 127,

2015, 144, 29–35.

[

18] a) S. K. Seth, P. Purkayastha, Eur. J. Inorg. Chem. 2020, 2990–2997; b)

C. Lu, S. Shah, B. Liu, W. Xu, L. Sun, S. Y. Qian, W. Sun, ACS Appl. Bio

Mater. 2020, DOI: 10.1021/acsabm.0c00784; c) L. Wang, S. Monro, P.

Cui, H. Yin, B. Liu, C. G. Cameron, W. Xu, M. Hetu, A. Fuller, S. Kilina,

S. A. McFarland, W. Sun, ACS Appl. Mater. Interfaces 2019, 11, 3629–

6877–6882.

[

4]

5]

a) S. H. Pine, G. S. Shen, H. Hoang, Synthesis 1991, 2, 165–166; b) R.

R. Schrock, C. Czekelius, Adv. Synth. Catal. 2007, 349, 55–77; c) A.

Fürstner, M. Liebl, C. W. Lehmann, M. Picquet, R. Kunz, C. Bruneau, D.

Touchard, P. H. Dixneuf, Chem. Eur. J. 2000, 6, 1847–1857.

3644; d) J. Pracharova, G. Vigueras, V. Novohradsky, N. Cutillas, C.

a) G. Gasser, Chimia 2015, 69, 442–446; b) N. Muhammad, Z. Guo, Curr.

Opin. Chem. Biol. 2014, 19, 144–153; c) I. Ott, R. Gust, Arch. Pharm.

Chem. Life Sci. 2007, 340, 117–126; d) U. Ndagi, N. Mhlomgo, M. E.

Soliman, Drug Des. Devel. Ther. 2017, 11, 599–616; P. Chellan, P. J.

Sadler, Chem. Eur. J. 2020, 26, 8676–8688.

Janiak, H. Kostrhunova, J. Kasparkova, J. Ruiz, V. Brabec, Chem. Eur.

J. 2018, 24, 4607–4619; e) C. Mari, H. Huang, R. Rubbiani, M. Schulze,

F. Würthner, H. Chao, G. Gasser, Eur. J. Inorg. Chem. 2017, 1745–1752.

19] a) M. Valenzuela-Valderrama, V. Bustamante, N. Carrasco, I. A.

González, P. Dreyse, C. E. Palavecino, Photodiagn. Photodyn. Ther.

[

[6]

[7]

[8]

a) D. E. Reichert, J. S. Lewis, C. J. Anderson, Coord. Chem. Rev. 1999,

2020, 30, 101662; b) E. Sauvageot, M. Elie, S. Gaillard, R. Daniellou, P.

1

84, 3–66; b) E. L. Que, C. J. Chang, Chem. Soc. Rev. 2010, 39, 51–60.

M. Patra, G. Gasser, N. Metzler-Nolte, Dalton Trans. 2012, 41, 6350–

358.

Fechter, I. J. Schalk, V. Gasser, J.-L. Renaud, G. L. A. Mislin,

Metallomics 2017, 9, 1820–1827.

6

[

20] a) D. F. Azar, H. Audi, S. Farhat, M. El-Sibai, R. J. Abi-Habib, R. S.

Khnayzer, Dalton Trans. 2017, 46, 11529–11532; b) H. Chan, J. B.

Ghrayche, J. Wei, A. K. Renfrew, Eur. J. Inorg. Chem. 2017, 1679–1686.

21] a) M. Yadav, A. K. Singh, D. S. Pandey, J. Organomet. Chem. 2011, 696,

a) Z. Liu, P. J. Sadler, Acc. Chem. Res. 2014, 47, 1174−1185; b) J. M.

Gichumbi, H. B. Friedrich, J. Organomet. Chem. 2018, 866, 123–143; c)

A. Zamora, G. Vigueras, V. Rodrígez, M. D. Santana, J. Ruiz, Coord.

Chem. Rev. 2018, 360, 34–76; d) R. Guan, L. Xie, L. Ji, H. Chao, Eur. J.

