Synthetic approaches to cytotoxic amidophosphates, aminophosphonates, and aminobisphosphonates with 3,5-bis(arylidene)piperid-4-one framework

Article abstract of DOI:10.1080/10426507.2010.514308

Facile synthetic approaches to a few novel classes of amidophosphates, ω- aminophosphonates, and bisphosphonates having a 3,5-bis(arylidene) piperid-4-one backbone have been elaborated starting from piperid-4-ones functionalized with phosphorus motives fo

Full text of DOI:10.1080/10426507.2010.514308

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Synthetic Approaches to Cytotoxic
Amidophosphates, Aminophosphonates,
and Aminobisphosphonates with 3,5-
Bis(arylidene)piperid-4-one Framework
a
a
a
Mikhail V. Makarov , Evgenia S. Leonova , Ekaterina V. Matveeva
b
c
,
Ekaterina Yu. Rybalkina , Gerd-Volker Röschenthaler , Tatiana V.
d
a
Timofeeva & Irina L. Odinets
a
A. N. Nesmeyanov Institute of Organoelement Compounds , Russian
Academy of Sciences , Moscow , Russian Federation
b
Institute of Carcinogenesis , N. N. Blokhin Russian Cancer Research
Center, Russian Academy of Medical Sciences , Moscow , Russian
Federation
c
Jacobs University Bremen GmbH , Bremen , Germany
d
New Mexico Highlands University , Las Vegas , New Mexico , USA
Published online: 25 Apr 2011.
To cite this article: Mikhail V. Makarov , Evgenia S. Leonova , Ekaterina V. Matveeva , Ekaterina Yu.
Rybalkina , Gerd-Volker Röschenthaler , Tatiana V. Timofeeva & Irina L. Odinets (2011) Synthetic
Approaches to Cytotoxic Amidophosphates, Aminophosphonates, and Aminobisphosphonates with 3,5-
Bis(arylidene)piperid-4-one Framework, Phosphorus, Sulfur, and Silicon and the Related Elements,
186:4, 908-917, DOI: 10.1080/10426507.2010.514308
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Phosphorus, Sulfur, and Silicon, 186:908–917, 2011
Copyright ꢀ
Taylor & Francis Group, LLC
C
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.514308
SYNTHETIC APPROACHES TO CYTOTOXIC
AMIDOPHOSPHATES, AMINOPHOSPHONATES,
AND AMINOBISPHOSPHONATES WITH
3,5-BIS(ARYLIDENE)PIPERID-4-ONE FRAMEWORK
1
1
Mikhail V. Makarov, Evgenia S. Leonova, Ekaterina V.
1
2
Matveeva, Ekaterina Yu. Rybalkina, Gerd-Volker
3
4
1
R o¨ schenthaler, Tatiana V. Timofeeva, and Irina L. Odinets
1
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy
of Sciences, Moscow, Russian Federation
2
Institute of Carcinogenesis, N. N. Blokhin Russian Cancer Research Center,
Russian Academy of Medical Sciences, Moscow, Russian Federation
3
Jacobs University Bremen GmbH, Bremen, Germany
4
New Mexico Highlands University, Las Vegas, New Mexico, USA
Abstract Facile synthetic approaches to a few novel classes of amidophosphates, ω-
aminophosphonates, and bisphosphonates having a 3,5-bis(arylidene)piperid-4-one backbone
have been elaborated starting from piperid-4-ones functionalized with phosphorus motives
followed by aldol-crotonic condensation with a range of (hetero)aromatic aldehydes or
via introduction of the corresponding phosphorus function into the preformed NH-3,5-
bis(arylidene)piperid-4-ones. Combination of phosphorus-containing moieties possessing
inherent bioactivity and cytotoxic 3,5-bis(arylidene)piperid-4-one moiety resulted in the
compounds with high antitumor activity towards human carcinoma cell lines Caov3, A549,
Scov3, PC3, KB 3-1, and KB 8–5 (IC50 in the range of 1–80 µM).
Keywords Aminobisphosphonates; aminophosphates; aminophosphonates; 3,5-bis(arylidene)
piperid-4-ones; cytotoxic properties; synthesis
INTRODUCTION
,5-bis(Arylidene)piperid-4-ones (and the related bis(arylidene)cycloalkanones) pos-
sessing the general structure I and bearing in the molecule 1,5-diaryl-3-oxo-1,4-pentadienyl
dienone) pharmacophore moiety have been intensively studied over last decades. The above
pharmacophore group has been shown to be responsible for different types of biological
3
(
1
2
3
activity, including free radical scavenging, α-glucosidase inhibitory, antimycobacterial,
Received 6 July 2010; accepted 3 August 2010.
This work was supported by the Deutsche Forschungsgemeinschaft (DFG No. 436 RUS 113/905/0-1;
RO 362/35-1); program of the president of the Russian Federation for young Ph.D. scientists (No. MK-
2
464.2008.3); program of the Chemistry and Material Science Division of RAS, NIH, via the RIMI program
(
grant 1P20MD001104-01); and NSF/DMR grant 0934212.
Address correspondence to I. L. Odinets, A. N. Nesmeyanov Institute of Organoelement Compounds RAS,
Vavilova str. 28, Moscow 119991, Russia. E-mail: odinets@ineos.ac.ru
9
08

