ISSN 0012-5008, Doklady Chemistry, 2009, Vol. 425, Part 2, pp. 80–83. © Pleiades Publishing, Ltd., 2009.Original Russian Text © A.V. Kuchin, M.V. Mal’shakova, D.V. Belykh, V.A. Ol’shevskaya, V.N. Kalinin, 2009, published in Doklady Akademii Nauk, 2009, Vol. 425, No. 6,pp. 769–772.

80

At present, chlorophyll

a

derivatives are exten-sively used for the synthesis of antitumor com-pounds, mainly photosensitizers for photodynamictherapy (PDT) of tumors [1]. Study of chlorins con-taining carborane fragment is aimed at designingpharmaceuticals with dual therapeutic action thatcan be used in binary antitumor strategies, such asboron neutron capture therapy (BNCT) and PDT[2–4]. The use of chlorin e

6

fragment as pharma-cophore that imparts cyto- and phototoxicity alsoprovides relatively low toxicity, along with the nec-essary spectral properties and tropicity to tumors[1, 2]. The introduction of several carborane frag-ments into natural porphyrin molecules can enhancethe BNCT efficiency owing to an increase in theboron content in the molecule of the active princi-ple. In this work, we obtained chlorins

IV

–

VI

withone and two carborane fragments at the periphery ofthe macrocycle, starting from methylpheophorbide

a

(

I

) (methylpheophorbide

a

(

I

) was obtained fromblue-green algae spirulina according to [5])(Scheme 1).

To attach boron-containing pharmacophores tothe chlorin macrocycle via the amide bond, we usedthe reactions of activated carboxylic groups; theinsertion of the carborane fragments was accom-plished sequentially. To obtain chlorin

III

with thecarboxylic group remote from the macrocycle (aposition more distant from the macrocycle favors

subsequent amidation), aminochlorin

II

, obtainedfrom methylpheophorbide

I

by the reaction with eth-ylenediamine [6, 7], was acylated with succinicanhydride. To attach the carborane polyhedron, weused the reaction of 3-amino-

o

-carborane with chlo-rin

III

whose carboxylic group was activated withdicyclohexylcarbodiimide (DCC). The reactionresulted in monocarboranylchlorin

IV

. For the intro-duction of the second carborane fragment, an addi-tional carboxylic group was formed by acidichydrolysis of the ester group at the 17(3)-position ofthe chlorin macrocycle by treatment with 70% aque-ous trifluoroacetic acid (TFA) (chlorin

V

).

The introduction of the second carborane frag-ment to form dicarboranylchlorin

VI

was performedsimilarly to the procedure used for preparing com-pound

V

when the 17(3)-carboxylic group of mono-carboranylchlorin

V

activated with DCC was reactedwith 3-amino-

o

-carborane. The structures of allobtained compounds were confirmed by IR andNMR spectroscopy and mass spectrometry (table).

Thus, in this work, we have accomplished thestepwise introduction of two carborane fragments atthe periphery of the chlorin macrocycle and preparedchlorin e

6

derivatives with one (

IV

,

V

) and two (

VI

)carborane fragments, starting from methylpheophor-bide

I

.

ACKNOWLEDGMENTS

This work was supported by the Council for Grantsof the President of the Russian Federation for Supportof Young Scientists (grant no. MK–3188.2008.3) andfor Support of Leading Scientific Schools (grantno. NSh–4028.2008.3).

Synthesis of Boronated Derivatives of Chlorin e

6

with Amide Bond

Corresponding Member of the RAS

A. V. Kuchin

a

, M. V. Mal’shakova

a

, D. V. Belykh

a

, V. A. Ol’shevskaya

b

, and V. N. Kalinin

b

Received November 5, 2008

DOI:

10.1134/S0012500809040041

a

Institute of Chemistry, Komi Research Center, Ural Division, Russian Academy of Sciences, Pervomaiskaya st. 48, Syktyvkar, 167982 Russia

b

Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,ul. Vavilova 28, Moscow, 119991 Russia

CHEMISTRY

DOKLADY CHEMISTRY

Vol. 425

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2009

SYNTHESIS OF BORONATED DERIVATIVES 81

Scheme 1.

Conditions: (a) stirring for 3 h, 20

°

C, CHCl

3

; (b) stirring for 1 h, 20

°

C, CHCl

3

; (c) DCC, CH

2

Cl

2

–Py,15 min; 3-NH

2

-

o

-C

2

B

10

H

11

, 1 h, 20

°

C; (d) 70% TFA, 48 h; (e) DCC, CH

2

Cl

2

–Py, 15 min; 3-NH

2

-

o

-C

2

B

10

H

11

,1 h, 20

°

C.