Inorg. Chem. 2020, DOI: 10.1002/ejic.202000754.

[

758–763; b) M. Yadav, A. K. Singh, D. S. Pandey, Organometallics 2009,

28, 4713–4723; c) S. A. Baudron, Dalton Trans. 2020, 49, 6161–6175;

[9]

a) V. Venkatesh, R. Berrocal-Martin, C. J. Wedge, I. Romero-Canelón,

C. Sanchez-Cano, J.-I. Song, J. P. C. Coverdale, P. Zhang, G. J.

Clarkson, A. Habtemariam, S. W. Magennis, R. J. Deeth, P. J. Sadler,

Chem. Sci. 2017, 8, 8271–8278; b) T. Mukherjee, M. Mukherjee, B. Sen,

S. Banerjee, G. Hundal, P. Chattopadhyay, J. Coord. Chem. 2014, 67,

d) R. S. Singh, R. P. Paitandi, R. K. Gupta, D. S. Pandey, Coord. Chem.

Rev. 2020, 414, 213269. See also the classical examples: a) A. W.

Johnson, I. T. Kay, J. Chem. Soc. 1961, 2418–2423; b) M. Elder, B. R.

Penfold, J. Chem. Soc. A 1969, 2556–2559; c) F. A. Cotton, D. G.

DeBoer, J. R. Pipal, Inorg. Chem. 1970, 9, 783–788; d) F. C. March, D.

A. Couch, K. Emerson, J. E. Fergusson, W. T. Robinson, J. Chem. Soc.

A 1971, 440–448; e) H. Fischer, M. Schubert, Ber. Dtsch. Chem. Ges.

2643–2660; c) J. J. Li, Z. Tian, Z. Xu, S. Zhang, Y. Feng, L. Zhang, Z.

Liu, Dalton Trans. 2018, 47, 15772–15782; d) Y. Qi, Z. Liu, H. Li, P. J.

Sadler, P. B. O'Connor, Rapid Commun. Mass Spectrom. 2013, 27,

1

924, 57, 610–617.

22] a) J. R. Storck, V. S. Thoi, S. M. Cohen, Inorg. Chem. 2007, 46, 11213–

1223; b) C. Brückner, V. Karunaratne, S. T. Rettig, D. Dolphin, Can. J.

2028–2032.

[

[10] a) S. Monro, K. L. Colón, H. Yin, J. Roque; III, P. Konda, S. Gujar, R. P.

1

Thummel, L. Lilge, C. G. Cameron, S. A. McFarland, Chem. Rev. 2019,

Chem. 1996, 74, 2182–2193; c) S. M. Cohan, S. R. Halper, Inorg. Chim.

Acta 2002, 341, 12–16.

119, 797–828; b) O. J. Stacey, S. J. A. Pope, RSC Adv. 2013, 3, 25550–

25564; c) C. Imberti, P. Zhang, H. Huang, P. J. Sadler, Angew. Chem.

2020, 132, 61–73, Angew. Chem. Int. Ed. 2020, 59, 61–73; d) J. Li, L.

[

23] a) D. Ramlot, M. Rebarz, L. Volker, M. Ovaere, D. Beljonne, W. Dahaen,

L. Van Meervelt, C. Moucheron, A. K.-D. Mesmaeker, Eur. J. Inorg.

Chem. 2013, 2031–2040; b) M. Yadav, A. K. Singh, B. Maiti, D. S.

Pandey, Inorg. Chem. 2009, 48, 7593–7603; c) R. P. Paitandi, R. S.

Singh, S. Mukhopadhyay, G. Sharma, B. Koch, P. Vishnoi, D. S. Pandey,

Inorg. Chim. Acta 2017, 454, 117–127.