CYTOTOXIC AMIDOPHOSPHATES
909
and antineoplastic properties.4,5 According to the proposed mechanism of antineoplastic
action, these compounds are capable of alkylating the biogenic cellular thiols (via the
SH-nucleophile addition to vinyl bonds), whereas the nitrogen-containing intracellular
nucleophiles, such as proteins and nucleic acids, are not affected by them. Therefore, 3,5-
bis(arylidene)-piperid-4-ones are considered as promising potential drug-candidates that
may be free of mutagenic properties of known alkylating anticancer agents used in current
6
7
medicine practice, especially taking into account their very low general toxicity. More-
over, recently N-alkylated 3,5-bis(arylidene)piperid-4-ones were found to have potential as
two-photon sensitizers useful for two-photon photodynamic therapy, which is more advan-
tageous than one-photon one due to deeper tissue penetration and being highly localized in
8
the effect.
Antineoplastic properties of these compounds may be adjusted, for example, by vari-
ation of aromatic substituents in their structure. Thus, increase of the electron-withdrawing
properties of these substituents usually results in more pronounced cytotoxicity apparently
due to the more electrophilic character of unsaturated carbon atoms in the pharmacophore
group. Furthermore, the introduction of different groups to the piperidone nitrogen atom
may influence bioactivity of the compound via their interactions with additional binding
sites of a biological target. In general, these groups can either increase the cytotoxic prop-
erties by facilitating the approach of the cytotoxin to a specific binding site or reduce them
by preventing this interaction.
O
1
R
1
R
R
R
Y
I
Bis(arylidene)cyclohexanones - Y=CH2;
Bis(arylidenepiperidones) - Y=NH
Our investigations in this field are focused on the exploitation of advantageous prop-
erties of phosphorus-containing groups, such as inherent bioactivity, ability to impart solu-
bility and bioavailability to the molecule, and improve the capacity of its transportation via
a cellular membrane, for modification of the 3,5-bis(arylidene)piperid-4-one structure. In
this article we outline the main synthetic approaches to the P-modified derivatives devel-
oped by us recently and briefly discuss the positive influence of the phosphorus substituents
on the cytotoxic properties of the compounds. Note that the results have partially been
published and some are communicated preliminary in this article.
RESULTS AND DISCUSSION
In general, the phosphorus-containing groups may be introduced to the nitrogen atom
of the 3,5-bis(arylidene)piperid-4-one molecule using either the direct P-N bonding with
formation of phosphorus amides or the phosphorus and heterocyclic nitrogen atoms can be
bound with additional linkers of different nature.
Therefore, direct phosphorylation of the preformed NH-3,5-bis(arylidene)piperid-4-
ones 1 with appropriate phosphorus acid chlorides in the presence of triethylamine as a