N

HNN

NH

CO2H

C O

CO2CH3NH

NHC

O

C NH

B

BBBB B

BB B

CCB

H

H

HH

HH

H

HHH

H

O

NH2H2N

OO O

I II III

(yield 80%)

a b

V

(yield 40%)

VI

(yield 43%)

70% TFA/H2O

DCC

c

e

DCC

d

N

HNN

NH

CO2CH3

OCO2CH3

N

HNN

NH

CO2CH3

C O

CO2CH3NH

NHC

O

CO OH

B

BBBB B

BB B

CCB

HH

H

NH2H

HH

H

H

HH

H

B

BBBB B

BB B

CCB

HH

H

NH2H

HH

H

H

HH

H

B

BBBB B

BB B

CCB

H

H

HH

HH

H

H

HH

H

N

HNN

NH

C

C O

CO2CH3NH

NHC

O

C NH

B

BBBB B

BB B

CCB

H

H

HH

HH

H

HHH

H

ONH

O

N

HNN

NH

CO2CH3

C O

CO2CH3NH

NHC

O

C NH

B

BBBB B

BB B

CCB

H

H

HH

HH

H

HHH

H

O

N

HNN

NH

CO2CH3

C O

CO2CH3NH

NH2

IV

(yield 42%)

82

DOKLADY CHEMISTRY

Vol. 425

Part 2

2009

KUCHIN et al.

Spectral characteristics of compounds

III

–

VI

Com-pound IR

(

ν

,

cm

–1

)

1

H NMR (

δ

, ppm)

11

B{

1

H} NMR(

δ

, ppm) Mass spectrum

III

1608 (chlorin band),1640 (amide I),1522 (amide II),1730 (C=O)

9.58 (s, 1H, 10-H), 9.55 (s, 1H, 5-H), 8.83 (s, 1H, 20-H), 7.98 (dd, 1H, 17.7 and 11.7 Hz, 3(1)-H), 6.86–6.67 (br m, 2H, 13(1)-NH, 13(3)-NH), 6.25 (br d, 1H, 17.7 Hz, 3(2)-H (

trans

)), 6.06 (br d, 1H, 11.7 Hz, 3(2)-H (

cis

)), 15(1)-CH

2

: 5.41 (d, 1H, 18.9 Hz), 5.18 (d, 1H, 19.5 Hz), 4.49 (br q, 1H, 6.9 Hz, 18-H), 4.37 (br d, 1H, 9.3 Hz, 17-H), 3.68 (s, 3H, 15(3)-CH

3

), 3.62 (s, 3H, 17(4)-CH

3

), 3.44 (s, 3H, 12(1)-CH

3

), 3.26 (s, 3H, 2(1)-CH

3

), 3.16 (s, 3H, 7(1)-CH

3

), 3.75–3.55 (m, 2H, 8(1)-CH

2

), 3.54–3.20 (m, 4H, 13(2)-CH

2

, 13(3)-CH

2

), 2.70–2.51 (m, 4H, 13(5)-CH

2

, 13(6)-CH

2

), 2.30–2.00 (m, 4H, 17(1)-CH

2

, 17(2)-CH

2

), 1.73 (d, 3H, 7.2 Hz, 18(1)-CH

3

), 1.66 (t, 3H, 7.2 Hz, 8(2)-CH

3

), –1.79 (br s, 1H, I-NH), –1.90 (br s, 1H, III-NH).

766.2 [M]

+

;767.3 [M + H]

+

;789.3 [M + Na]

+

IV

1603 (chlorin band),3075 (carbo-rane CH),2592 (carbo-rane BH),1643 (amide I),1520 (amide II),1734 (C=O)

9.67 (s, 1H, 10-H), 9.60 (s, 1H, 5-H), 8.83 (s, 1H, 20-H), 8.05 (dd, 1H, 17.9 and 11.6 Hz, 3(1)-H), 6.97–6.80 (br m, 2H, 13(1)-NH, 13(3)-NH), 6.52–6.44 (br m, 1H, 13(7)-NH), 6.33 (br d, 1H, 18 Hz, 3(2)-H (

trans

)), 6.13 (br d, 1H, 11.1 Hz, 3(2)-H (

cis

)), 15(1)-CH

2

: 5.49 (d, 1H, 19.2 Hz), 5.26 (d, 1H, 18.3 Hz), 4.50 (br q, 1H, 7.2 Hz, 18-H), 4.40 (br d, 1H, 9.6 Hz, 17-H), 4.31–4.15 (br m, 2H, carborane CH), 3.72 (s, 3H, 15(3)-CH

3

), 3.64 (s, 3H, 17(4)-CH

3

), 3.49 (s, 3H, 12(1)-CH

3

), 3.43 (s, 3H, 2(1)-CH

3

), 3.24 (s, 3H, 7(1)-CH

3

), 3.85–3.69 (m, 2H, 8(1)-CH

2

), 3.67–3.46 (m, 4H, 13(2)-CH

2

, 13(3)-CH

2

), 2.64–2.37 (m, 4H, 13(5)-CH

2

, 13(6)-CH

2

), 2.34–1.98 (m, 4H, 17(1)-CH

2

, 17(2)-CH

2), 1.78–1.68 (m, 6H, 18(1)-CH3, 8(2)-CH3), 1.02–2.68 (br m, 10H, carborane BH), –1.55 (s, 1H, I-NH), –1.75 (s, 1H, III-NH).

