CC BY
9Порфирины Porphyrins
Макрогэтэроцмклы
http://macroheterocycles.isuct.ru
Статья Paper
A One Step Synthesis of Boronated meso-Tetraphenylporphyrins
Valentina А. Ol'shevskaya,^ Аndrei V. Zaitsev,3 Yulia V. Dutikova,3b Valentina N. Luzgina,b Elena G. Kononova,a Pavel V. Petrovsky,a and Valery N. Kalinina
"AN. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow, 119991, Russia bMoscow State Academy of Fine Chemical Technology, Moscow 117571, Russia @Corresponding author E-mail: olshevsk@ineos.ac.ru
5,10,15,20-Tetrakis(4-aminophenyl)porphyrin and their metal complexes were used for a one stage synthesis of boronated porphyrins with elevated boron content (~30-35%). The reaction of amino groups in para position of porphyrin phenyl rings with carborane triflates, epoxides and isocyanates smoothly led to carboranylsubstituted secondary amines, amino alcohols and amides potentially applicable in anticancer boron neutron capture therapy (BNCT). 5-(4-Aminophenyl)-10,15,20-triphenylporphyrin was used as a model compound in reactions with above mentioned functionally substituted carboranes.
Keywords: Porphyrins, carboranylmethyl triflates, carboranylepoxides, carboranylisocyantes, carboranylporphyrins, boron neutron capture therapy (BNCT).
Introduction
The boronated derivatives of porphyrins and chlorins are under an extensive investigation as clinically applicable drugs for binary anticancer strategy called boron neutron capture therapy (BNCT).[1-3] In this method the tetrapyrrole macrocycle plays a vector-like role in preferential delivery of the conjugate to the tumor cells whereas 10B isotope serves for generating a local radioactive reaction upon tumor irradiation with thermal neutrons. Moreover, low-to-null dark toxicity and fluorescent characteristics of boronated tetrapyrrole containing agents allow for visual control of intratumoral drug accumulation. Second generation drugs such as disodium salt of mercapto-closo-dodecaborate (BSH) and L-4-dihydroxyboryl phenylalanine (BPA) are currently used in clinical protocols.[4] Unfortunately, for these agents the ratio tumor:extratumoral milieu is limited. Furthermore, BSH is chemically unstable and is oxidized by air oxygen.[5-6] The boron content in BPA is relatively low (~ 5 %) which requires dose escalation for efficient therapy. These drawbacks make necessary the search for novel compounds with optimized characteristics.
Recently the meso-tetraphenylporphyrin-based boronated porphyrins with elevated (20%) boron content have been reported.[1] These compounds have ester, amide and ether bonds between the boron polyhedra and the porphyrin macrocycle. In this study we developed a one stage synthesis of borona-ted porphyrins with hydrolytically resistant spacer groups using the available amino derivatives of meso-tetraphenyl-porphyrin, namely, (5-(4-aminophenyl)-10,15,20-triphenyl-porphyrin (1)[7] and 5,10,15,20-tetrakis(4-aminophenyl)por-phyrin (2)[8]), and functionally substituted carboranes (such as triflates, epoxides or isocyanates). The aminoporphyrin 1 that contains one amino group in the macrocycle was used as a model compound for optimization of synthesis of tetrasub-stituted carboranylporphyrins from aminoporphyrin 2.
Experimental
The XH NMR spectra were recorded on Bruker Avance-400 spectrometer.The IRspectrawereregisteredonSpecordM-82ofCarl Zeiss spectrometer in KBr tablets or in hexachloro-1,3-butadiene. The UV-vis spectra were measured on a spectrophotometer Jasco UV 7800 series in CHCl3. The mass spectra were obtained using VISION 2000 (MALDl) mass spectrometer, the most intense peaks were given for each compound. The identities of new compounds were verified on TLC 60 F254 plates (Merck). Merck silica gel L 0.04-0.08 mesh was used for column chromatography. The solvents were purified according to standard procedures.
General procedure of synthesis of carboranylporphyrins 5, 6.
