Synthetic strategies towards ruthenium-porphyrin conjugates for anticancer activity

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www.rsc.org/dalton | Dalton Transactions

Synthetic strategies towards ruthenium–porphyrin conjugates for anticancer

activity†

Teresa Gianferrara,*^aIoannis Bratsos,^bElisabetta Iengo,^bBarbara Milani,^bAdrian Osˇtric´,^bCinzia Spagnul,^a

Ennio Zangrando^band Enzo Alessio*^b

Received 11th June 2009, Accepted 31st July 2009

First published as an Advance Article on the web 27th August 2009

DOI: 10.1039/b911393b

The conjugation of porphyrins to metal fragments is a strategy for making new compounds that are

expected to combine the phototoxicity and the tumour-localization properties of the porphyrin

chromophore with the cytotoxicity of the metal fragment for additive antitumour effect. We report here

the preparation of new classes of porphyrin–ruthenium conjugates with potential bio-medical

applications. Ruthenium was chosen because several Ru compounds have shown promising anticancer

activity. The conjugation with the porphyrin moiety was accomplished either through peripheral

pyridyl rings (e.g. meso-4¢-tetrapyridylporphyrin, 4¢TPyP) or through bpy units (e.g. meso-(p-bpy-

phenyl)porphyrins, bpy_n-PPs, n = 1–4). The number of Ru fragments attached to the porphyrins ranges

from 1 to 4 and the total charge of the conjugates from -4 to +8. Different types of peripheral

fragments, both Ru(III) and Ru(II), have been used: in some cases they are structurally similar to

established anticancer compounds. Examples are [Na]₄[4¢TPyP{trans-RuCl₄(dmso-S)}₄] (2), that bears

four NAMI-type Ru(III) fragments, or [4¢TPyP{Ru([9]aneS3)(en)}₄][CF₃SO₃]₈(3) and [bpy₄-PP{Ru([9]-

aneS3)(dmso-S)}₄][CF₃SO₃]₈(9) (en = ethane-1,2-diamine, [9]aneS3 = 1,4,7-trithiacyclononane) that

have four half-sandwich Ru(II) compounds. The Ru fragments may either contain one or more labile

ligands, such as in 2 or in 9, or be coordinatively saturated and substitutionally inert, such as in 3 or in

[bpy₄-PP{Ru([12]aneS4)}₄][CF₃SO₃]₈(11) ([12]aneS4 = 1,4,7,10-tetrathiacyclododecane). Most of the

ruthenium-porphyrin conjugates described in this work are soluble—at least moderately—in aqueous

solution and are thus suitable for biological investigations, in particular for cytotoxicity and

photo-cytotoxicity tests.

ROS) through electron—or hydrogen—transfer reactions, whereas

Introduction

the more common type II PDT is mediated by tissue oxygen: the

Natural and synthetic porphyrins and metalloporphyrins are

excited photosensitizer converts normal triplet oxygen (³O₂) into

extensively investigated—and in some cases clinically applied—as

singlet oxygen (¹O₂). The highly cytotoxic free radicals and/or

photosensitizers in the photodynamic therapy of cancer (PDT).¹

singlet oxygen, through uncontrolled reactivity, induce cell death.³

PDT is a selective non-invasive therapy used in the early diagnosis

Beside photoinduced cytotoxicity, some water-soluble porphyrins

and treatment of various neoplasms that combines the preferential

possess light-independent antiviral activity,⁴whereas others have

uptake of photosensitizers into malignant tissues and their local

shown activity in the photoinactivation of pathogenic bacteria.⁵

irradiation with visible light.²Basically, two types of processes can

occur in PDT after visible-light activation of the photosensitizer

Synthetic water-soluble porphyrins are typically obtained by

functionalization of the chromophore, mainly at the meso posi-

to its ﬁrst excited triplet state (T₁), provided that T₁is sufﬁciently

tions, with hydrophilic or easily ionized groups. The conjugation

long-lived. Type I PDT implies that the excited photosensitizer

of porphyrins to peripheral metal fragments is an intriguing

directly generates free radicals (mainly reactive oxygen species,

alternative strategy for making water-soluble compounds. Such

conjugates might have improved characteristics for biomedical

applications (not limited to PDT): (i) they might combine the

^aDepartment of Pharmaceutical Sciences, University of Trieste, 34127,

Trieste, Italy

phototoxicity of the porphyrin chromophore to the cytotoxicity

^bDepartment of Chemical Sciences, University of Trieste, 34127, Trieste,

of the metal fragment for additive antitumour effect. (ii) They

Italy. E-mail: alessi@units.it

might have increased tumour selectivity. Porphyrins typically show

† Electronic supplementary information (ESI) available: Spectral data for

selected meso-(p-nitrophenyl)porphyrins p(NO₂)_nPP (n = 1–4) and meso-

(p-aminophenyl)porphyrins p(NH₂)_nPP (n = 1–4); time-evolution of the

electronic absorption spectrum of 2; ¹H NMR spectra of 3 and 12;

preferential uptake and retention by tumour tissues (tumour-

localization properties), possibly via receptor mediated endocy-

tosis of low density lipoproteins (LDL) (cancer cells over-express

LDL receptors).⁶Thus, they might behave as carrier ligands for

the active transport of anticancer metal fragments into cancer

cells. (iii) Provided that the conjugates are sufﬁciently stable, the

ﬂuorescence emission of the chromophore might be exploited

for tracking the biodistribution of the metal in the extra- and

1

temperature dependence of the H NMR spectra of 3 and 4; details (bH

resonances) of the ¹H NMR spectra of Bpy₂-cisPP and Bpy₂-transPP; time-

evolution of the ¹H NMR spectrum of 10; schematic drawing of 4; scheme

of the preparation of 6; ﬂuorescence spectra_◦of Bpy₄-PP and 9; selected

˚

coordination bond lengths (A) and angles ( ) for 10. CCDC reference

numbers 735952 and 735953. For ESI and crystallographic data in CIF or

other electronic format see DOI: 10.1039/b911393b

10742 | Dalton Trans., 2009, 10742–10756

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The Royal Society of Chemistry 2009

©

intra-cellular environment of malignant cells through ﬂuorescence

microscopy.

ported that neutral conjugates of meso-pyridylporphyrins with

organometallic [Ru(h -arene)Cl₂] fragments, that are moderately

6

Not surprisingly, the ﬁrst porphyrin-metal conjugates developed

for biomedical applications concerned Pt(II) fragments struc-

turally similar to the classical anticancer drugs cisplatin and

carboplatin. Such compounds are expected to behave at the

same time as photodynamic and chemotherapeutic agents.^7–9In

addition, the high binding afﬁnity of Pt(II) for nucleobases might

help to localize the porphyrin close to DNA, thus enhancing the

photo-induced damage.

Since several years also ruthenium compounds have attracted

intense research interest as potential anticancer agents.¹⁰Two

Ru(III) coordination compounds, NAMI-A and KP1019 (Fig. 1),

developed by us and by the group of Keppler, respectively,^11,12have

completed phase 1 clinical trials and have started already (NAMI-

A), or are scheduled to start soon (KP1019), a phase 2 study.

cytotoxic in the dark against Me300 human melanoma cells,

become cytotoxic upon irradiation with visible light.¹⁵

In addition to potential PDT activity, in porphyrin-metal

conjugates the excitation of the chromophore with visible light

might induce photoreactivity in the peripheral metal fragment(s).

A particularly attractive target is the photochemical delivery

of NO from metal-nitrosyls that would offer a mean for

promoting NO-induced apoptosis (programmed cell-death) in

cancer cells under the control of visible light. To this regard,

Mascharak and co-workers showed that photo-induced release

of NO with visible light can be obtained by conjugation of Ru-

nitrosyls to light-harvesting chromophores,¹⁶whereas Ford and

co-workers reported that the conjugate of protoporphyrin IX

with an iron-sulfur-nitrosyl cluster is an efﬁcient photo-inducible

NO donor upon irradiation with low-energy light.¹⁷With this

purpose, we recently prepared and structurally characterized

several conjugates of meso-4¢pyridylporphyrins with ruthenium-

nitrosyl complexes, including the water soluble tetraruthenated

derivative of zinc meso-4¢-tetrapyridylporphyrin (Zn·4¢TPyP),

Na₄[Zn·4¢TPyP{RuCl₄(NO)}₄], in which each pyridyl N atom is

bound to a [RuCl₄(NO)]^-fragment.¹⁸

Beside to ruthenium compounds that have one or more

substitutionally labile ligands, i.e. that are expected to open up

coordination positions in vivo allowing direct coordination to

biological targets (functional compounds), porphyrins can also be

conjugated to peripheral ruthenium fragments that are coordina-

tively saturated and substitutionally inert (structural compounds).¹⁹

For reasons more clearly detailed in the Discussion, also such

water-soluble porphyrin conjugates are worth being investigated

in a biomedical context, in particular as telomerase inhibitors and

K⁺channel blockers.

Conjugation strategies

The coordination of a porphyrin to peripheral metal fragments

can occur either through a single bond or through multiple

bonds (i.e. through a chelating moiety). Typically, pyridyl rings

are used as peripheral ligands for the coordination of late

transition metal ions.^20–22‡ The former synthetic approach has an

indubitable advantage: the commercially available, or otherwise

easily prepared, meso-pyridylporphyrins (PyPs) can be exploited.

In PyPs, the pyridyl N atoms can be either in 3¢ (3¢PyPs) or, more

commonly, in 4¢ positions (4¢PyPs). Even though synthetically

more demanding, also PyPs in which the pyridyl rings are not

directly bound at the meso positions, but are connected thorough a

spacer, have been used occasionally.²³In the case of ruthenium, the

vast majority of the conjugates reported in the literature involve

the symmetrical coordination of four equal Ru fragments to a

meso-tetrapyridylporphyrin (TPyP).^24–26Aside from the already

mentioned compounds made by us¹⁸and by Therrien and co-

workers,¹⁵relatively few TPyP-(Ru)₄conjugates were explicitly

prepared for biomedical investigations. In such context, the

peripheral Ru fragments were typically of the type Ru(chel)₂X,

Fig. 1 Schematic structures of some of the most promising and

thoroughly investigated anticancer Ru compounds: NAMI-A (top-left),

KP1019 (top-right), RM175 (bottom-left), and RAPTA-C (bottom-right).