–4.64; –7.04;–11.10; –13.09;

–14.56

909.5 [M]+;910.5 [M + H]+

V 1601 (chlorin band),3076 (carbo-rane CH),2594 (carbo-rane BH),1641 (amide I),1518 (amide II),1728 (C=O)

9.68 (s, 1H, 10-H), 9.62 (s, 1H, 5-H), 8.82 (s, 1H, 20-H), 8.06 (dd, 1H, 17.7 and 11.7 Hz, 3(1)-H), 6.33 (br d, 1H, 17.4 Hz, 3(2)-H (trans)), 6.14 (br d, 1H, 11.4 Hz, 3(2)-H (cis)), 15(1)-CH2: 5.51 (d, 1H, 18.6 Hz), 5.35 (d, 1H, 19.2 Hz), 4.46 (br q, 1H, 6.8 Hz, 18-H), 4.37 (br d, 1H, 9.9 Hz, 17-H), 4.38–4.31 (br m, 2H, carborane CH), 3.68 (s, 3H, 15(3)-CH3), 3.50 (s, 3H, 12(1)-CH3), 3.47 (s, 3H, 2(1)-CH3), 3.29 (s, 3H, 7(1)-CH3), 3.82–3.72 (m, 2H, 8(1)-CH2), 3.92–3.70 (m, 2H, 13(2)-CH2), 3.65–3.57 (m, 2H, 13(3)-CH2), 2.30–2.10 (m, 4H, 13(5)-CH2, 13(6)-CH2), 2.07–1.85 (m, 4H, 17(1)-CH2, 17(2)-CH2), 1.74–1.63 (m, 6H, 18(1)-CH3, 8(2)-CH3), 0.75–2.28 (br m, 10H, carborane BH).

–4.60; –7.10;–11.13; –13.10;

–14.60

895.9 [M]+;896.9 [M + H]+

VI 1603 (chlorin band),3076 (carbo-rane CH),2592 (carbo-rane BH),1643 (amide I), 1499 (amide II),1728 (C=O)

9.67 (s, 1H, 10-H), 9.61 (s, 1H, 5-H), 8.82 (s, 1H, 20-H), 8.17–7.94 (br m, 1H, 3(1)-H), 7.08–6.95 (br m, 1H, 13(1)-NH), 6.91–6.79 (br m, 1H, 13(3)-NH), 6.46–6.34 (br m, 2H, 13(7)-NH, 17(3)-NH), 6.46–6.08 (br m, 2H, 3(2)-H (trans), 3(2)-H (cis)), 5.61–5.21 (br m, 2H, 15(1)-CH2), 4.58–4.39 (br m, 2H, 18-H, 17-H), carborane CH: 5.42–5.34 (br m, 1H), 5.06–4.92 (br m, 1H), 4.31–4.14 (br m, 2H), 3.72 (s, 3H, 15(3)-CH3), 3.50 (s, 3H, 12(1)-CH3), 3.47 (s, 3H, 2(1)-CH3), 3.27 (s, 3H, 7(1)-CH3), 3.89–3.56 (m, 6H, 8(1)-CH2, 13(2)-CH2, 13(3)-CH2), 2.57–2.25 (m, 4H, 13(5)-CH2, 13(6)-CH2), 2.23–1.96 (m, 4H, 17(1)-CH2, 17(2)-CH2), 1.84–1.65 (m, 6H, 18(1)-CH3, 8(2)-CH3), 0.68–2.70 (br m, 20H, carborane BH), –1.57 (s,1H, I-NH), –1.75 (s, 1H, III-NH).

–4.81; –7.48;–1.36; –13.45;

–14.60

1038.1 [M]+; 1039.1 [M + H]+

Note: 1H and 11B{1H} NMR spectra were recorded on a Bruker Avance-300 spectrometer operating at 300 MHz for 1H and 75 MHz for11B in CDCl3 solutions (in CDCl3 with addition of CD3OD for compound V). IR spectra were recorded on a Specord M-80 spec-trophotometer as KBr pellets. Mass spectra were obtained on a Vision 2000 (MALDI) mass spectrometer. Column chromatographywas performed using silica gel from Lachema (40–100 mesh). The spectral characteristics of methylpheophorbide I and aminochlo-rin II are similar to those described earlier [4–7].

DOKLADY CHEMISTRY Vol. 425 Part 2 2009

SYNTHESIS OF BORONATED DERIVATIVES 83

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