To the solution of 0.035 mmol of porphyrin 1 in 10 ml of THF 0.35 mmol of sodium acetate and 0.07 mmol of carborane 3 or 4 were added, and the mixture was refluxed for 12 h. Then the reaction mixture was poured into water (20 ml) and extracted with CHCl3 (3x5 ml). The organic solution was washed with water, dried over Na2SO4, and evaporated in vacuo. The residue was chromatographed on a SiO2 column (1x15 cm) using CHCl3 as an eluent.
5-[4-(o-Carboran-1-yl)methyl]aminophenyl-10,15,20-triphenyl porphyrin, 5. Yield 26 mg (73%). Found: C 71.10, H 5.56, B 14.08, N 9.26 %. C47H43B10N5 requires C 71.82, H 5.51, B 13.75, N 8.91 %. m/z (MALDI): 786 [M+]. IR (KBr) vmax cm-1: 3442 (NH), 2595 (BH). UV-vis (CHCl3) Xmax nm (lg e): 418x(4.05), 515 (3.57), 550 (3.18), 647 (2.81). XH NMR^CDCy 8 ppm: 8.84 (8H, s, pyrrole-H), 7.74 - 8.20 (19H, m, Ph), 4.32 (1H, br.s, NH), 3.76 (1H, br.s, carborane-CH), 1.82 (2H, s, CH2), -2.78 (2H, s, pyrrole-NH).
{5-[4-(1-Carba-closo-dodecaboran-1-yl) methylaminophenyl]-10,15,20-triphenyl porphyrin}cesium, 6. Yield 31 mg (74%). Found: C 60.73, H 4.86, B 12.24, N 7.92 %. C46H43BnCsN5 requires C 60.20, H 4.72, B 12.96, N 7.63 %. m/z (MALDI): 785 [M-Cs+]. IR (KBr) vmax cm-1: 3448 (NH), 2531 (BH). UV-vis Xmax (CHCl3) nm (lg e): 42T(4.11), 516 (3.36), 553 (3.15), 649 (2.85).^ NMR (CDCl3) 8 ppm: 8.83 (8H, s, pyrrole-H), 7.76 - 8.20 (19H, m, Ph), 4.35 (1H, br.s, NH), 1.81 (2H, s, CH2), -2.80 (2H, s, pyrrole-NH).
General procedure of synthesis of carboranylporphyrins 7, 8.
To the solution of 0.035 mmol of porphyrin 2 in 20 ml of acetonitrile 0.35 mmol of sodium acetate and 0.24 mmol carborane
3 or 4 were added, and the mixture was refluxed for 10-15 h. Then the reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (3x7 ml). The organic solution was dried over Na2SO4, and evaporated in vacuo. The residue was washed with hexane (2x5 ml) and chromatographed on a SiO2 column (1x20 cm) using CHCl3:CH3OH (8:1 v/v) as an eluent.
5,10,15,20-Tetrakis[4-(o-carboran-1-yl)methyl] aminophenylporphyrin, 7. Yield 32 mg (67%). Found: C 52.08, H 6.39, B 32.79, N 8.74 %. C56H82B40N8 requires C 51.75, H 6.36, B 33.27, N 8.62 %. m/z (MALDI): 129)9 [M +]. IR (KBr) vmax cm-1: 3389 (NH), 2595 (BH). UV-vis (CHCl3) X^ nm (lg e): 421(4.17), 515(3.48), 550(3.15), 650(3.09). 1H NMR (CDCl3) 8 ppm: 8.81 (8H, s, pyrrole-H), 7.75 - 8.29 (16H, m, Ph), 4.33 (4H, br.s, NH), 3.60 (4H, br.s, carborane-CH), 1.81 (8H, s, CH2), -2.78 (2H, s,pyrrole-
NH). 2
{5,10,15,20-Tetrakis[4-(1-carba-closo-dodecaboran-1-yl) methyl]aminophenylporphyrin} cesium, 8. Yield 48 mg (72%). Found: C 34.65, H 4.61, B 25.53, N 6.24 %. C52H82B44Cs4N8 requires C 34.19, H 4.52, B 26.04, N, 6.13 %. m/z (MALDI): 1295 [M-4Cs+]. IR (KBr) vmjx cm-1: 3335 (NH), 2534 (BH). UV-vis (CHCl3) Xmax nm (lg e): 427(4.23), 522(2.34), 561(2.30), 657(2.15). 1H NMR (CDCl3) 8 ppm: 8.90 (8H, s, pyrrole-H), 7.80 - 8.42 (16H, m, Ph), 3.61 (4H, br.s, NH), 1.81 (8H, s, CH2), -2.72 (2H, s, pyrrole-NH).