Both compounds are moderately cytotoxic in vitro and, in

animal models, have activities different from established Pt

drugs: NAMI-A was found to be particularly active against

the development and growth of metastases of solid tumours,¹¹

whereas KP1019 showed excellent activity against platinum-

resistant colorectal tumours.¹²

In more recent years new classes of cationic and neutral

half-sandwich Ru(II)-arene compounds, developed by the groups

of Sadler and of Dyson,^13,14were found to have promising in

vitro and in vivo anticancer activity. Representative examples of

these organometallic compounds (also called piano-stool com-

6

pounds) are [(h -biphenyl)Ru(en)Cl][PF₆] (RM175, en = ethane-

6

1,2-diamine) and [(h -p-cymene)RuCl₂(pta)] (RAPTA-C, pta =

1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane) (Fig. 1). In general,

Ru compounds have a lower toxicity compared to Pt drugs.

For the reasons mentioned above, it is therefore of great interest

to investigate the anticancer properties of porphyrin-ruthenium

conjugates. Indeed, very recently, Therrien and co-workers re-

‡ Porphyrins bearing peripheral organometallic fragments at meso or b

positions have been recently reviewed: B. M. J. M. Suijkerbuijk and

R. J. M. Klein Gebbink, Angew. Chem., Int. Ed., 2008, 47, 7396.

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Dalton Trans., 2009, 10742–10756 | 10743

©

where chel is a polypyridyl ligand.^27,28The choice of ruthenium-

polypyridyl complexes was motivated by two main reasons: (i) they

have a good afﬁnity for DNA.²⁹Thus, similarly to Pt(II) fragments,

they might behave as chaperones and help localizing the porphyrin

photosensitizer close to DNA where the photoinduced generation

of ROS would be more effective for inducing cell damage. (ii)

They are potential photosensitizers, and some of them were found

capable of DNA photooxidation and photocleavage.^27,30,31

Examples of mono- and di-pyridylporphyrins conjugated to Ru-

polypyridyl fragments were also recently reported and their DNA

binding properties and photocleavage capability described.^32–34

The residual meso-phenyl groups may be exploited for increasing

water solubility (e.g. through appropriate substituents) or for

enhancing the photophysical properties (e.g. by ﬂuorination).

Some ﬂuorinated porphyrins bearing one or two peripheral

[Ru(bpy)₂Cl]⁺fragments were also found to induce apoptosis in

melanoma skin cells upon irradiation in the visible range (PDT

activity).^32,34

Nevertheless, the single-bond conjugates might be insufﬁciently

stable towards aquation under in vivo conditions, with consequent

loss of the peripheral Ru fragments. Conjugation through multiple

bonds increases the stability of the adducts but poses the necessity

of developing affordable synthetic strategies towards porphyrins

with peripheral chelating moieties. Even though a few examples of

such Ru-porphyrin conjugates are known in the literature, we are

unaware that any of them was explicitly prepared and investigated

for biomedical purposes so far.

(dmso-S)(NO₃)][NO₃]⁴¹were prepared according to the published

procedures.

The Ru–porphyrin conjugates precipitate with variable amounts

of crystallization solvent, that depend on the batch. For this

reason elemental analysis of such conjugates did not afford reliable

and reproducible results and—aside for complex 12—the values

are not reported here (typically, some of the elemental analysis

values, especially for C, differ from calculated values by > 0.5%).

Nevertheless, the proposed formulas are all consistent with the

¹H NMR and ESI spectra, and (for conjugate 4) with X-ray

crystallographic analysis.

Synthesis of porphyrins

5-(4¢-Pyridyl)-10,15,20-tris(4¢-carboxyphenyl)porphyrin

(4¢-

MPyCbPP). As previously described by us, 4¢-MPyCbPP

was obtained by hydrolysis of the ester groups of 5-(4¢-

pyridyl)-10,15,20-tris(4¢-carboxymethylphenyl)porphyrin

(4¢-

MPyCbMePP) under basic conditions in THF–methanol

mixtures.⁴²

Meso-(p-nitrophenyl)porphyrins p(NO₂)_nPP (n = 1–3) and

meso-(p-aminophenyl)porphyrins p(NH₂)_nPP (n = 1–3). 5-(p-

nitrophenyl)-10,15,20-triphenylporphyrin (p(NO₂)PP), 5,15-bis(p-

nitrophenyl)-10,20-diphenylporphyrin (p(NO₂)₂trans-PP), 5,10-

bis(p-nitrophenyl)-15,20-diphenylporphyrin (p(NO₂)₂cis-PP), and

5,10,15-tris(p-nitrophenyl)-20-phenylporphyrin (p(NO₂)₃PP) were

prepared by regioselective nitration of the phenyl groups of

meso-tetraphenylporphyrin using NaNO₂and TFA, as re-

ported in the literature.⁴³The crude products were charac-

terized by ¹H NMR spectroscopy and then reduced to the

corresponding aminophenyl-porphyrins using standard SnCl₂–

HCl conditions.^43,44The aminophenyl-porphyrins (p(NH₂)PP,

p(NH₂)₂trans-PP, p(NH₂)₂cis-PP, and p(NH₂)₃PP) were obtained

in pure form by column chromatography on silica gel eluted

with CHCl₃–EtOH or CHCl₃–MeOH mixtures (see below). All

compounds gave ¹H NMR and UV-vis spectra (ESI)† consistent

with those reported in the literature.

Herein, we describe Ru–porphyrin conjugates whose total

charge varies from -4 to +8. Beside several conjugates with

pyridylporphyrins, we describe the preparation in acceptable yields

of a series of porphyrins that bear from 1 to 4 peripheral bipyridine

moieties (meso-(p-bpy-phenyl)porphyrins, bpy_n-PPs, n = 1–4) and

their use for the coordination of ruthenium fragments.

Experimental

Mono and bidimensional (H–H COSY, NOESY, ROESY, and

HSQC) ¹H NMR spectra were recorded at 400 or 500 MHz on a

JEOL Eclipse 400FT or on a Varian 500 spectrometer, respectively.

All spectra were run at ambient temperature, unless otherwise

stated. ¹H chemical shifts in D₂O were referenced to the internal

standard 2,2-dimethyl-2,2-silapentane-5-sulfonate (DSS) at d =

0.00. In other solvents chemical shifts were referenced to the peak

of residual non-deuterated solvent (d = 7.26 for CDCl₃, 4.33 for

CD₃NO₂, 3.31 for CD₃OD, 2.50 for DMSO-d₆, 1.73 for THF-d₈).

UV-vis spectra were obtained at T = 25 ^◦C on a Jasco V-500 UV-vis

spectrophotometer equipped with a Peltier temperature controller,

using 1.0 cm path-length quartz cuvettes (3.0 mL). Infrared spectra

were recorded on a Perkin-Elmer 983G spectrometer. Electrospray

mass spectra were recorded in the positive ion mode on a Bruker

Esquire ESI-MS instrument. Fluorescence spectra were recorded

on a F-4550 Hitachi spectroﬂuorimeter.

Meso-(p-bpy-phenyl)porphyrins (bpy_n-PPs). The meso-phe-

nylporphyrins peripherally substituted with bipyridyl groups—

meso-(p-bpy-phenyl)porphyrins (bpy_n-PP, n = 1–4)—were pre-

pared by direct coupling of the meso-(p-aminophenyl)porphyrins

with bpyAc. The reactions were carried out in pyridine using

1 equiv. of N-(3-dimethylaminopropyl)-N¢-ethylcarbodiimide hy-

drochloride (EDCI) as coupling agent and 2 equiv. of bpyAc for

each aminophenyl group. The general procedure is described in

detail only for bpy-PP.

5-[4-(4-Methyl-2,2¢-bipyridine-4¢-carboxyamidyl)phenyl]-10,15,

20-triphenylporphyrin (bpy-PP). A 81.6 mg amount of bpyAc

(0.38 mmol) and 72.9 mg of ECDI (0.38 mmol) were dissolved

in 6 mL of pyridine. The solution was stirred for 10 min, then a

120 mg amount of p(NH₂)PP (0.19 mmol) was added and stirring

was continued at r.t. The reaction was monitored by TLC (silica

gel, CHCl₃–EtOH 90 : 10). After 1 h, water (20 mL) was added

to the reaction mixture. The purple precipitate was removed by

ﬁltration, washed with water (80 mL) and vacuum dried at r.t. The

solid was puriﬁed on a plug of silica gel eluting with CHCl₃for

removal of residual p(NH₂)PP and then with CHCl₃–EtOH 85 :

Meso-tetra(p-aminophenyl)porphyrin

(p(NH₂)₄PP)

was

purchased from TCI-Europe. 4-methyl-2,2¢-bipyridine-4¢-carbo-

xylic acid (bpyAc),³⁵[nBu₄N][trans-RuCl₄(dmso-S)₂],³⁶[Ru-

([9]aneS3)(dmso)₃][CF₃SO₃]₂,³⁷[Ru([9]aneS3)(en)Cl][CF₃SO₃],³⁸

[Ru([9]aneS3)(bpy)(dmso-S)][CF₃SO₃],³⁸[Ru([9]aneS3)(bpyAc)-

(dmso-S)][CF₃SO₃]₂(10),³⁹[Ru([12]aneS4)(dmso-S)Cl][Cl],⁴⁰[Ru-

([12]aneS4)(dmso-S)(H₂O)][CF₃SO₃]₂,⁴¹and [Ru([12]aneS4)-

10744 | Dalton Trans., 2009, 10742–10756

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15 for recovering the product. Removal of solvent yielded 129 mg

(82%) of the title compound.