Zeng, K. Xiong, T. W. Rees, C. Jin, W. Wu, Y. Chen, L. Ji, H. Chao,

Chem. Commun. 2019, 55, 10972–10975; e) F. Heinemann, J. Karges,

G. Gasser, Acc. Chem. Res. 2017, 50, 2727–2736; f) X. Tong, L. Zhang,

L. Li, Y. Li, Z. Yang, D. Zhu, Z. Xie, Dalton Trans. 2020, 49, 11493–

11497; g) P. Zhang, H. Huang, S. Banerjee, G. J. Clarkson, C. Ge, C.

[24] a) C. Bronner, S. A. Baudron, M. W. Hosseini, Inorg. Chem. 2010, 49,

Imberti, P. J. Sadler, Angew. Chem. 2019, 131, 2372–2376, Angew.

Chem. Int. Ed. 2019, 58, 2350–2354.

8659–8661; b) R. Matsuoka, T. Nabeshima, Front. Chem. 2018, 6, 349;

c) N. Singh, J.-H. Jo, Y. H. Song, H. Kim, D. Kim, M. S. Lah, K.-W. Chi,

Chem. Commun. 2015, 51, 4492–4495; d) J. Zhao, X. Zhang, L. Fang,

C. Gao, C. Xu, S. Gou, Small 2020, 16, 2000363; e) R. Matsuoka, R.

Toyoda, R. Sakamoto, M. Tsuchiya, K. Hoshiko, T. Nagayama, Y.

Nonoguchi, K. Sugimoto, E. Nishibori, T. Kawai, H. Nishihara, Chem. Sci.

[

11] a) P. Agostinis, K. Berg, K. A. Cengel, T. H. Foster, A. W. Girotti, S. O.

Gollnick, S. M. Hahn, M. R. Hamblin, A. Juzeniene, D Kessel, M. Korbelik,

J. Moan, P. Mroz, D. Nowis, J. Piette, B. C. Wilson, J. Golab, Ca-Cancer

J. Clin. 2011, 61, 250–281; b) D. E. J. G. J. Dolmans, D. Fukumura, R.

K., Jain, Nat. Rev. Cancer 2003, 3, 380–387; c) Á. Juarranz, P. Jaén, F.

Sanz-Rodríquez, J. Cuevas, S. González, Clin. Transl. Oncol. 2008, 10,

2015, 6, 2853–2858.

148–154; d) C.-M. Che, F.-M. Siu, Curr. Opin. Chem. Biol. 2010, 14,

1

8

Chemistry - A European Journal

10.1002/chem.202004776

FULL PAPER

[

25] a) G. Li, L. Ray, E. N. Glass, K. Kovnir, A. Khoroshutin, S. I. Gorelsky, M.

Shatruk, Inorg. Chem. 2012, 51, 1614–1624; b) J. Sun, W. Wu, H. Gou,

J. Zhao, Eur. J. Inorg. Chem. 2011, 3165–3173.

[40] a) R. Pretorius, J. Olguín, M. Albrecht, Inorg. Chem. 2017, 56, 12410–

12420; b) M.-J. Li, P. Jiao, W. He, C. Yi, C.-W. Li, X. Chen, G.-N. Chen,

M. Yang, Eur. J. Inorg. Chem. 2011, 197–200; c) M. Felici, P. Contreras-

Carballada, Y. Vida, J. M. M. Smits, R. J. M. Nolte, L. De Cola, R. M.

Williams, M. C. Feiters, Chem. Eur. J. 2009, 15, 13124–13134.

[41] a) N. Shivran, M. Tyagi, S. Mula, P. Gupta, B. Saha, B. S. Padro, S.

Chattopadhyay, Eur. J. Med. Chem. 2016, 122, 352–365; b) D. Lim, M.

A. Brimble, R. Kowalczyk, A. J. A. Watson, A. J. Fairbanks, Angew.

Chem. 2014, 126, 12101–12105; Angew. Chem. Int. Ed. 2014, 53,

11907–11911; c) S. Bhatia, M. Dimde, R. Haag, Med. Chem. Commun.