General procedure of synthesis of carboranylporphyrins 15-18.
To the solution of 0.07 mmol of porphyrins 11 or 12 in 10 ml of acetonitrile 0.22 mmol of carboranes 9 or 10 and a catalytic amount (1 mg, 0.007 mmol) of ZnCl2 were added. The reaction mixture was refluxed for 15 h and monitored by thin-layer chromatography in CHCl3:hexane (3:1 v/v). Then acetonitrile was evaporated in vacuo. The residue was dissolved in 10 ml of CHCl3, washed with water (2x10 ml), dried over Na2SO4. CHCl3 was evaporated and residue was purified on a SiO2 column (1x20 cm) using CHCl3 as an eluent, affording carboranylporphyrins 15-18.
Zn complex of 5,10,15-triphenyl-20-[p-(1'-o-carboranyl-phenyl-2'-hydroxypropyl)aminophenyl]porphyrin, 15. Yield 50 mg (71.4%). Found: C 68.74, H 5.15, B 10.78, N 7.29 %. C55H49B10N5OZn requires C 68.14, H 5.09, B 11.15, N 7.22 %. m/z (MALDI): 970 [M+]. IR (hexachloro-1,3-butadiene) vmax cm-1: 3383 (OH, NH), 2586 (BH). UV-vis (CHCl3) Xmax nm (lg™) 424 (4.95), 556 (4.08), 599 (3.75). 1H NMR (CDCl3) 8ppm: 8.96 (2H, s,pyrrole-H), 8.86 (6H, s,pyrrole-H), 8.12 (1H, s, NH), 7.05 - 7.95 (24H, m, Ph), 3.78 - 3.83 (1H, m, CH), 2.45 (1H, br.s, OH), 2.18 (1H, dd, CHH-N, 2Jhh = 14.2 Hz, 3J = 4.0 Hz), 1.90 (1H, dd, CHH-N, 2J = 14.2 Hz, 3J =
' HH 77 v ' ' ' HH ' HH
12.1 Hz), 1.85 (1H, dd, CHH-C-carborane, 2J = 16.4 Hz, 3J = 7.5
/5 V 5 5 5 HH ' HH
Hz), 1.64 (1H, dd, CHH-carborane, 2J = 16.4 Hz, 3J = 3.8 Hz).
\ 7 7 HH HH '
Zn complex of 5,10,15-triphenyl-20-[p-(1'-o-carboranyl-2'-hydroxypropyl)aminophenyl]porphyrin, 16. Yield 50 mg (83.3%). Found: C 65.21, H 5.13, B 12.54, N 7.96 %. C49H45B10N5OZn requires C 65.87, H 5.08, B 12.10, N 7.84 %. m/z (MALDI): 893 [M+]. IR (hexachloro-1,3-butadiene) v^ cm-1: 3496 (OH, NH), 2591 (BH). UV-vis (CHCl3) Xmax nm (lge): 425 (4.97), 555 (4.11), 595 (3.83). 1H NMR (CDCl3) 8°ppm: 8.99 (2H, s,pyrrole-H), 8.85 (6H, s, pyrrole-H), 8.19 (1H, s, NH), 7.12 - 8.02 (19H, m, Ph), 4.08 (1H, br.s, carborane-H), 3.77 - 3.83 (1H, m, CH), 2.42 (1H, br.s, OH), 2.22 (1H, dd, CHH-N, 2Jhh = 15,2 Hz, 3Jhh = 5,1 Hz), 2.13 (1H, dd, CHH-N, 2J = 15,2 Hz, 3J" = 13,0 Hz),"i.97 (1H, dd, CHH-
HH ' ' HH ' 77 v ' '
C-carborane, 2J = 16,2 Hz, 3J = 8,1 Hz), 1.71 (1H, dd, CHH-
HH ' ' HH ' 77 v ' '
carborane, 2J = 16,2 Hz, 3J = 4,5 Hz).