(14.0), 592 (9.0), 648 (7.9). ESI-MS: m/z 1248.5 [MH⁺]; 1270.5

[M + Na⁺].

d_H(CDCl₃): -2.78 (br, 2 H, NH), 2.51 (s, 3 H, CH₃), 7.24 (d, 1

H, H5¢), 7.77 (m, 9 H p + mPh), 8.03 (d, J = 4.8 Hz, 1 H, H5),

8.14 (d, 2 H, J = 8.4, mbg), 8.27 (m, 8 H, oPh + obg), 8.37 (s, 1

H, H3¢), 8.61 (d, 1 H, J = 4.9 Hz, H6¢), 8.68 (s, 1 H, H3), 8.84

(m, 6 H, bH), 8.94 (d, 2 H, bH), 8.95 (d, 1 H, J = 4.9 Hz, H6);

5,10,15,20-Tetrakis[4-(4-methyl-2,2¢-bipyridine-4¢-carboxy-

amidyl)phenyl]-porphyrin (bpy₄-PP). Same procedure as for bpy-

PP, with the following parameters: bpyAc (42.0 mg, 0.196 mmol);

EDCI (52.0 mg, 0.267 mmol); p(NH₂)₄PP (30 mg, 0.045 mmol);

pyridine (4 mL); reaction time (3 h). Yield: 60 mg (91%).

d

_H(THF-d₈): -2.79 (br, 2 H, NH), 2.32 (s, 3 H, CH₃), 7.09 (d, J =

d

_H(CDCl₃): -2.76 (br s, 2 H, NH), 2.52 (s, 12 H, CH₃), 7.26 (d,

4.2 Hz, 1 H, H5¢), 7.64 (m, 9 H p + mPh), 7.82 (d, J = 4.4 Hz, 1

H, H5), 8.09 (m, 8 H, oPh + mbg), 8.18 (d, J = 8.1 Hz, 2 H, obg),

8.33 (s, 1 H, bipy H3¢), 8.42 (d, J = 4.8 Hz, 1 H, H6¢), 8.70 (m, 8

H, bH), 8.80 (d, J = 4.2 Hz, 1 H, H6), 8.99 (s, 1 H, H3), 10.17 (s,

1 H, CONH). UV-vis l_max(CHCl₃)/nm (e ¥ 10^-3/dm³mol^-1cm^-1):

420 (470), 516 (19.7), 551 (11), 590 (8.0), 648 (6.7). ESI-MS: m/z

826.4 [MH⁺].

4 H, H5¢ overlapped with the resonance of residual CHCl₃), 8.03

(d, 4 H, J = 0.7, 4.1 Hz, H5), 8.13 (d, 8 H, J = 8.3 Hz, mbg), 8.28

(m, 8 H, J = 8.2 Hz obg), 8.38 (s, 4 H, H3¢), 8.55 (s, 4 H, H3),

8.64 (d, 4 H, J = 5.0, H6¢), 8.95 (m, 12 H, bH + H6). UV-vis l_max

(CHCl₃)/nm: 424, 518, 556, 594, 651. ESI-MS: m/z 1481.5 [M +

Na⁺].

Synthesis of complexes and porphyrin conjugates

5,10-Bis[4-(4-methyl-2,2¢-bipyridine-4¢-carboxyamidyl)phenyl]-

15,20-diphenylporphyrin (bpy₂-cisPP). Same procedure as for

bpy-PP, with the following parameters: bpyAc (53.1 mg,

0.24 mmol); EDCI (47.5 mg, 0.24 mmol); p(NH₂)₂cis-PP (40 mg,

0.062 mmol); pyridine (4 mL); reaction time (1.5 h). Yield: 42 mg

(65%).

d_H(CDCl₃): -2.77 (br, 2 H, NH), 2.50 (s, 6 H, CH₃), 7.24 (d, 2

H, H5¢), 7.76 (m, 6 H, m + pPh), 8.02 (d, 2 H, J = 5.1 Hz, H5),

8.12 (d, 4 H, J = 8.4 Hz, mbg), 8.21–8.27 (m, 8 H obg + oPh),

8.36 (s, 2 H, H3¢), 8.62 (d, 2 H, J = 4.9 Hz, H6¢), 8.75 (s, 2 H,

H3), 8.84–8.93 (m, 10 H, bH + H6). UV-vis l_max(CHCl₃)/nm (e ¥

10^-3/dm³mol^-1cm^-1): 421 (409), 517 (21.1), 553 (12.5), 591 (8.4),

647 (7.4).

[Na]₄[4¢TPyP{trans-RuCl₄(dmso-S)}₄] (2). A 119 mg amount

of sodium tetraphenylborate (0.34 mmol) dissolved in 2 mL of

nitromethane was added to a solution of 1 (50 mg, 0.017 mmol) in

1 mL of nitromethane. The precipitate that formed immediately

was collected by ﬁltration, washed with acetone and diethyl ether

and dried under vacuum at r.t. Yield: 34.6 mg (97%).

Selected d_H(D₂O): -13.0 (v br, dmso-S). UV-vis l_max(H₂O)/nm

(relative intensity): 414 (100), 515 (5.6), 550 (1.7), 580 (2.0), 634

(0.5).

[4¢TPyP{Ru([9]aneS3)(en)}₄][CF₃SO₃]₈(3).

A

46.5 mg

amount of [Ru([9]aneS3)(en)Cl](CF₃SO₃) (0.14 mmol) dissolved

in 2 mL of MeOH was added to a suspension of 4¢TPyP (20 mg,

0.032 mmol) in 15 mL of CHCl₃. After addition of AgCF₃SO₃

(35.7 mg, 0.14 mmol), the reaction mixture was heated to reﬂux

for 4 h. The reaction was monitored by TLC analysis (silica gel,

CH₂Cl₂–EtOH 90 : 10). The dark solution was concentrated in

vacuo to ca. 10 mL and a few drops of diethyl ether were added.

A purple solid formed upon standing, which was removed by

ﬁltration and vacuum dried. The solid was redissolved in 10 mL

of MeOH and centrifuged to eliminate AgCl. The solution was

evaporated to dryness under reduced pressure to obtain the title

compound. Yield 59 mg (92%).

5,15-Bis[4-(4-methyl-2,2¢-bipyridine-4¢-carboxyamidyl)phenyl]-

10,20-diphenylporphyrin (bpy₂-transPP). Same procedure as for

bpy-PP, with the following parameters: bpyAc (13.7 mg,

0.064 mmol); EDCI (12.2 mg, 0.064 mmol); p(NH₂)₂trans-PP

(10 mg, 0.016 mmol); pyridine (2 mL); reaction time (1.5 h).

After addition of water (10 mL), the product was extracted with

chloroform (4 ¥ 20 mL). The organic layer was then evaporated

to dryness and the purple residue (11 mg) puriﬁed on a column of

silica gel eluted ﬁrst with CHCl₃followed by CHCl₃–MeOH 95 :

5. Yield: 3 mg (18%).

d_H(D₂O): 2.6–3.1 (m, 64 H, CH₂[9]aneS3 + en), 4.17 (m, 8 H,

NH₂), 5.09 (m, 8 H, NH₂), 8.52 (d, 8 H, J = 5.67, H3,5), 9.11 (v

br s, 8 H, bH), 9.36 (d, 8 H, J = 5.71, H2,6). d_H(CD₃OD, 25 ^◦C):

2.5–3.1 (m, 64 H, [9]aneS3 + en), 4.38 (br m, 8 H, NH₂), 5.32 (m,

8 H, NH₂), 8.42 (d, 8 H, J = 6.48, H3,5), 9.04 (v br, 8 H, bH), 9.33

(d, 8 H, J = 6.34, H2,6). d_H(CD₃OD, -15 ^◦C): 2.5–3.1 (m, 64 H,

[9]aneS3 + en), 4.46 (m, 8 H, NH₂), 5.43 (m, 8 H, NH₂), 8.42 (d, 8

H, J = 6.21, H3,5), 8.97 (s, 4 H, bH), 9.30 (s, 4 H, bH), 9.34 (d, 8

H, J = 6.18, H2,6). UV-vis l_max(CH₃OH)/nm (relative intensity

(%)): 419 (100), 513 (7.7), 549 (4.0), 589 (2.8), 646 (1.8).

d_H(CDCl₃): -2.77 (br s, 2 H, NH), 2.50 (s, 3 H CH₃), 7.24 (d,

2 H, H5¢), 7.76 (m, 6 H p + mPh), 8.01 (d, J = 4.8 Hz, 2 H, H5),

8.12 (d, J = 8.4 Hz, 4 H, mbg), 8.20–8.27 (m, 8 H, obg + oPh),

8.36 (s, 2 H, H3¢), 8.60 (d, 2 H, J = 4.9 Hz, H6¢), 8.81 (s, 2 H, H3),

8.86–8.94 (m, 10 H, bH + H6).

5,10,15-Tris[4-(4-methyl-2,2¢-bipyridine-4¢-carboxyamidyl)phe-

nyl]-20-phenylporphyrin (bpy₃-PP). Same procedure as for bpy-

PP, with the following parameters: bpyAc (88.2 mg, 0.46 mmol);

EDCI (87.4 mg, 0.46 mmol); p(NH₂)₃PP (50 mg, 0.077 mmol);

pyridine (7 mL); reaction time (1.5 h). After addition of water

(10 mL), the product was extracted with chloroform (4 ¥ 20 mL).

Yield: 69 mg (73%).

d_H(CDCl₃): -2.77 (br s, 2 H, NH), 2.50 (s, 9 H, CH₃), 7.24 (d,

3 H, H5¢), 7.76 (m, 3 H, m + pPh), 8.01 (d, 3 H, J = 4.6 Hz, H5),

8.12 (d, 6 H, J = 8.3 Hz, mbg), 8.23 (m, 8 H, obg + oPh), 8.35

(s, 3 H, H3¢), 8.60 (d, 3 H, J = 5.0, H6¢), 8.75 (s, 3 H, H3), 8.86

(d, 3 H, H6), 8.90 (m, 2 H, bH), 8.93 (m, 6 H, bH). UV-vis l_max

(CHCl₃)/nm (e ¥ 10^-3/dm³mol^-1cm^-1): 423 (450), 518 (21.0), 554

[4¢TPyP{Ru([9]aneS3)(bpy)}₄][CF₃SO₃]₈(4).

A

90.0 mg

amount of [Ru([9]aneS3)(bpy)(dmso-S)][CF₃SO₃]₂(0.11 mmol)

dissolved in 2 mL of methanol was added to a suspension of

4¢TPyP (15.5 mg, 0.025 mmol) in 15 mL of CHCl₃. The mixture

was heated to reﬂux for 8 h, until disappearance of the spot of

unreacted porphyrin according to TLC analysis (silica gel, CHCl₃–

EtOH 90 : 10). Dropwise addition of diethyl ether to the solution

induced the precipitation of a purple solid, that was removed by

ﬁltration and washed with diethyl ether and dried under vacuum

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©

at r.t. The solid, that according to ¹H NMR spectroscopic analysis

contained unreacted Ru complex, was recrystallized twice from

nitromethane/diethyl ether. Yield: 64 mg (71%).