2014, 5, 862–878; d) T. Papalia, A. Barattucci, S. Campagna, F.

Puntoriero, T. Salerno, P. Bonaccorsi, Org. Biomol. Chem. 2017, 15,

8211–8217.

[

26] a) R. P. Paitandi, R. K. Gupta, R. S. Singh, G. Sharma, B. Koch, D. S.

Pandey, Eur. J. Med. Chem. 2014, 84, 17–29; b) R. K.Gupta, A. Kumar,

R. P. Paitandi, R. S. Singh, S. Mukhopadhyay, S. P. Verma, P. Das, D.

S. Pandey, Dalton Trans. 2016, 45, 7163–7177.

[

27] a) C. S. Gutsche, S. Gräfe, B. Gitter, K. J. Flanagan, M. O. Senge, N.

Kulak, A. Wiehe, Dalton Trans. 2018, 47, 12373–12384; b) J. Karges, U.

Basu, O. Blacque, H. Chao, G. Gasser, Angew. Chem. 2019, 131,

1

4472–14478, Angew. Chem. Int. Ed. 2019, 58, 14334–14340; c) S.

Swavey, K. Morford. M. Tsao, K. Comfort, M. K. Kilroy, J. Inorg. Biochem.

017, 175, 101–109.

2

[

28] a) C. S. Gutsche, M. Ortwerth, S. Gräfe, K. J. Flanagan, M. O. Senge,

[42] a) R. Klingenburg, C. B. W. Stark, A. Wiehe, Org. Lett. 2019, 21, 5417–

5420; b) S. Singh, A. Aggarwal, S. Thompson, J. P. C. Tomé, X. Zhu, D.

Samaroo, M. Vinodu, R. Gao, C. M. Drain, Bioconjugate Chem. 2010, 21,

2136–2146; c) F. Faschinger, S. Aichhorn, M. Himmelsbach, W.

Schoefberger, Synthesis 2014, 46, 3085–3096

H.-U. Reissig, N. Kulak, A. Wiehe, Chem. Eur. J. 2016, 22, 13953–

1

3964; b) H. R. A. Golf, H.-U. Reissig, A. Wiehe, Org. Lett. 2015, 17,

82–985; c) Y. Volkova, B. Brizet, P. D. Harvey, F. Denat, C. Goze, Eur.

9

J. Org. Chem. 2014, 2268–2274; d) B. F. Hohlfeld, K. J. Flanagan, N.

Kulak, M. O. Senge, M. Christmann, A. Wiehe, Eur. J. Org. Chem. 2019,

[43] X. Chen, L. Hui, D. A. Foster, C. M. Drain, Biochemistry, 2004, 43,

10918–10929.

4

020–4033; e) B. F. Hohlfeld, B. Gitter, K. J. Flanagan, C. J. Kingsbury,

N. Kulak, M. O. Senge, A. Wiehe, Org. Biomol. Chem. 2020, 18, 2416–

431.

29] a) J. S. Smalley, M. R. Waterland, S. G. Telfer, Inorg. Chem. 2009, 48,

3–15; b) K. Hanson, A. Tamayo, V. V. Diev, M. T. Whited, P. I. Djurovich,

[44] a) J. M. Zimbron, K. Passador, B. Gatin-Fraudet, C.-M. Bachelet, D.

Plażuk, L.-M. Chamoreau, C. Botuha, S. Thorimbert, M. Salmain,

Organometallics 2017, 36, 3435–3442; b) B. Liu, S. Monro, M. J. Jabed,

C. G. Cameron, K. L. Colón, W. Xu, S. Kilina, S. A. McFarland, W. Sun,

Photochem. Photobiol. Sci. 2019, 18, 2381–2396; c) G. Gupta, P. Kumari,

J. Y. Ryu, J. Lee, S. M. Mobin, C. Y. Lee, Inorg. Chem. 2019, 58,

8587−8595, d) G. Gupta, S. Cherukommu, G. Srinivas, S. W. Lee, S. H.