9
10
M. V. MAKAROV ET AL.
base was the method of choice for the formation of the P-N bond between the phosphorus
atom in different surroundings and the nitrogen one of 3,5-bis(arylidene)piperid-4-one
scaffold (Scheme 1). After appropriate purification, the desired P-amides 2 were isolated
O
R1
R2
O
O
O
P
Cl
ArC(H)O
Ar
Ar
Ar
Ar
THF / Et N
Lewis acid
3
N
H
N
H
1
N
P
2
R1
R
O
2
Ar = 3-Py, 4-Py, 2-Th, 4-Me2N-C6H4
R1 = R2 = OEt, OPh; R1 = Me, R2 = OEt, OPh
Scheme 1
in yields of about 60% excluding the compounds having 4-pyridine rings.9,10 It should
be noted that the aldol-crotonic condensation of the corresponding aromatic aldehyde,
including heteroaromatic ones, with piperid-4-one to afford the starting NH-precursors
can be efficiently carried out in the presence of Lewis acids (LiClO4, MgBr2, or boron
11
trifluoride etherate) according to the procedures elaborated by us recently.
In contrast, for the synthesis of N-(ω-phosphorylalkyl)-bis(arylidene)piperid-4-ones
the aldol-crotonic condensation followed the synthesis of N-(ω-phosphorylalkyl)-piperid-
6
4
9
,12,13
-ones 3–5.
The synthetic approach to compounds 3–5 differed depending on the
number of methylene units in alkylene chain between the phosphorus and nitrogen atoms.
Thus, the three-component Kabachnik-Fields reaction of diethyl phosphite, commercially
available 1,4-dioxa-8-azaspiro[4.5]decane, and formaldehyde was used for the preparation
of piperidinyl-substituted α-aminophosphonate 3 in the dioxalane protected form. For the
synthesis of β-aminophosphonate 4 the aza-Michael reaction was utilized. It should be
emphasized that both syntheses were performed in water as a sole medium without any
cosolvent or catalyst, which is especially advantageous from a green chemistry point of
14
view. Finally, the starting phosphorylated piperidones having longer alkylene linker (n =
or 4) were readily obtained in good yields via the alkylation of piperid-4-one hydrochlo-
ride monohydrate with the corresponding diethyl ω-bromoalkylphosphonate under phase
3
12
transfer catalysis (PTC) conditions (Scheme 2).
Further condensation of these phosphorylated precursors 3–5 with aromatic aldehydes
performed under typical acidic conditions provided the final products 6 in low to moderate
yields (25–40%) due to partial dealkylation of ethoxy groups at the phosphorus atom.
Application of Lewis acids such as MgBr2 in the presence of Et3N and BF3·OEt2 and,
in some instances, basic conditions (piperidine/EtOH) increased the yields up to ca 50%
(Scheme 2). In any case, the condensation was accompanied by simultaneous deprotection
of the ketal group in compounds 3 and 4. Note that the compounds 6 may be considered as
ω-aminophosphonates bearing a 3,5-bis(arylidene)piperid-4-one scaffold.
An alternative approach to the ligation of the phosphorus moiety to the 3,5-
bis(arylidene)piperid-4-one scaffold may be performed by means of bioorthogonal re-
actions. Note that in general chemistry in particular, bioorthogonal reactions is a generic
term for a set of reactions that use the reaction of modular building blocks to construct
heteroatom-C bond and combine two biologically active modules with high effectivity and
chemoselectivity. In this line, the Cu(I)-catalyzed 1,2,3-triazole formation from azides and