(368), 516 (19), 552 (13), 591 (97), 647 (92). ESI-MS: m/z 1256.1

[{Bpy-PP}{Ru([9]aneS3)(CF₃SO₃)}]⁺.

d_H(CD₃NO₂, see ESI† for labelling scheme): -3.35 (s, 2 H, NH),

3.5–2.7 (m, 48 H, CH₂[9]aneS3), 7.92 (t, 8 H, H5,5¢), 8.13 (d, 8

H, H3,5), 8.33 (t, 2 H, H4,4¢), 8.63 (m, 16 H, bH + H2,6), 9.22

(d, 2 H, H3,3¢), 9.48 (d, 2 H, H6,6¢). UV-vis l_max(CH₃NO₂)/nm

(relative intensity (%)): 425 (100), 518 (8.8), 553 (5.4), 590 (4.2),

646 (2.8).

[Bpy₂-cisPP{Ru([9]aneS3)(dmso-S)}₂][CF₃SO₃]₄

(7). A

17.6 mg amount of Bpy₂-cisPP (0.017 mmol) dissolved in 2 ml of

CHCl₃was added to a solution of [Ru([9]aneS3)(dmso)₃][CF₃SO₃]₂

(30.0 mg, 0.036 mmol) dissolved in 5 ml of acetone. The resulting

solution was heated to reﬂux for 5 h, during which time a purple

sticky precipitate formed. After decanting the solution, the solid

was washed with diethyl ether and dried under vacuum. A second

fraction of solid product (that was treated as above) was obtained

upon dropwise addition of diethyl ether to the mother liquor.

Total yield: 22 mg (55%).

[nBu₄N][trans-RuCl₄(dmso-S)(4¢-MPyCbPP)].

A

129 mg

amount of [nBu₄N][trans-RuCl₄(dmso-S)₂] (0.20 mmol) was

added to a solution of 4¢-MPyCbPP (50 mg, 0.067 mmol) in

THF (10 mL) containing 200 mL of DMSO. After 24 h at

ambient temperature, dropwise addition of diethyl ether afforded

a purple precipitate that was removed by ﬁltration, washed with

chloroform and diethyl ether and dried under vacuum at room

temperature. Yield: 74 mg (83%).

d_H(CD₃NO₂): -2.83 (br s, 2H, NH), 2.74 (s, 6H, CH₃), 2.80 (s,

6H, dmso-S), 2.89 (s, 6H, CH₃dmso-S), 2.6–3.45 (m, 24H, CH₂

[9]aneS3), 7.74 (d, 2H, J = 4.8 Hz, H5¢), 7.87 (m, 6H, m+pPh),

8.37 (m, 14H, mbg + obg + oPh + H5), 8.76 (s, 2H, H3¢), 8.98 (m,

10H, bH + H6¢), 9.16 (s, 2H, H3), 9.31 (d, 2H, J = 5.8 Hz, H6),

10.04 (s, 2H, CONH). d_H(acetone-d₆): -2.70 (br, 2H, NH), 2.74 (s,

6H, CH₃), 2.90 (s, 6H, dmso-S), 3.03 (s, 6H, dmso-S), 2.74–3.55

(m, 24H, CH₂[9]aneS3), 7.86 (m, 8H, p+mPh + H5¢), 8.37 (m,

12H, mbg + obg + oPh), 8.39 (d, J = 5.9 Hz, 2H, H5), 8.91 (m,

8H, bH), 9.02 (s, 2H, H3¢), 9.18 (d, J = 5.9 Hz, 2H, H6¢), 9.30

(s, 2H, H3), 9.46 (d, J = 5.6 Hz, 2H, H6), 10.73 (s, 2H, CONH).

UV-Vis l_max(acetone)/nm (e¥10^-3/dm³mol^-1cm^-1): 419 (184),

514 (19.9), 549 (13.9), 591 (9.2), 647 (8.8). ESI-MS: m/z 947.4

[{bpy₂-cisPP}{Ru([9]aneS3)(CF₃SO₃)}₂]²⁺.

Selected d_H(CD₃OD): -13.0 (v br, dmso-S), -1.1 and 5,7 (br,

H2,6 and H3,5), 7.8 and 8.2 (m, oH + mH + bH), 8.5 (br, bH).

UV-vis l_max(CH₂Cl₂)/nm (e ¥ 10^-3/dm³mol^-1cm^-1): 416 (513),

513 (25), 547 (12) 589 (7.7), 644 (5.3). Selected IR (KBr) n_max/cm^-1

=

3315 (m, NH), 1119 (s, S O).

Na[trans-RuCl₄(dmso-S)(4¢-MPyCbPP)] (5).

A

50.0 mg

amount of Na[B(C₆H₅)₄] (0.15 mmol) was added to a solution of

[nBu₄N][trans-RuCl₄(dmso-S)(MPyCbPP)] (50.0 mg, 0.037 mmol)

in acetone (20 mL) containing 50 mL of DMSO. Dropwise addition

of diethyl ether (10 mL) induced the precipitation of a purple

solid, that was removed by ﬁltration, washed with nitromethane

and diethyl ether and dried under vacuum at room temperature.

Yield: 39.5 mg (95%).

d_H(DMSO-d₆): -12.7 (v br, dmso-S), -4.0 (br, NH), -0.8 and

5.8 (br, H2,6 and H3,5), 8.13 and 8.55 (m, oH + mH + bH), 13.2

(s, COOH). UV-vis l_max(acetone)/nm (e ¥ 10^-3/dm³mol^-1cm^-1):

416 (273), 513 (15), 547 (7), 589 (5), 645 (4).

[Bpy₃-PP{Ru([9]aneS3)(dmso-S)}₃][CF₃SO₃]₆(8). A 20.0 mg

amount of bpy₃-PP (0.016 mmol) dissolved in 2.5 mL of CHCl₃

was added to a solution of [Ru([9]aneS3)(dmso)₃][CF₃SO₃]₂

(43.0 mg, 0.053 mmol) dissolved in 7 mL of acetone. The resulting

solution was heated to reﬂux for 24 h, during which time a purple

sticky precipitate formed. After decanting the solution, it was

washed with diethyl ether and dried under vacuum. Yield: 30 mg

(58%).

[Bpy-PP{Ru([9]aneS3)(dmso-S)}][CF₃SO₃]₂(6). A 33.5 mg

amount of Bpy-PP (0.041 mmol) and 30 mg of [Ru([9]aneS3)-

(dmso)₃][CF₃SO₃]₂(0.036 mmol) were added to a CHCl₃–CH₃NO₂

(1 : 3) mixture (12 mL). The solution was stirred at r.t. and

monitored by TLC (alumina plates, CHCl₃–MeOH 90 : 10). After

24 h it was evaporated to dryness under vacuum, and the solid

residue redissolved in CHCl₃(5 mL). Dropwise addition of diethyl

ether to the purple-brown solution induced the precipitation of a

purple solid, that was removed by ﬁltration and washed repeatedly

with diethyl ether and dried under vacuum at r.t. Yield: 40 mg

(72%).

d_H(CD₃NO₂): -2.81 (br, 2 H, NH), 2.74 (s, 3 H, CH₃), 2.81 (s,

3 H, CH₃dmso-S), 2.88 (s, 3 H, CH₃dmso-S), 2.53–3.41 (m, 12

H, CH₂[9]aneS3), 7.77 (d, 1 H, J = 5.6 Hz, H5¢), 7.87 (br m, 9

H m + pPh), 8.30 (br m, 11 H, oPh + mbg + obg + H5), 8.74 (s,

1 H, H3¢), 8.97 (9 H, bH + H6¢), 9.12 (s, 1 H, H3), 9.33 (d, J =

5.3 Hz, 1 H, H6), 9.75 (s, 1 H, CONH). d_H(CD₂Cl₂): -2.86 (br,

2 H, NH), 2.63 (s, 3 H, CH₃), 2.67 (s, 3 H, CH₃dmso-S), 2.85 (s,

3 H, CH₃dmso-S), 2.26–3.36 (m, 12 H, CH₂[9]aneS3), 7.56 (d,

1 H, J = 5.3 Hz, H5¢), 7.76 (br m, 9 H m + pPh), 8.24 (br m, 11

H, oPh + mbg + obg + H5), 8.53 (s, 1 H, H3¢), 8.70 (d, 1 H, J =

5.2 Hz, H6¢), 8.85–8.92 (m, 10 H, bH + H3 + H6), 10.61 (s, 1 H,

CONH). UV-vis l_max(CHCl₃)/nm (e ¥ 10^-3/dm³mol^-1cm^-1): 420

d_H(CD₃NO₂): -2.77 (br s, 2 H, NH), 2.75 (s, 9 H CH₃), 2.81

(s, 9 H, dmso-S), 2.89 (s, 9 H, dmso-S), 2.65–3.47 (m, 24 H, CH₂

[9]aneS3), 7.78 (d, 3 H, J = 5.6 Hz, H5¢), 7.89 (m, 3 H, m + pPh),

8.38 (m, 17 H, oPh + H5 + mbg + obg), 8.76 (s, 3 H, H3¢), 8.99

(d, 3 H, J = 5.7 Hz, H6), 9.07 (m, 8 H, bH), 9.15 (s, 3 H, H3),

9.34 (d, 3 H, J = 5.8 Hz, H6), 9.92 (s, 2 H, CONH), 9.99 (s, 1 H,

CONH). UV-vis l_max(CH₃NO₂)/nm (e ¥ 10^-3/dm³mol^-1cm^-1):

421 (386), 517 (24), 553 (19), 591 (12), 647 (12). ESI-MS: m/z

846.8 [{bpy₃-PP}{Ru([9]aneS3)(CF₃SO₃)}₃]³⁺.

Bpy₄-PP{Ru([9]aneS3)(dmso-S)}₄][CF₃SO₃]₈(9). A 20.0 mg

amount of bpy₄-PP (0.014 mmol) dissolved in 10 mL of CHCl₃was

added to a solution of [Ru([9]aneS3)(dmso)₃][CF₃SO₃]₂(47.5 mg,

0.058 mmol) dissolved in 45 mL of acetone. The resulting solution

was heated to reﬂux for 2 h, during which time a purple precipitate

formed. The solution was concentrated under vacuum to ca.