Mun, J. Jung, N. Nagesh, C. Y. Lee, J. Inorg. Biochem. 2018, 189, 17–

29, e) R. P. Paitandi, S. Mukhopadhyay, R. S. Singh, V. Sharma, S. M.

Mobin, D. S. Pandey, Inorg. Chem. 2017, 56, 12232−12247, f) L. Tabrizi,

H. Chiniforoshan, RSC Adv. 2017, 7, 34160–34169.

2

[

1

M. E. Thompson, Inorg. Chem. 2010, 49, 6077–6084; c) C. Bronner, M.

Veiga, A. Guenet, L. De Cola, M. W. Hosseini, C. A. Strassert, S. A.

Baudron, Chem. Eur. J. 2012, 18, 4041–4050.

[

30] K. Takaki, E. Sakuda; A. Ito; S. Horiuchi, Y. Arikawa, K. Umakoshi, Inorg.

Chem. 2019, 58, 14542–14550.

31] D. Samaroo, M. Vinodu, X. Chen, C. M. Drain, J. Comb. Chem. 2007, 9,

9

98–1011.

32] a) N. T. Anderson, P. H. Dinolfo, X. Wang, J. Mater. Chem. C 2018, 6,

452–2459; b) M. C Bennion, M. A. Burch, D. G. Dennis, M. E. Lech, K.

[45] a) H. R. A. Golf, H.-U. Reissig, A. Wiehe, Eur. J. Org. Chem. 2015, 1548–

1568; b) P. K. B. Palomaki, P. H. Dinolfo, ACS Appl. Mater. Interfaces

2011, 3, 4703–4713; c) M. D. Yilmaz, O. A. Bozdemir, E. U. Akkaya, Org.

Lett. 2006, 8, 2871–2873.

2

Neuhaus, N. L. Fendler. M. R. Parris, J. E. Cuadra, C. F. Dixon, G. T.

Mukosera, D. N. Blauch. L. Hartmann, N. L. Snyder and J. V. Ruppel,

Eur. J. Org. Chem. 2019, 6496–6503; c) M. H. Staegemann, S. Gräfe, B.

Gitter, K. Achazi, E. Quaas, R. Haag, A. Wiehe, Biomacromolecules

[46] Z. Liu, P. J. Sadler, Acc. Chem. Res. 2014, 47, 1174–1185.

[47] C. R. Groom, I. J. Bruno, M. P. Lightfoot, S. C. Ward, Acta Cryst. 2016,

B72, 171–179.

2018, 19, 222–238.

[

33] C. S. Gutsche, B. F. Hohlfeld, K. J. Flanagan, M. O. Senge, N. Kulak, A.

Wiehe, Eur. J. Org. Chem. 2017, 3187–3196.

[48] M. A. Filatov, S. Karuthedath, P. M. Polestshuk, S. Callaghan, K. J.

Flanagan, T. Wiesner, F. Laquai, M. O. Senge, ChemPhotoChem 2018,

2, 606–615.

[34] L. Yu, K. Muthukumaran, I. V. Sazanovich, C. Kirmaier, E. Hindin, J, R.

Diers, P. D. Boyle, D. F. Bocain, D. Holten, J. S. Lindsey, Inorg. Chem.

[49] R. K. Gupta, R. Pandey, G. Sharma, R. Prasad, B. Koch, S. Srikrishna,

P. Z. Li, Q. Xu, D. S. Pandey, Inorg. Chem. 2013, 52, 3687–3698.

[50] N. Singh, J. H. Jo, Y. H. Song, H. Kim, D. Kim, M. S. Lah, K. W. Chi,

Chem. Commun. 2015, 51, 4492–4495.

2

003, 42, 6629–6647.