HH ' HH '
Pd complex of 5,10,15-triphenyl-20-[p-(1'-o-carboranyl-phenyl-2'-hydroxypropyl)aminophenyl]porphyrin, 17. Yield 50 mg (78.5%). Found: C 65.91, H 4.92, B 10.61, N 7.01 %. C55H49B10N5OPd requires C 65.37, H 4.89, B 10.02, N 6.93 %. m/z (MALDI): 1011 [M+]. IR (hexachloro-1,3-butadiene)vmax cm-1: 3321 (OH, NH), 2586 (BH). UV-vis (CHCl3) Xmax nm (lg e):^ (4.93), 558 (4.04), 595 (3.69). 1H NMR (CDCl3) Tppm: 9.01 (2H, s, pyrrole-H), 8.92 (6H, s,pyrrole-H), 8.21 (1H, s, NH), 7.15 - 7.88 (24H, m, Ph), 3.78 - 3.85
(1H, m, CH), 2.40 (1H, br.s, OH), 2.25 (1H, dd, CHH-N, 2Jhh = 14.2 Hz, 3J = 4.0 Hz), 2.00 (1H, dd, CHH-N, 2J = 13.9 Hz, J™ = 12.6
' HH 77 v 7 7 7 HH ' HH
Hz), 1.91 (1H, dd, CHH-C-carborane, 2J = 14.8 Hz, 3J = 7.6 Hz),
77 v ' ' ' HH ' HH 77
1.71 (1H, dd, CHH-C-carborane, 2J = 14.8 Hz, 3J = 3.5 Hz).
\ 7 7 HH HH '
Pd complex of 5,10,15-triphenyl-20-[p-(1'-o-carboranyl-2'-hydroxypropyl)aminophenyl]porphyrin, 18. Yield 60 mg (82.7%). Found: C 63.56, H 4.91, B 10.91, N 7.55 %. C49H45B10N5OPd requires C 62.98, H 4.85, B 11.57, N 7.49 %. m/z (MALDI): 934 [M+]. IR (hexachloro-1,3-butadiene) vmax cm-1: 3319 (OH, NH), 2585 (BH). UV-vis (CHCl3) X^ nm (lg^ "e;): 423 (4.97), 555 (4.10), 595 (3.78). 1H NMR (CDCl3) 8ppm: 9.02 (2H, s, pyrrole-H), 8.87 (6H, s,pyrrole-H), 8.23 (1H, s, NH), 7.20 - 8.14 (19H, m, Ph), 4.13 (1H, br.s, carborane-H), 3.82 - 3.91 (1H, m, CH), 2.50 (1H, br.s, OH), 2.22 (1H, dd, CHH-N, 2Jhh = 15,2 Hz, 3Jhh = 5,1 Hz), 2.06 (1H, dd, CHH-N, 2J = 11.9 Hz, 3JHH= 10.2 Hz), 1.98 (1H, dd, CHH-C-
HH ' HH 77 v ' '
carborane, 2J = 15.3 Hz, 3J = 8.0 Hz), 1.69 (1H, dd, CHH-C-
HH ' HH 77 v ' '
carborane, 2J = 15.3 Hz, 3J = 4.8 Hz).
HH HH '
General procedure of synthesis of carboranylporphyrins 19-22.