15 mL. The solid was removed by ﬁltration, washed with diethyl

ether and dried under vacuum. Yield: 46 mg (81%).

d_H(CD₃NO₂): -2.72 (br s, 2 H, NH), 2.75 (s, 12 H, CH₃), 2.81

(s, 12 H, dmso-S), 2.89 (s, 12 H, dmso-S), 2.65–3.50 (m, 12 H, CH₂

[9]aneS3), 7.76 (d, 4 H, J = 5.4 Hz, H5¢), 8.35 (m, 20 H, H5 +

mbg + obg), 8.75 (s, 4 H, H3¢), 8.98 (d, 4 H, J = 5.8 Hz, H6¢), 9.08

(m, 8 H, bH), 9.13 (s, 4 H, H3), 9.33 (d, 4 H, J = 5.6 Hz, H6), 9.92

10746 | Dalton Trans., 2009, 10742–10756

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(br s, 4 H, CONH). UV-vis l_max(DMSO)/nm (relative intensity

(%)): 424 (100), 519 (5.9), 557 (4.8), 593 (2.1), 651 (2.6).

d_H(CD₃NO₂): -2.72 (br s, 2 H, NH), 2.72 (s, 12 H CH₃), 2.80–

3.90 (m, CH₂[12]aneS4), 7.64 (d, 4 H, J = 5.2 Hz, H5¢), 8.40 (m,

20 H, H5 + mbg + obg), 8.87 (s, 4 H, H3¢), 9.09 (br, 8 H, bH), 9.30

(br m, 4 H, H6¢), 9.43 (s, 4 H, H3), 9.69 (br m, 4 H, H6), 10.92

(br s, 4 H, CONH). d_H(CD₃NO₂, T = -15 ^◦C): -2.81 (br s, 2 H,

NH), 2.68 (s, 12 H CH₃), 2.80–3.90 (m, CH₂[12]aneS4), 7.61 (d, 4

H, J = 4.6 Hz, H5¢), 8.41 (m, 20 H, H5 + mbg + obg), 8.85 (s, 4 H,

H3¢), 9.10 (br, 8 H, bH), 9.37 (d, 4 H, H6¢), 9.44 (s, 4 H, H3), 9.75

(d, 4 H, H6), 11.13 (br s, 4 H, CONH). UV-vis l_max(CH₃NO₂)/nm

(relative intensity (%)): 423 (100), 517 (5.8), 554 (4.9), 592 (2.6),

649 (2.6).

[Bpy₄-PP{Ru([12]aneS4)}₄][CF₃SO₃]₈(11). To a 15.0 mg

amount of bpy₄-PP (0.010 mmol) dissolved in 8 mL of CHCl₃

a solution of [Ru([12]aneS4)(dmso-S)(H₂O)][CF₃SO₃]₂(32.2 mg,

0.044 mmol) dissolved in 35 mL of methanol was added. The

resulting solution was heated to reﬂux for 36 h (the reaction

was monitored by TLC, silica plates, CHCl₃–EtOH 9 : 1), during

which time a ﬁne purple precipitate formed. The suspension was

concentrated under vacuum to ca. 15 mL and diethyl ether (ca.

3 mL) was added dropwise to increase the amount of precipitate.

The solid was removed by ﬁltration, washed with diethyl ether and

dried under vacuum. Yield: 19 mg (67%).

[Bpy₄-PP{Ru([12]aneS4)}₄][Cl]₈(14). To a 20.0 mg amount of

bpy₄-PP (0.014 mmol) dissolved in 10 mL of CHCl₃a solution of

[Ru([12]aneS4)(dmso-S)Cl][Cl] (28.6 mg, 0.058 mmol) dissolved

in 45 mL of methanol was added. The resulting solution was

heated to reﬂux for 15 h (the reaction was monitored by TLC,

silica plates, CHCl₃–EtOH 9 : 1), during which time a ﬁne purple

precipitate formed. The solid was removed by ﬁltration and

washed with diethyl ether and dried under vacuum. The mother

liquor was concentrated under vacuum to ca. 15 mL. Dropwise

addition of diethyl ether (ca. 10 mL) induced the formation of a

second batch of precipitate, that was treated as above. Total yield:

30 mg (70%).

d

_H(CD₃NO₂): -2.72 (br s, 2 H, NH), 2.73 (s, 12 H, CH₃), 2.80–

4.00 (m, 16 H, CH₂[12]aneS4), 7.66 (d, 4 H, J = 5.4 Hz, H5¢),

8.36 (m, 20 H, H5 + mbg + obg), 8.77 (s, 4 H, H3¢), 9.00–9.20 (m,

12 H, bH + H3), 9.35 (br m, 4 H, H6¢), 9.74 (br m, 8 H, CONH +

H6). d_H(acetone-d₆): -2.65 (br s, 2 H, NH), 2.71 (s, 12 H CH₃),

2.80–4.00 (m, 16 H, CH₂[12]aneS4), 7.72 (d, 4 H, J = 6.1 Hz,

H5¢), 8.37 (m, 20 H, H5 + mbg + obg), 9.00 (m, 12 H, H3¢ + bH),

9.35 (s, 4 H, H3), 9.47 (br m, 4 H, H6¢) 9.83 (br m, 4 H, H6),

10.67 (s, 4 H, CONH). d_H(acetone-d₆, T = -60 ^◦C): -2.65 (br s, 2

H, NH), 2.69 (s, 12 H CH₃), 2.80–4.00 (m, 16 H, CH₂[12]aneS4),

7.77 (d, 4 H, J = 5.9 Hz, H5¢), 8.40 (m, 20 H, J = 5.8 Hz, H5 +

mbg + obg), 8.90 (s, 4 H, bH), 9.06 (s, 4 H, H3¢), 9.19 (s, 4 H, bH),

9.41 (s, 4 H, H3¢), 9.53 (d, 4 H, J = 6.0 Hz H6¢), 9.90 (d, 4 H, J =

5.9 Hz, H6), 10.91 (s, 4 H, CONH). UV-vis l_max(CH₃NO₂)/nm

(relative intensity (%)): 423 (100), 518 (5.8), 556 (4.3), 593 (2.1),

649 (2.5).

d_H(DMSO-d₆): -2.83 (br s, 2 H, NH), 2.67 (s, 12 H CH₃),

2.70–4.10 (m, CH₂[12]aneS4), 7.39 (m, 4 H, H5¢), 8.09 (m, 4 H,

H5), 8.32 (m, 20 H, H3¢ + mbg + obg), 8.67 (m, 4 H, H6¢), 8.98

(m, 16 H, bH + H6¢ + H3), 11.14 (br s, 4 H, CONH). UV-vis

l

_max(DMSO)/nm (relative intensity (%)): 426 (100), 519 (4.5), 557

(3.7), 594 (1.7), 651 (1.9).

[Ru([12]aneS4)(bpyAc)][CF₃SO₃]₂(12). A 30 mg amount of

[Ru([12]aneS4)(dmso-S)(H₂O)][CF₃SO₃]₂(0.041 mmol) was par-

tially dissolved in acetone (15 mL) and heated to reﬂux. Upon

complete dissolution of the complex, a 8.73 mg amount of bpyAc

(0.041 mmol) was added and the solution was reﬂuxed for 2 h and

then concentrated under vacuum to ca. 5 mL. Dropwise addition

of diethyl ether (ca. 3 mL) induced the formation of a precipitate,

that was removed by ﬁltration, washed with diethyl ether and dried

under vacuum. Yield: 8.2 mg (62%). Found: C 30.6, H 3.66, N 2.95.

C₂₂H₂₆N₂F₆O₈RuS₆·(CH₃)₂SO (932.00) requires: C 30.9, H 3.46, N

3.00%.

d_H(D₂O): 2.43 (s, 3 H, CH₃), 2.50–3.90 (m, 16 H, CH₂

[12]aneS4), 7.38 (d, 1 H, H5¢), 7.79 (d, 1 H, H5), 8.28 (s, 1

H, H3¢), 8.61 (s, 1 H, H3), 9.05 (br m, H6¢), 9.34 (br m, 1 H,

H6). d_H(acetone-d₆): 2.68 (s, 3 H, CH₃), 2.50–4.30 (m, 16 H,

CH₂[12]aneS4), 7.71 (d, 1 H, H5¢), 8.15 (d, 1 H, H5), 8.96 (s,

1 H, H3¢), 9.10 (s, 1 H, H3), 9.43 (br m, 1 H, H6¢), 9.81 (br m,

1 H, H6).

Crystallographic data

Crystals of 4 and 10 suitable for X-ray diffraction were obtained

by layering diethyl ether on top of nitromethane solutions of the

products.

Data collection for 4 was performed at the X-ray synchrotron

Elettra diffraction beamline, Trieste (Italy), using a monochro-

˚

matized wavelength of 1.00 A at 100 K, whereas that for 10 was

carried out on a Nonius DIP-1030H system (MoKa radiation, l =

˚

0.71073 A, graphite monochromatized, room temperature). Cell

reﬁnement, indexing and scaling of the data sets were performed

using programs Denzo and Scalepack.⁴⁵Both structures were

solved by direct methods and subsequent Fourier analyses,⁴⁶and

reﬁned by the full-matrix least-squares method based on F²with

all observed reﬂections.⁴⁶In 4 some restraints on bond distances

were applied to the disordered eight CF₃SO₃^-anions, which affect

the crystal quality. Moreover, 13.5% of the unit cell is solvent

accessible void and the DFourier map revealed the presence of two

nitromethane molecules in the asymmetric unit. The contribution

of hydrogen atoms at calculated positions were included in ﬁnal

cycles of reﬁnement. All the calculations were performed using the

WinGX System, Ver 1.80.05.⁴⁷

[Bpy₄-PP{Ru([12]aneS4)}₄][NO₃]₈(13). To a 20.0 mg amount

of bpy₄-PP (0.014 mmol) dissolved in 10 mL of CHCl₃a solution

of [Ru([12]aneS4)(dmso-S)(NO₃)][NO₃] (31.7 mg, 0.058 mmol)

dissolved in 45 mL of methanol was added. The resulting solution

was heated to reﬂux for 8 h (the reaction was monitored by TLC,

silica plates, CHCl₃–EtOH 9 : 1). The solution was concentrated

under vacuum to ca. 15 mL. Dropwise addition of diethyl ether (ca.

2 mL) induced the formation of a precipitate, that was removed

by ﬁltration, washed with diethyl ether and dried under vacuum.

Yield: 32 mg (69%).

Crystal data and details of data collections and reﬁnements

for the structures are summarized in Table 1. A selection of

coordination bond lengths (A) and angles ( ) for 4 is reported

◦

˚

in Table 2.