35] a) S. F. Vyboishchikov, M. Bühl, W. Thiel, Chem. Eur. J. 2002, 8, 3962–

975; b) A. Fürstner, Angew. Chem. 2013, 125, 2860–2887; Angew.

[

3

Chem. Int. Ed. 2013, 52, 2794–2819.

[51] T. Soya, A. Osuka, Chem. Eur. J. 2015, 21, 10639–10644.

[52] A. C. Carrasco, V. Rodríguez-Fanjul, A. Habtemariam, A. M. Pizarro, J.

Med. Chem. 2020, 63, 4005–4021.

[

36] a) M. B. France, J. Feldman, R. H. Grubbs, J. Chem. Soc., Chem.

Commun. 1994, 1307–1308; b) R. Ahuja, S. Kundu, A. S. Goldman, M.

Brookhart, B. C. Vicenté, S. L. Scott, Chem. Commun. 2008, 253–255;

c) A. J. Nawara-Hultzsch, J. D. Hackenberg, B. Punji, C. Supplee, T. J.

Emge, B. C. Bailey, R. R. Schrock, M. Brookhart, A. S. Goldman, ACS

Catal. 2013, 3, 2505–2514.

[53] S. Ladouceur, D. Fortin, E. Zysman-Colman, Inorg. Chem. 2010, 49,

5625–5641.

[54] S. J. Garden, J. L. Wardell, J. M. S. Skakle, J. N. Low, C. Glidewell, Acta

Cryst. 2004, C60, o328–o330.

[

37] a) M. Tsuchiya, R. Sakamoto, M. Shimada, Y. Yoshinori, Y. Hattori, K.

Sugimoto, E. Nishibori, H. Nishihara, Inorg. Chem. 2016, 55, 5732–5734;

b) Q. Miao, J.-Y. Shin, B. O. Patrick, D. Dolphin, Chem. Commun. 2009,

[55] K. Takaki, E. Sakuda, A. Ito, S. Horiuchi, Y. Arikawa, K. Umakoshi, Inorg.

Chem. 2019, 58, 14542–14550.

[56] C. Bronner, M. Veiga, A. Guenet, L. De Cola, M. W. Hosseini, C. A.

Strassert, S. A. Baudron, Chem. Eur. J. 2012, 18, 4041–4050.

[57] C. Bronner, S. A. Baudron, M. W. Hosseini, Inorg. Chem. 2010, 49,

8659–8661.

2541–2543; c) J. Karges, O. Blacque, H. Chao, G. Gasser, Inorg. Chem.

2019, 58, 12422–12432; d) R. Sakamoto, T. Iwashima, J. F. Kögel, S.

Kusaka, M. Tsuchiya, Y. Kitagawa, H. Nishihara, J. Am. Chem. Soc.

016, 138, 5666–5677; R. Toyoda, M. Tsuchiya, R. Sakamoto, R.

Matsuoka, e) K.-H. Wu, Y. Hattori, H. Nishihara, Dalton Trans. 2015, 44,

5103–15106.

2

[58] J. H. Hong, S. Kim, H. So, J. H. Lee, H. Hwang, K. M. Lee, Dyes

Pigments 2020, 183, 108706.

1

[59] a) R. Bonnett, Chem. Soc. Rev. 1995, 24, 19–33; b) F. Li, Q. Liu, Z. Liang,

J. Wang, M. Pang, W. Huang, W. Wu, Z. Hong, Org. Biomol. Chem. 2016,

14, 3409–3422; c) C. N. Lunardi, A. C. Tedesco, Curr. Org. Chem. 2005,

9, 813–821.

[38] X. Lu, H. Nan, W. Sun, Q. Zhang, M. Zhan, L. Zou, Z. Xie, X. Li, C. Lu,

Y. Cheng, Dalton Trans. 2012, 41, 10199–10210.

[39] a) K. Jain, P. Kesharwani, U. Gupta, N. K. Jain, Biomaterials 2012, 33,

4

166–4186; b) H. Zhang, Y. Ma, X.-L. Sun, Med. Res. Rev. 2010, 30,

70–289; c) S. V. Moradi, W. M. Hussein, P. Varamini, P. Simerska, I.