CYTOTOXIC AMIDOPHOSPHATES
911
O
O
HP(O)(OEt) /CH O
2
2
H O
2
N
O
O
P(O)(OEt)2
O
3
O
N
N
Ar
Ar
O
H
H C=CHP(O)(OEt)
2
2
ArCHO
cat.
H O
2
N
(CH ) P(O)(OEt)
2 n 2
6
4
P(O)(OEt)2
O
Ar = 4-NO C H
6 4
2
4
4
3
2
-FC H4
-NMe C H
6 4
-Py
-Th
6
O
2
Br(CH ) P(O)(OEt)
2
2
n
K CO / CH CN
2
3
3
n = 1, 2, 3, 4
N
N
H HCl H O
2
(
CH ) P(O)(OEt)
2 n 2
n = 3, 4
5
Scheme 2
terminal alkynes according to 1,3-dipolar Huisgen cycloaddition scheme (often referered
to as a click reaction) is a particular powerful ligation reaction working well both for
15
phosphorylated alkynes and phosphorylated azides, whose efficient synthesis in ionic
liquids was reported by us recently.1 The complexing properties of the phosphoryl group
toward copper did not affect the chemoselectivity of the process to afford exclusively the
corresponding 4-regioisomers.
5b
Hence, for the design of phosphorus-substituted 3,5-bis(arylidene)piperid-4-ones
having a 1,2,3-triazole linker we used two approaches differing in the sequence of reaction
steps. In the first approach, the propargyl group was firstly introduced into the molecule of
4-piperidone in the presence of sodium carbonate as a base followed by 1,3-cycloaddition
reaction with phosphorylated azide yielding a substituted 4-diethoxyphosphorylalkyl-1,2,3-
triazole 8 bearing piperidone ring. Subsequent aldol-crotonic condensation of triazole 8 with
an appropriate aldehyde in the presence of boron trifluoride etherate and further neutral-
ization of intermediate tetrafluoroborate salt led to the final compounds 9 (Scheme 3).
O
N
O
N
O
N
1.ArC(H)O
O
N
Br
.
N3(CH2)3P(O)(OEt)2
BF3 OEt2
Ar
Ar
Na2CO3/CH3CN/H2O
.
CuSO4/Sodium Ascorbate
2. NaHCO3
t BuOH/H2O
.
H HCl H O
2
N
(CH2)3P(O)(OEt)2
N
(CH2)3P(O)(OEt)2
N
N
N
N
7
(60%)
8 (quant)
9 (20–40%)
Ar = 4-O NC H 4-FC H 3-Py
2
6
4,
6 4,
Scheme 3

9
12
M. V. MAKAROV ET AL.
In the second procedure, the propargyl group was introduced into the molecule of the
preformed NH-piperidones 1 using the excess of potassium carbonate as a base, dimethyl
sulfoxide (DMSO) as a solvent, and tetrabutylammonium chloride as a phase transfer
catalyst. The reaction completed in 2 h to give the desired alkyne in 48–89% yield after
purification. Further, N-propargyl-3,5-bis(arylidene)piperid-4-ones 10 were used as the
starting substrates in the 1,3-dipolar cycloaddition with phosphorylated azides (Scheme 4).
O
O
N
O
N
Br
4
N
3
(CH
2 4 2
) P(O)(OEt)
Ar
Ar
Ar
Ar
Ar
Ar
eq K
DMSO
cat. Bu NCl
2 3
CO
cat.CuI/MeOH
N
H
4
1
2 4 2
N(CH ) P(O)(OEt)
N
N
1
0 (48–89%)
11 (30–73%)
Ar = 4-CNC H4, 4-Me NC H , 4-MeOC H4, 2-Th, 3-Py
6 2 6 4 6
Scheme 4
Note that in the typical procedure for the regioselective Cu(I)-catalyzed alkyne-azide
coupling, the catalyst can be directly introduced as a Cu(I) salt or generated in situ by
reduction of Cu(II) salts,16 usually in organoaqueous systems, or by oxidation of Cu(0).17
For the synthesis of the intermediate compounds 8 from propargyl substituted precursor
7
(soluble in t-BuOH/H2O mixed solvent) the second approach in which Cu(I) salt was
generated from Cu(II) precursor in the reaction with sodium ascorbate was more preferable,
resulting in 1,2,3-triazole 8 in a quantitative yield. In contrast, for less soluble N-propargyl-
3,5-bis(arylidene)piperid-4-ones 10 the first method using CuI as a catalyst and MeOH as a
solvent provided better results (up to 73% in the case of Ar = 4-MeOC6H4; Scheme 4). In
any case, the lowest yields of the compounds 9,11 were observed in the case of heterocyclic
side rings (2-thienyl and 3-pyridinyl).
Furthermore, it seems reasonable to obtain potential twin drugs combining in the
molecule the useful properties of 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore moiety
and the bisphosphonate residue. Indeed, bisphosphonates (BPs), which are analogs of
naturally occurring diphosphates, are known as powerful inhibitors of bone resorption and
some are currently clinically applied to treat diseases connected with calcium disorders,
18
19
such as malignant hypercalcemia, Paget’s disease, osteoporosis, and tumoral metastasis.
BPs are also of interest in the context of cancer and immunotherapy as well as they possess
potent effects against parasites responsible for sleeping sickness, Chagas disease, malaria,
and leishmaniasis.20 The third-generation BP drugs, which are up to 10,000-fold more
active than those of the first generation (e.g., etidronate), contain an additional moiety in
the molecule comprising the nitrogen atom within a cyclic structure, such as in risedronate
and zoledronate.1
8a
In order to introduce the bisphosphonate residue in the 3,5-bis(arylidene)piperid-
4-one scaffold we used the aza-Michael addition, which is probably the most important
method for C-N bond formation, starting from ethylidenbisphosphonate as vinylphosphoryl
compound and NH-3,5-bis(arylidene)piperid-4-ones 1 as N-nucleophiles (Scheme 5). This
reaction was found to proceed readily in DCM solution in the presence of tertiary amine as
21
a catalyst providing high yields of the desired compounds even on multi-gram scale.