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Dalton Trans., 2009, 10742–10756 | 10747

©

Table 1 Crystallographic data and details of structure reﬁnements for

compounds 4 and 10

porphyrin bears four NAMI-type fragments (with a meso pyridyl

group instead of imidazole as axial N-donor ligand trans to dmso-

S, Fig. 1) and is therefore of interest for its potential antimetastatic

properties.¹¹However compound 1, being totally insoluble in

aqueous solution, is as such unsuited for biological tests. We

found that the corresponding sodium salt, [Na]₄[4¢TPyP{trans-

RuCl₄(dmso-S)}₄] (2, Fig. 2) can be obtained in almost quan-

titative yield by treatment of 1 with excess Na[B(C₆H₅)₄] in

nitromethane solution.

4·4(CH₃NO₂)

10

Empirical formula

Formula weight

Crystal system

Space group

C₁₁₆H₁₁₈F₂₄N₂₀O₃₂Ru₄S₂₀C₂₂H₂₈F₆N₂O₉RuS₆

3805.78

Monoclinic

P2₁/c

871.89

Monoclinic

P2₁/c

˚

a/A

23.157(5)

16.581(4)

20.833(5)

97.01(3)

7939(3)

2

10.026(3)

23.075(4)

14.057(3)

96.40(2)

3231.8(13)

4

˚

b/A

˚

c/A

b/^◦

V/A

3

˚

Z

D

_calcd/g cm^-3

1.592

1.792

m/mm^-1

0.890

3844

0.958

1760

F(000)

◦

q_max

/

25.52

49 860

4833

28.28

35 958

7081

Reﬂections collected

Unique reﬂections

R_int

Observed I > 2s(I)

Parameters

0.0404

3965

733

0.0532

4120

418

GOF

1.117

0.870

R1 (I > 2 s(I))^a

0.0844

0.2515

1.161^b–0.831

0.0427

0.1043

0.420–0.425

a

wR₂

-3

˚

Dr/e A

ꢀ

1

2

2 2

^aR₁

=

ꢀF_o| - |F_cꢀ/ |F_o|, wR₂= [ w(F_o- F_c²)²/ w(F_o) ] .

^bResidual peak close to a triﬂate anion.

◦

˚

Table 2 Selected coordination bond lengths (A) and angles ( ) for

compound 4

˚

Bond lengths/A

Ru(1)–N(1)

Ru(1)–N(2)

Ru(1)–N(5)

Ru(1)–S(1)

Ru(1)–S(2)

Ru(1)–S(3)

2.175(12)

2.165(12)

2.194(11)

2.376(4)

2.378(5)

2.376(4)

Ru(2)–N(3)

Ru(2)–N(4)

Ru(2)–N(6)

Ru(2)–S(4)

Ru(2)–S(5)

Ru(2)–S(6)

2.152(12)

2.163(12)

2.212(12)

2.381(5)

2.361(4)

2.365(5)

Fig. 2 Schematic structure of [Na]₄[4¢TPyP{trans-RuCl₄(dmso-S)}₄] (2).

Compound 2 is well soluble in aqueous solution, where it

shows the typical broad NMR resonance for dmso-S bound to

a Ru(III) paramagnetic center at ca. d = -13.^11,48Similar to the

corresponding model complex Na[trans-RuCl₄(dmso-S)(py)] (and

to NAMI-A), the stability of compound 2 in aqueous solution—as

evaluated from the changes of its electronic absorption spectrum

in the visible range—depends strongly on pH. The compound

is essentially stable at mildly acidic pH (25.0 ^◦C), whereas a ca.

four-fold decrease of intensity of the Soret band, accompanied

by remarkable broadening, was observed within 3 h at pH 7.4

(ESI).† At this pH stepwise dissociation of chlorides from the

Ru(III) fragments is expected to occur.¹¹Since it is unlikely

that chloride dissociation from the peripheral Ru centers affects

signiﬁcantly the electronic absorption spectrum of the porphyrin,

the observed spectral changes were attributed to aggregation as a

consequence of the progressive decrease of the negative charge of

2. The general increase of the background absorption in the whole

visible range registered for longer observation times suggests that,

as found for the NAMI-type Ru(III) complexes,¹¹formation of

polynuclear aggregates with m-oxo or m-hydroxo bridges between

Ru(III) centers occurs.

Bond angles/^◦

N(1)–Ru(1)–N(2)

N(1)–Ru(1)–N(5)

N(1)–Ru(1)–S(1)

N(1)–Ru(1)–S(2)

N(1)–Ru(1)–S(3)

N(2)–Ru(1)–N(5)

N(2)–Ru(1)–S(1)

N(2)–Ru(1)–S(2)

N(2)–Ru(1)–S(3)

N(5)–Ru(1)–S(1)

N(5)–Ru(1)–S(2)

N(5)–Ru(1)–S(3)

S(1)–Ru(1)–S(2)

S(1)–Ru(1)–S(3)

S(2)–Ru(1)–S(3)

76.6(5)

87.4(4)

175.6(4)

96.6(4)

92.7(3)

84.5(4)

99.1(4)

172.2(4)

95.3(3)

91.6(3)

91.4(3)

N(3)–Ru(2)–N(4)

N(3)–Ru(2)–N(6)

N(3)–Ru(2)–S(4)

N(3)–Ru(2)–S(5)

N(3)–Ru(2)–S(6)

N(4)–Ru(2)–N(6)

N(4)–Ru(2)–S(4)

N(4)–Ru(2)–S(5)

N(4)–Ru(2)–S(6)

N(6)–Ru(2)–S(4)

N(6)–Ru(2)–S(5)

N(6)–Ru(2)–S(6)

S(4)–Ru(2)–S(5)

S(4)–Ru(2)–S(6)

S(5)–Ru(2)–S(6)

78.4(5)

88.2(4)

96.8(4)

175.7(4)

91.7(3)

87.0(5)

174.9(4)

97.4(4)

94.0(4)

91.1(3)

91.0(3)

179.8(4)

87.70(16)

88.32(15)

88.83(16)

179.0(4)

87.43(16)

87.91(17)

89.12(16)

Results

Conjugates through single-bond coordination

We also performed the coordination of 4¢TPyP to half-sandwich

Ru(II) fragments. We have recently investigated the cytotoxicity of

Ru(II)-[9]aneS3 complexes ([9]aneS3 = 1,4,7-trithiacyclononane)

of the type [Ru([9]aneS3)(N-N)Cl][CF₃SO₃], [Ru([9]aneS3)(N-

N)(dmso-S)][CF₃SO₃]₂(N-N = nitrogen chelating ligand such

Conjugates with meso 4¢-tetrapyridylporphyrin (4¢-TPyP). We

reported that treatment of 4¢TPyP with the Ru(III) precursor

[n-Bu₄N][trans-RuCl₄(dmso-S)₂] affords the tetra-anionic Ru(III)-

conjugate [n-Bu₄N]₄[4¢TPyP{trans-RuCl₄(dmso-S)}₄] (1).⁴⁸This

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as ethane-1,2-diamine (en), bpy, or substituted bpy), and

˚

14.213(3) A (Ru1 ◊ ◊ ◊ Ru2¢). The Ru centers have a distorted octahe-

2

[Ru([9]aneS3)(h -dicarb)(dmso-S)] (dicarb = oxalate, malonate,

dral coordination sphere, with Ru–S and Ru–N(bpy) coordination

distances that average to 2.17(1) A and 2.373(5) A, respectively,

(i.e. they are longer by ca. 0.05 and 0.03 A, respectively, than those

methylmalonate).^39,49These complexes are structurally similar to

antitumour active organometallic half-sandwich compounds,¹³

with the face-capping sulfur macrocycle replacing the aromatic

fragment.

˚

found in the Ru(II) precursor).³⁸The two independent meso pyridyl

rings N5 and N6 form a dihedral angle with the porphyrin mean

plane of ca. 68^◦and deviate slightly from a linear coordination,

with Ru–N(py) ◊ ◊ ◊ C(meso) angles signiﬁcantly narrower than 180^◦

(168.3 and 172.9^◦, respectively). As a consequence, the bpy ligands

are considerably canted towards the adjacent meso pyridyl rings

(dihedral angles between the mean planes of 62.4(4) and 72.8(4)^◦,

Fig. 4). A pyridine ring of each bpy is located approximately in the

We report now that treatment of 4¢TPyP with a slight excess

of [Ru([9]aneS3)(en)Cl][CF₃SO₃] (in the presence of Ag(CF₃SO₃)

for removing the chlorido ligand) affords the octacationic conju-

gate [4¢TPyP{Ru([9]aneS3)(en)}₄][CF₃SO₃]₈(3) in excellent yield.

Compound 3, beside being soluble in organic solvents such as

methanol and nitromethane, is also well soluble in aqueous

1

solution. Overall, the H NMR spectrum of 3 is consistent with

˚

porphyrin plane (Fig. 4), at a distance of ca. 4.45 A from a pyrrole

the symmetry of the compound: all peripheral Ru fragments are

equivalent. All proton resonances are sharp at 20 ^◦C, with the

exception of the bH signal that is remarkably broad (see below).

The four equivalent pyridyl rings give two well resolved doublets in

the aromatic region of the spectrum. The upﬁeld region is similar

to that of the precursor Ru complex: in D₂O the two pairs of

diastereotopic protons on the equivalent NH₂groups give two

well resolved resonances at d = 4.17 and 5.09 (coupled in the H–H

COSY spectrum), whereas the CH₂protons of en and of [9]aneS3

resonate as a series of partially overlapping multiplets between d =

2.6 and 3.1 (ESI).† Only four aliphatic ¹³C resonances are observed

in the HSQC spectrum (one for the en carbons and three for the

[9]aneS3 carbons), consistent with a C_ssymmetry in solution for

each equivalent Ru fragment, as found in the precursor.³⁸

The corresponding conjugate with bpy in the place of en,

[4¢TPyP{Ru([9]aneS3)(bpy)}₄][CF₃SO₃]₈(4), was obtained by

treatment of 4¢TPyP with [Ru([9]aneS3)(bpy)(dmso-S)][CF₃SO₃]₂

upon replacement of dmso by the pyridyl groups. Compound 4 was

also characterized in the solid state by X-ray crystallography: the

tetranuclear cation is composed of four [Ru([9]aneS3)(bpy)]²⁺units

bound to the meso pyridyl moieties in a centro-symmetric arrange-

ment (Fig. 3).

hydrogen atom. This feature, probably dictated by packing effects,

might be compatible with weak CH ◊ ◊ ◊ p interactions.

Fig. 4 Top: side view of the complex cation of 4 along the Ru2 ◊ ◊ ◊ Ru2¢

direction ([9]aneS3 ligands at Ru2 ions omitted for clarity). Bottom: top

view showing the canting of the bpy ligands towards the pyrrole rings.