[60] a) Z. Liu, A. Habtemariam, A. M. Pizarro, S. A. Fletcher, A. Kisova, O.

Vrana, L. Salassa, P. C. A. Bruijnincx, G. J. Clarkson, V. Brabec, P. J.

Sadler, J. Med. Chem. 2011, 54, 3011–3026; b) J. M. Hearn, G. M.

Hughes, I. Romero-Canelón, A. F. Munro, B. Rubio-Ruiz, Z. Liu, N. O.

Carragher, P. J. Sadler, Metallomics 2018, 10, 93–107.

2

Toth, Chem. Sci. 2016, 7, 2492–2500; d) E. Cho, S. Jung, Molecules

015, 20, 19620–19646.

2

1

9

Chemistry - A European Journal

10.1002/chem.202004776

FULL PAPER

[61] L. Tabrizi, Dalton Trans. 2017, 46, 7242–7252.

[

62] a) S. Yi, Z. Lu, J. Zhang, J. Wang, Z. Xie, L. Hou, ACS Appl. Mater.

Interfaces 2019, 11, 15276–15289; b) J. S. Nam, M.-G. Kang, J. Kang,

S.-Y. Park, S. J. C. Lee, H.-T. Kim, J. K. Seo, O.-H. Kwon, M. H. Lim, H.-

W. Rhee, T.-H. Kwon, J. Am. Chem. Soc. 2016, 138, 10968–10977; c)

F.-X. Wang, M.-H. Chen, Y.-N. Lin, H. Zhang, C.-P. Tan, L.-N. Ji, Z.-W.

Mao, ACS Appl. Mater. Interfaces 2017, 9, 42471–42481.

[

63] H. F. Chambers, F. R. DeLeo, Nat. Rev. Microbiol. 2009, 7, 629–641.

64] a) D. Vecchio, T. Dai, L. Huang, L- Fantetti, G. Roncucci, M. R. Hamblin,

J. Biophotonics 2013, 6, 733–742, b) X. Hu, Y.-Y. Huang, Y. Wang, X.

Wang, M. R. Hamblin, Front. Microbiol. 2018, 9, 01299.

[

[65] a) Z. Pang, R. Raudonis, B. R. Glick, T.-J. Lin, Z. Cheng, Biotechnol. Adv.

2

019, 37, 177–192; b.) P. Pachori, R. Gothalwal, P. Gandhi, Genes Dis.

019 6, 109–119; c) F. Lucca, M., Guarnieri, M. Ros, G. Muffato, R. Rigoli,

2

L. D. Dalt, Clin. Respir. J. 2018, 12, 2189–2196.

[66] a) T. Dai, Y.Y. Huang, M. R. Hamblin, Photodiagn. Photodyn. Ther. 2009,

6

, 170–188; b) G. Jori, C. Fabris, M. Soncin, S. Ferro, O. Coppellotti, D.

Dei, L. Fantetti, G. Chiti and G. Roncucci, Lasers Surg. Med. 2006, 38,

68–481; c) T. Dai, Y.-Y. Huang, S. K. Sharma, J. T. Hashmi, D. B. Kurup

and M. R. Hamblin, Recent Patents Anti-Canc. Drug Discov. 2010, 5,

24–151.

67] a) L.-C. Lu, Y.-W. Chen, C.-C. Chou, Int. J. Food Microbiol. 2005, 102,

13–220; b) T. E. Shehata, A. G. Marr, J. Bacteriol. 1970, 103, 789–792;

4

1

[

2

c) G. A. Pankey, L. D. Sabath, Clin. Infect. Dis. 2004, 38, 864–870; d) R.

M. abd El-Baky, Am. J. Microbiol. Res. 2016, 4, 1–15; e)

Bekanntmachung des Robert Koch-Institutes, Bundesgesundheitsbl.