CYTOTOXIC AMIDOPHOSPHATES
913
P(O)(OEt)2
O
O
O
N
H C
2
C
Ar
Ar
P(O)(OEt)2
Ar
Ar Me SiBr
Ar
Ar
3
Et N / CH Cl
3
2
2
N
H
1
N
CHCl3
(
EtO) (O)P
(HO) (O)P
2
2
P(O)(OEt)2
P(O)(OH)2
12
13
t
Ar = 4-NMe C H 4-MeOC H 4-CNC H 4-NO C H 3,5- Bu-4-OHC H 3-Py, 2-Th
2
6
4,
6
4,
6
4,
2
6
4,
6 2,
Scheme 5
It should be noted that all compounds bearing phosphonate or phosphinate groups
can be readily converted to the corresponding free phosphonic (phosphinic) acids via the
reaction with trimethylbromosilane in chloroform followed by the treatment with aq. MeOH
of the intermediate trimethylsilyl esters formed as illustrated in Scheme 5 for the synthesis
of the corresponding bisphosphonic acids 13.
X-ray crystallography8
–10,12
of a few representative phosphorus-modified 3,5-
bis(arylidene)piperid-4-ones has revealed that the olefinic double bonds adopt the
E,E-configuration similar to the parent NH-piperid-4-ones and the products of their
22
N-acylation. For illustration, Figure 1 shows the general view of the compound 2 having
the direct P-N bonding and thiophene side rings (top) and that for the compound 3 in
which the phosphorus atom is attached to the 3,5-bis(arylidene)piperid-4-one scaffold via
an ethylene linker (bottom). Studies of N-phosphorylated 3,5-bis(arylidene)piperid-4-ones
have shown that introduction of even bulky substituents at the N atom of the piperidone
ring does not cause significant rotation of the planes of phenyl or thiophene rings from
that of the central heterocycle. The values of dihedral angles show that a conjugated
pharmacophore fragment in the molecules of N-alkyl-3,5-bis(arylidene)piperid-4-ones
usually is closer to planarity than those in the molecules of their N-phosphorylated
analogues. Such deviation from planarity might be caused by a higher volume of the
phosphorus substituent at the piperidone nitrogen atom and in some cases by unusual
conformation of the phosphorus group in the molecule.
It should be mentioned that under the action of visible light, thermodynamically
more stable E,E-isomers were found to undergo slow photochemical conversion in CDCl3
solution to the corresponding E,Z-isomers, and we succeeded in isolating E,Z-N-methyl-
10
3
,5-bis(thienylidene)piperid-4-one in an individual state.
Biological evaluations of the compounds in vitro were performed on several human
tumor cell lines such as Scov3 and Caov3 (ovarian carcinoma), A549 (lung carcinoma), PC3
prostate carcinoma), KB 3-1 (human oral epidermoid carcinoma cells), and drug-resistant
(
subclone of the latter one, that is, KB 8–5. In general, activity of all of the compounds tested
was one order higher compared to that of melphalan used as a positive control. These studies
have revealed that the introduction of the phosphorus group directly to the nitrogen atom of
the 3,5-bis(arylidene)piperid-4-one molecule resulted in a significant increase of cytotoxic
properties compared to the parent NH-analogues and N-alkylated derivatives. Hence, N-
ω-phosphorylalkyl substituted compounds 6 in general are slightly less active compared to
phosphorus amides 2. As expected, among the compounds belonging to the particular series,