Compound 4 is mildly soluble in water, but becomes soluble

upon addition of 0.02% of DMSO and also in phosphate buffer

at pH 7.4. As for 3, the ¹H NMR spectrum of 4 in CD₃OD shows

◦

sharp signals at 20 C (with the exception of the bH resonance,

see below) and is consistent with the symmetry of the molecule

(ESI).† The single set of bpy and pyridyl signals (four and two,

respectively) implies that all four metal fragments are equivalent

and that each of them has a C_ssymmetry. The anisotropic

shielding of the bpy rings, that are perpendicular to the plane

of the porphyrin, more than counteracts the deshielding typically

observed upon coordination of 4¢PyPs to Ru(II) fragments;⁴⁸as a

consequence, the resonances of 4¢TPyP are shifted slightly upﬁeld

Fig. 3 Molecular structure of the centro-symmetric complex cation of

[4¢TPyP{Ru([9]aneS3)(bpy)}₄][CF₃SO₃]₈(4).

The cation presents a pseudo four fold axis normal to the

porphyrin mean plane: the four Ru fragments are iso-oriented,

˚

with intermetallic side distances of 14.303(4) A (Ru1 ◊ ◊ ◊ Ru2) and

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compared to 3 (d H2,6 = 9.12 in 4 vs. 9.31 in 3; d H3,5 = 8.11 in

4 vs. 8.41 in 3).

Conjugates with 4¢-monopyridylporphyrins. Conjugates of 4¢-

monopyridylporphyrin (4¢-MPyP), with a single peripheral Ru

fragment, are typically not water soluble, regardless of the

charge of the complex. However, they may become soluble

if the three meso phenyl rings are functionalized with appro-

priate groups. Along this strategy, that was used already for

Pt and Ru-polypyridyl conjugates,^8,32we prepared the series

of meso-pyridyl/carboxyphenyl porphyrins with the aim of ex-

ploiting the pyridyl N atoms for coordination to Ru fragments

and the deprotonation of the carboxylic groups at physiolog-

ical pH for increasing water solubility.⁴²We report here the

monoruthenated adduct Na[trans-RuCl₄(dmso-S)(4¢-MPyCbPP)]

(5, Fig. 6), where 4¢-MPyCbPP = 5-(4¢-pyridyl)-10,15,20-tris(4¢-

carboxyphenyl)porphyrin, in which the coordination sphere of

Ru(III) is again very similar to that of NAMI. Compound 5,

that was conveniently obtained by cation exchange from the

corresponding tetrabutylammonium salt, is sparingly soluble in

water, but becomes soluble in phosphate buffer solution at pH 7.4.

At this pH, time-dependent spectral changes similar to those of

compound 2, but less pronounced (suggesting the occurrence of

less aggregation), were observed.

As already mentioned, both 3 and 4 have very broad bH

resonances at 20 ^◦C, suggesting the occurrence of conformational

equilibria. Variable-temperature (VT) NMR experiments showed

that for 3, in CD₃NO₂solution, the reso_◦nance of the eight pyrrole

◦

protons becomes a sharp singlet at 65 C, whereas at -30 C in

CD₃OD solution it splits into two equally intense sharp singlets

(d = 9.30 and 8.97, ESI)† that are not correlated in the H–H

COSY spectrum but show a strong exchange crosspeak in the

ROESY spectrum. The bH resonance of the bpy derivative 4 has

a very similar temperature dependence in CD₃OD–CD₃NO₂

(99 : 1) solution and splits into two equally intense sharp singlets at

-40 ^◦C (d = 8.89 and 8.51, ESI).† The upﬁeld singlet was assigned

to the four pyrrole protons that are directly shielded by the bpy

rings. The bH NMR pattern found for both 3 and 4 at low T is

compatible with the presence in solution of a frozen conformer

with a D_2hsymmetry, with adjacent Ru fragments arranged in

a pairwise fashion: en (or bpy) ligands on Ru units at meso

positions 5, 10 (and 15, 20) face each other, while those on the

meso positions 5, 20 (and 10, 15) are far apart (Fig. 5). The two

types of bH protons, a and b, are exchanged by the concerted

rotation of the four Ru complexes. This geometry is different from

that found in the solid state for 4, where all Ru fragments are iso-

oriented, but is similar to that found by us for the Re(I) conjugate

[4¢TPyP{Re(CO)₃(bpy)}₄][CF₃SO₃]₄.⁵⁰

Fig. 6 Schematic drawing of Na[trans-RuCl₄(dmso-S)(4¢-MPyCbPP)]

(5).

Conjugates through two-bond coordination

We report here the preparation and characterization of a series

of porphyrins that bear from 1 to 4 peripheral bpy moieties at

meso positions, meso-(p-bpy-phenyl)porphyrins (bpy_n-PPs, n =

1–4) (Fig. 7) and their conjugates with half-sandwich Ru(II)

fragments. Bpy_n-PPs were obtained by coupling of meso-(p-

aminophenyl)porphyrins, p(NH₂)_nPPs (n = 1–4), with 4-methyl-

2,2¢-bipyridine-4¢-carboxylic acid (bpyAc).

Fig. 5 Schematic structure of the prevailing conformer of 3 at low T.

Dotted lines indicate the two symmetry planes. The two sets of bH protons,

responsible for the two singlets in the low T NMR spectrum, are labelled

a and b.

Re(I) conjugates of Zn·Bpy-PP have been extensively inves-

tigated for their photophysical properties by Perutz and co-

workers.⁵¹A heteroleptic Re(I)/Ru(II) conjugate of Zn·Bpy₂-cisPP

has been also described.⁵²

Details for the stepwise preparation of bpy_n-PPs are reported

in the experimental section. Bpy₃-PP and bpy₄-PP are described

Both porphyrin conjugates 3 and 4 are very stable in aqueous

solution and in phosphate buffer at physiological pH: their NMR

and visible spectra remain unchanged for hours. This behaviour

is consistent with the substitutionally inert coordination sphere of

the Ru(II) fragments.

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d = 10–11 and rapidly decreases in time due to H/D exchange

with the solvent. The two isomeric disubstituted porphyrins, bpy₂-

cisPP and bpy₂-transPP, can be unambiguously distinguished only

by a close examination of the resonances of the pyrrole protons:

two doublets of 4 H each for the trans isomer and two (partially

overlapped) singlets and two doublets of 2 H each for the cis isomer

(ESI).†⁴⁸As expected, the spectrum of bpy₄-PP is the simplest of

the series and the eight equivalent pyrrole protons resonate as a

singlet.

With the exception of bpy₂-transPP, whose amount was insufﬁ-

cient, all bpy_n-PPs were treated with an appropriate amount of the

half-sandwich Ru(II) precursor [Ru([9]aneS3)(dmso)₃][CF₃SO₃]₂

in CHCl₃–CH₃NO₂or CHCl₃–acetone mixtures: replacement

of two adjacent dmso ligands by the bpy moieties afforded

the corresponding conjugates [bpy_n-PP{Ru([9]aneS3)(dmso-

S)}_n][CF₃SO₃]_2n(6, n = 1; 7, n = 2; 8, n = 3; 9, n = 4; ESI)†

in acceptable-to-good yields. All conjugates (Fig. 9) have been

characterized by mono- and bidimensional NMR spectroscopy

(they are soluble in CDCl₃, CD₂Cl₂, CD₃NO₂, DMSO but scarcely

soluble in water) and give consistent molecular peaks in ESI-MS

mass spectra (in each case the molecular peak corresponds to the

conjugate in which each dmso-S ligand has been replaced by a

triﬂate anion).

The previously reported model complex [Ru([9]aneS3)(bpyAc)-

(dmso-S)][CF₃SO₃]₂(10)³⁹was now characterized also by

X-ray crystallography (Fig. 10) and used as reference for NMR

assignments.

In general, all proton NMR resonances of conjugates

6–9 are slightly broader than those in the free porphyrin or

in the model complex 10. The ¹H NMR spectrum of [bpy₃-

PP{Ru([9]aneS3)(dmso-S)}₃][CF₃SO₃]₆(8) is described in detail

as an example (Fig. 11).

Fig. 7 Schematic drawing of bpy_n-PPs, n = 1–4.

here for the ﬁrst time. The ¹H NMR spectra of bpy_n-PPs in

CDCl₃solution are quite similar to one another (with the obvious

exception of the relative intensities of the bpyAc and of the phenyl

resonances that depend on n). Assignments, performed through

conventional 2D correlation spectra, were consistent with those

already reported in the literature for bpy-PP and bpy₂-cisPP.^51,52

The spectrum of bpy-PP is reported in Fig. 8 as a representative

example.

For each porphyrin the six inequivalent bpyAc protons give six

resolved resonances (four doublets and two singlets). The most

downﬁeld of them is typically the H6 doublet, often partially

overlapped with the bH resonance. The chemical shifts of all the

aromatic resonances, and that of H3 in particular, were found

to depend on the concentration probably because of aggregation

mediated by p–p stacking.§ The singlet of the methyl group

in 4¢ position, that falls at ca. d = 2.5, is correlated in a

NOESY spectrum to the resonances of the adjacent H3¢ and

H5¢ protons. This feature, in conjunction with the H–H COSY

spectrum, allowed us to distinguish the two inequivalent halves

of bpyAc. The amidic NH resonance typically falls in the range

The upﬁeld region, beside the multiplets of [9]aneS3 (d =

2.5–3.4), shows three singlets of equal intensities between d

2.7 and 2.9. By analogy with the spectrum of 10, the upﬁeld

singlet was attributed to the methyl on bpyAc (attribution

conﬁrmed by the NOESY experiment) and the other two to the

diastereotopic methyls of dmso-S.¶ In the downﬁeld region, the

1

¶ As in the H NMR spectrum of 10, the dmso-S resonances are shifted

§ Depending on the solvent and concentration, in some cases the H3 singlet

can resonate more upﬁeld than the H6¢ doublet.

upﬁeld compared to their usual range by the anisotropic shielding of the

adjacent bpy moiety.

Fig. 8 ¹H NMR spectrum (500 MHz) of bpy-PP in CDCl₃. See Fig. 7 for labelling scheme.

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Fig. 9 Schematic drawing of conjugates [bpy_n-PP{Ru([9]aneS3)(dmso-S)}_n][CF₃SO₃]_2n(6–9).