2013, 56, 1696–1701; f) NCCLS. Methods for determining bactericidal

activity of antibacterial agents; approved guideline. NCCLS document

M26 A. Villanova, PA: NCCLS, 1999 and also EN 13727.

[68] a) F. Chen, J. Moat, D. McFeely, G. Clarkson, I. J. Hands-Portman, J. P.

Furner-Pardoe, F. Harrison, C. G. Dowson, P. J. Sadler, J. Med. Chem.

2

018, 61, 7330−7344; b) M. Pandrala, F. Li, M. Feterl, Y. Mulyana, J. M.

Warner, L. Wallace, F. R. Keene, J. G. Collins, Dalton Trans. 2013, 42,

686–4694; c) A. Lapasam, L. Dkhar, N. Joshi, K. M. Poluri, M. R.

4

Kollipara, Inorg. Chim. Acta 2018, 484, 255−263; d) A. Gupta, P. Prasad,

S. Gupta, P. K. Sasmal, ACS Appl. Mater. Interfaces 2020, 12, 35967–

35976.

[

69] Q.-Y. Yi, W.‑Y. Zhang, M. He, F. Du, X.‑Z. Wang, Y.‑J. Wang, Y.‑Y. Gu,

L. Bai, Y.‑J. Liu, J. Biol. Inorg. Chem. 2019, 24, 151–159.

70] B. M. Amos-Tautua, S. P. Songca, O. S. Oluwafemi, Molecules 2019, 24,

2456.

71] X. Ragàs, D. Sánchez-García, R. Ruiz-González, T. Dai, M. Agut, M. R.

Hamblin, S. Nonell, J. Med. Chem. 2010, 53, 7796–7803.

72] a) T. G. M. Smijs, M. J. M. Nivard, H. J. Schuitmaker, Photochem.

Photobiol. 2004, 79, 332–338; b) R. A. Floyd, J. E. Schneider Jr., D. P.

Dittmer, Antiviral Res. 2004, 61, 141–151; c) J. M. Mundt, L. Rouse, J.

Van den Bossche, R. P. Goodrich, Photochem. Photobiol. 2014, 90,

957–964; d) T. Qin, K. Liu, D. Song, C. Yang, H. Su, Chem. Asian J.

2017, 12, 1578–1586.

[73] a) H. Hope, Prog. Inorg. Chem. 1994, 41, 1–19; b) M. O. Senge, Z.

Naturforsch. 2000, 55b, 336–344.

[

74] Bruker (2012). APEX3. Bruker AXS Inc., Madison, Wisconsin, USA.

75] G. M. Sheldrick, Acta Cryst. 2015, A71, 3–8.

76] C. B. Hübschle, G. M. Sheldrick, B. Dittrich, J. Appl. Cryst. 2011, 44,

1281–1284.

2

0

Chemistry - A European Journal

10.1002/chem.202004776

FULL PAPER

Entry for the Table of Contents

Heteroleptic dipyrrinato iridium complexes were synthesized and evaluated for their phototoxic activity against tumor cells and

bacteria, the Gram-positive germ S. aureus and the Gram-negative Germ P. aeruginosa. Specifically, glycosylated phenylpyridyl-

dipyrrinato complexes showed a high phototoxic effect against cells and S. aureus. Certain cyclopentadienyl-dipyrrinato complexes

exerted a high phototoxic effect on S. aureus and P. aeruginosa.

2

1

Article Doi

Dipyrrinato-Iridium(III) Complexes for Application in Photodynamic Therapy and Antimicrobial Photodynamic Inactivation

DOI: 10.1002/chem.202004776

Source and publish data:

Authors:

Article abstract of DOI:10.1002/chem.202004776

Full text of DOI:10.1002/chem.202004776

Products guided by the article

R&D Labs maybe for 1394285-02-9

Relevant to this article

Hot Product