9
14
M. V. MAKAROV ET AL.
Figure 1 Molecular structure of N-methylphenoxyphosphoryl-3,5-bis(thienylidene)-4-piperid-4-one 2 (top) and
N-(diethoxyphosphoryl)ethyl-3,5-bis(pyridinylmethylene)-4-piperidone 6 (bottom) drawn at 40% probability of
thermal ellipsoids.
those bearing strong electron-withdrawing pyridine or 4-nitrosubstituted benzene rings ex-
hibited higher antitumor activity, with IC50 values in the range of 1–2 µM compared to those
containing fewer acceptor thiophene rings or benzene ones with donor 4-dimethylamino
groups (IC50 up to 80 µM).1
0,12,13
Furthermore, among the compounds having 3- and 4-
pyridine rings and N-P bonding the investigation has revealed those that possess practically
the same high level of activity toward drug-resistant cell line KB 8–5, differing from normal
subclone KB 3-1 by the expression of transmembrane-transporting protein Pgp170. This
protein, which is responsible for elimination of hydrophobic compounds including the cyto-
statics from tumor cells, is a plausible reason for the classical multidrug resistances. These

CYTOTOXIC AMIDOPHOSPHATES
915
Photosensibilization of 2 (A549 cell line)
1
1
20
00
8
6
4
2
0
0
0
0
0
absence of light
1
2
0 min
0 min
30 min
O
0
2
4
6
8
10
12
Me N
N
P
NMe2
2
Me
OPh
O
Photosensibilization of 2 (Caov3 cell line)
1
2
2
(R =Me, R =OPh)
1
40
20
00
1
1
absence of light
10 min
8
6
4
2
0
0
0
0
0
2
3
0 min
0 min
0
2
4
6
8
10
12
Figure 2 Action of white light on the cytotoxic properties of O-phenyl methyl[(3E,5E)-4-oxo-3,5-bis(4-
dimethylaminobenzylidene)-1-piperidinyl]phosphinate 2.
data allow us to suggest that N-phosphorylated-3,5-bis(pyridinylmethylene)-4-piperidones
are not the substrates for Pgp170 and hence can be of interest for treatment of resistant
tumors. However, this problem requires additional detailed studies.
Regardless of the fact that the individual E,Z-isomer of N-methyl-3,5-bis(2-
thienylmethylene)piperidin-4-one demonstrated decreased cytotoxic properties compared
to those of the corresponding E,E-isomer, the cytotoxicity of N-phosphorylated 3,5-
bis(arylidene)piperidin-4-ones with donor substituents in the aromatic rings significantly
increased after irradiation of cell cultures treated with the test compound with white
light. In other words, these compounds belong to photosensibilized cytostatics. Thus, in
the representative assay the percentage of surviving cells (A549, lung carcinoma, and
Caov3, ovarian carcinoma) in the presence of methyl(phenoxy)substituted phosphinate 2
decreased significantly under exposure to white light (Figure 2).
CONCLUSIONS
This study has demonstrated suitable synthetic approaches to the introduction of the
phosphorus moiety either directly to the nitrogen atom of the 3,5-bis((hetero)arylidene)-
piperid-4-one molecule or via an additional linker to afford a few novel series of cytotoxic

9
16
M. V. MAKAROV ET AL.
compounds belonging to amidophosphates, aminophosphonates, or methylene bisphos-
phonates. Among the compounds obtained, those bearing 3- and 4-pyridine rings or 4-
nitrobenzene ones possess excellent antitumor properties toward both ordinary human
carcinoma cell lines and drug-resistant subclones. Thus, we proved the hypothesis of the
fruitful combination of the phosphorus residue and 3,5-bis((hetero)arylidene)-piperid-4-
one framework yielding promising drug candidates for further investigation.
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