As evidenced by ¹H NMR spectroscopy, in aqueous solu-

tion the reference compound 10 slowly releases the dmso-S;

according to integration, at equilibrium (after ca. 5 d at 25 ^◦C)

almost equal amounts of 10 and of its aquated derivative

[Ru([9]aneS3)(bpyAc)(H₂O)]²⁺were found (ESI).† Despite being

scarcely soluble in water, conjugates 7–9 become moderately

soluble in 50 mM phosphate buffer at pH 7.4 (the solubility

increases upon increasing the charge). At 25.0 ^◦C the visible

spectrum of each conjugate in this medium remains basically

unchanged in shape for hours, except for a slow progressive

decrease of intensity (ca. 2.5% in 1 h) that might be compatible

with the replacement of dmso with water in the peripheral Ru

moieties, a process that—by itself—is not expected to affect

signiﬁcantly the electronic absorption spectrum of the porphyrin

chromophore. The stability of the spectra also suggests that no

signiﬁcant aggregation occurs in solution.

Optically matched DMSO solutions of bpy₄-PP and conjugate 9

showed very similar ﬂuorescence spectra upon selective excitation

at the Soret band (l_exc= 425 nm, l_em= 656 nm). The emission

intensity of 9 is ca. 20% lower than that of the parent porphyrin

(ESI),† as expected because of the peripheral heavy atoms.²⁰

Finally, the tetra-ruthenated porphyrin conjugate [bpy₄-

PP{Ru([12]aneS4}₄][CF₃SO₃]₈(11, Fig. 12), in which the periph-

eral Ru fragments have no labile ligands, was prepared in good

yield by reaction of bpy₄-PP with a slight excess of the Ru(II)

precursors [Ru([12]aneS4)(dmso-S)(H₂O)][CF₃SO₃]₂([12]aneS4 =

1,4,7,10-tetrathiacyclododecane).⁴¹

Fig. 10 ORTEP drawing (40% probability ellipsoid) of the complex cation

of 10.

six resonances of the bpyAc protons maintain the same order

as in the free bpy-PP. The resonances of H5,5¢ are scarcely

affected by coordination to Ru, whereas those of H6,6¢ and

H3,3¢ are shifted downﬁeld by ca. 0.2 ppm. As in the free

porphyrin, in 8 the resonances of the moiety at meso position

10 could not be distinguished from those at the equivalent meso

positions 5 and 15. The symmetry of this T-shaped compound

was reﬂected only in the resonances of the amidic NH protons

that in CD₃NO₂give two well resolved singlets of 2 : 1 intensity

ratio at d = 9.92 (the two equivalent NHs at meso positions 5,15)

and d = 9.99 (NH at meso position 10) (Fig. 11). In the more

symmetrical [bpy₂-cisPP{Ru([9]aneS3)(dmso-S)}₂][CF₃SO₃]₄(7)

and [bpy₄-PP{Ru([9]aneS3)(dmso-S)}₄][CF₃SO₃]₈(9) conjugates,

the peripheral Ru fragments are equivalent. The resonance of the

pyrrole protons, that in 6 is moderately broad at 20 ^◦C, becomes

broader upon increasing the number of peripheral Ru compounds

(Fig. 11).

We also prepared the corresponding model complex

[Ru([12]aneS4)(bpyAc)][CF₃SO₃]₂(12) as a reference for NMR

1

purposes. The downﬁeld region of the H NMR spectrum of 11

in deuterated acetone or nitromethane is similar to that of 9,

with the additional feature that, beside the bH resonance, also

the doublets of H6 and H6¢ are quite broad at 20 ^◦C (Fig. 13).

The same broadening of the signals of H6 and H6¢ was observed

in the spectrum of the model complex 12 (ESI),† and of the

corresponding bpy complex as well, and it was attributed to

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Fig. 11 ¹H NMR spectrum (500 MHz, 20 ^◦C) of [bpy₃-PP{Ru([9]aneS3)(dmso-S)}₃][CF₃SO₃]₆(8) in CD₃NO₂. See Fig. 7 for labelling scheme.

conformational equilibria of the [12]aneS4 ligand.⁵³The H6 and

H6¢ resonances became two sharp doublets upon lowering the

temperature to -40 ^◦C (acetone-d₆), whereas at -60 ^◦C the bH

resonance split into two equally intense sharp singlets (Fig. 13).

This last feature is similar to what already observed for 3 and 4

and might be attributed to the presence, at low T, of a prevailing

conformer in which the four lateral meso arms are oriented in

pairwise fashion (see above).

With the aim of assessing how the solubility of this 8+ tetra-

ruthenated porphyrin conjugate is affected by the nature of

the counter anion, also the corresponding nitrate and chloride

compounds [bpy₄-PP{Ru([12]aneS4)}₄][NO₃]₈(13) and [bpy₄-

PP{Ru([12]aneS4)}₄][Cl]₈(14) (Fig. 12) were prepared by reaction

of bpy₄-PP with the Ru(II) precursors [Ru([12]aneS4)(dmso-

S)X][X] (X = Cl, NO₃, respectively). The ¹H NMR spectra of 13

and 14 are very similar to that of 11. No signiﬁcant difference in the

solubility in aqueous solution was observed: the three conjugates

11, 13 and 14 are sparingly soluble in water and become moderately

soluble in phosphate buffered solution at physiological pH.

PPs with half-sandwich Ru(II) compounds, will be preliminary

tested in vitro for anticancer activity, both in the dark and under

illumination in the porphyrin absorption region. They are either

soluble in water or DMSO. Those conjugates that are not well

soluble in aqueous solution, usually become moderately soluble

in phosphate buffer at physiological pH.

For potential PDT applications it is important that the por-

phyrin conjugates have a low general toxicity (high IC₅₀) and

become cytotoxic only in selected locations upon activation

with visible light.^15,32,34Our cationic Ru compounds are scarcely

cytotoxic in the dark, thus they seem to be appropriate candidates

for conjugation to porphyrins with the aim of obtaining photo-

cytotoxicity.

It is perhaps less obvious why it might be worth preparing and

investigating in the biomedical context porphyrin conjugates with

coordinatively saturated Ru fragments. We have recently reported

that a number of coordinatively saturated and substitutionally

inert metal complexes, including Ru, that we deﬁned as structural

compounds, have indeed interesting biological properties (e.g. as

enzyme inhibitors, DNA intercalators).¹⁹Coordination of such

compounds to porphyrins might result in novel attractive features.

In general, peripherally bound inert Ru compounds, beside

improving water solubility (if appropriately chosen) are expected

to alter the redox and photophysical parameters of the porphyrin,

and to inﬂuence signiﬁcantly its biodistribution. The metal

fragments will also affect the steric proﬁle of the porphyrin and

might introduce additional functionalities. In particular, the total

charge of the porphyrin–Ru conjugates can be tuned according

Discussion

The motivation for making water-soluble porphyrin conjugates

with Ru fragments that are structurally similar to anticancer

compounds are quite obvious and were detailed in the In-

troduction already. The NAMI-type conjugates with meso-

tetrapyridylporphyrin and with meso-pyridyl/carboxyphenyl por-

phyrins described in this work, as well as the conjugates of bpy_n-

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Fig. 12 Schematic drawing of conjugates 11, 13, and 14.

to the number of peripheral ruthenium compounds and to their

relative charge. It is extremely difﬁcult to predict if such conjugates

might show some kind of interesting biological activity, perhaps

through preferential interactions with speciﬁc biomolecules.

As anticipated above, we can however suggest two ﬁelds in which

the positively charged porphyrin–Ru conjugates described in this

work might deserve being investigated: as inhibitors of human

telomerase and of K⁺channels.

Telomerase is a potential selective target for the design of new

antitumour drugs, since it is an enzyme involved in the immortality

of cancer cells (i.e. it is needed for tumour cell proliferation).^54,55

One approach for inhibiting telomerase activity is to target the G-

quadruplex DNA that is associated with the telomerase reaction

cycle.^56,57The G-quadruplex is made by four guanine residues

with a square-like geometry and an electron-rich p surface.

Positively charged planar p-delocalized molecules, including metal

compounds, have been demonstrated to be effective quadruplex

binders.^58,59Cationic meso-tetrasubstituted porphyrins, by virtue

of their intrinsic four-fold symmetry, are likely to provide an appro-

priate stereo-electronic match for G-quartets. Indeed, 5,10,15,20-

tetrakis-(N-methyl)-4-pyridylporphyrin (TMPyP4) and its deriva-

tives are a family of effective inhibitors of human telomerase

in cell-free systems.^60–62Recent structural results suggest that

Fig. 13 Aromatic region in the ¹H NMR spectrum of

[bpy₄-PP{Ru([12]aneS4}₄][CF₃SO₃]₈(11) in acetone-d₆at 20 ^◦C

(bottom) and at -60 ^◦C (top). See Fig. 12 for numbering scheme.

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cationic porphyrins with relatively long and ﬂexible side-arms

might be better binders of G-quartets compared to TMPyP4

as they might allow stacking of the G-tetrad with the aromatic

porphyrin core and minimize steric clashes with the G-tetrad

edges.⁶²Appropriately designed inhibitors should bind more

strongly to quadruplex DNA than to duplex DNA, so that relevant

inhibition of telomerase activity can be achieved at subcytotoxic

concentrations (i.e. concentrations that do not have general

toxic effects on healthy cells). Indeed, Meunier and co-workers

reported that a Mn(III) porphyrin with four ﬂexible cationic arms

at meso positions inhibits human telomerase at submicromolar

concentration and, most importantly, binds G-quadruplex DNA

four orders of magnitude more strongly than duplex DNA.⁶³

Finally, a number of cationic porphyrins with four-fold symme-

try were found to bind with nanomolar afﬁnity to K⁺channels, and

partially block their conductance, presumably by simultaneous

interaction with all four channel subunits (most likely through

salt bridges).⁶⁴

either before or after conjugation, depending on the nature of the

peripheral ruthenium fragments.

Acknowledgements

Financial support from Regione FVG, Fondazione CRTrieste,

Fondo Trieste, COST D39, and Fondazione Beneﬁcentia Stiftung

is gratefully acknowledged. Fondazione CRTrieste is also grate-

fully acknowledged for the muniﬁcent donation of a Varian 500

NMR spectrometer to the Department of Chemical Sciences. A

generous donation of hydrated ruthenium chloride from BASF

Italia Srl is also gratefully acknowledged.

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Conclusions and perspectives

In this work we have described different synthetic approaches to

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Article Doi

Synthetic strategies towards ruthenium-porphyrin conjugates for anticancer activity

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