To the solution of 0.07 mmol of porphyrins 13 or 14 in 15 ml of THF 0.72 mmol of carboranes 9 or 10 and a catalytic amount (2 mg, 0.014 mmol) of ZnCl2 were added. The reaction mixture was refluxed for 18 h and monitored by thin-layer chromatography in CHCl3:hexane (5:1 v/v). THF was evaporated in vacuo. The residue was dissolved in 10 ml of CHCl3, washed with water (2x10 ml), dried over Na2SO4. The solvent was evaporated and the residue was purified on a SiO2 column (1x20 cm) using the mixture of
CHCl3:CH3OH (15:1 v/v) as eluent, affording carboranylporphyrins 19-223. 3
Zn complex of 5,10,15,20-tetra[p-2-hydroxy-3-(1'-o-phenyl-carboran-2'-yl)propyl]aminophenylporphyrin, 19. Yield 90 mg (75.0%). Found: C 57.81, H 6.22, B 22.89, N 6.17 %. C88H112B40N8O4Zn requires C 57.33, H 6.12, B 23.45, N 6.08 %. m/z (MALDI): 1842 [M+]. IR (hexachloro-1,3-butadiene) vmax cm-1: 3417 (OH, NH), 2585 (BH). UV-vis (CHCl3) Xmax nm (lge): 437 (4.91), 560 (3.80), 607 (3.38). 1H NMR (CDCl3) 8 "ppm: 9.67 (8H, s, pyrrole-H), 8.89 (4H, s, NH), 7.23 - 8.61 (36H, m, Ph), 3.64 - 3.76 (4H, m, CH), 2.60 (4H, br.s, OH), 2.42 (4H, dd, CHH-N, 2J = 14.1 Hz, 3J = 3.9
v ' ' 77 v ' ' ' HH ' HH
Hz), 2.26 (4H, dd, CHH-N, 2Jhh = 14.1 Hz, 3Jhh = 12.7 Hz), 2.03 (4H, dd, CHH-C-carborane, 2J = "16.3 Hz, 3J =""7.6 Hz), 1.58 (4H, dd,
HH ' HH 77 v ' '
CHH-C-carborane, 2J = 16.3 Hz, 3J = 3.3 Hz).
HH HH '
Zn complex of 5,10,15,20-tetra[p-2-hydroxy-3-(1'-o-car-boran-2'-yl)propyl]aminophenylporphyrin, 20. Yield 80 mg (83.0%). Found: C 50.37, H 6.21, B 27.78, N 7.35 %. C64H96B40N8O4Zn requires C 49.94, H 6.29, B 28.09, N 7.28 %. m/z (MALDI): 1539 [M+]. vmax (hexachloro-1,3-butadiene)/cm-1 3410 (OH, NH), 2590 (BH). UV-vis X^ (CHCl3) nm (lg e): 436 (4.91), 561 (3.90), 607 (3.53). 1H NMR m(CDCl3) 8 ppm: 9.66 (8H, s, pyrrole-H), 8.79 (4H, s, NH), 7.20 - 8.60 (16H, m, Ph), 3.62 - 3.73 (4H, m, CH), 3.20 (4H, br.s, carborane-H), 2.65 (4H, br.s, OH), 2.40 (4H, dd, CHH-N, 2J = 14.3 Hz, 3J = 4.0 Hz), 2.24 (4H, dd, CHH-N, 2J = 14.0 Hz,
HH ' HH 77 v ' ' ' HH
3J = 12.5 Hz), 2.00 (4H, dd, CHH-C-carborane, 2J = 16.0 Hz,
HH 77 v ' ' ' HH
3J = 7.9 Hz), 1.50 (4H, dd, CHH-C-carborane, 2J = 16.1 Hz,
HH 77 v ' ' ' HH
3J = 3.5 Hz).
HH '
Pd complex of 5,10,15,20-tetra[p-2-hydroxy-3-(1'-o-phenylcarboran-2'-yl)propyl]aminophenylporphyrin, 21. Yield 130 mg (84.5%). Found: C 56.71, H 5.87, B 22.45, N 6.05 %. C88H112B40N8O4Pd requires C 56.08, H 5.99, B 22.94, N 5.95 %. m/z (MALDI): 1886 [M+]. IR (hexachloro-1,3-butadiene) vmax cm-1: 3338 (OH, NH), 2585 (BH). UV-vis (CHCl3) Xmax nm (lg e):428 (4.90), 535 (3.76), 610 (3.30). 1H NMR (CDCl3) 8 ppm: 9.48 (8H, s,pyrrole-H), 8.67 (4H, s, NH), 7.17 - 8.55 (36H, m, Ph), 3.64 - 3.79 (4H, m, CH), 2.55 (4H, br.s, OH), 2.31 (4H, dd, CHH-N, 2J = 13.5 Hz, 3J = 3.9 Hz), 2.16 (4H, dd, CHH-N, 2J = 13.5 Hz,
HH ' HH 77 v ' ' ' HH
3J = 11.4 Hz), 2.11 (4H, dd, CHH-C-carborane, 2J = 14.6 Hz,
HH 77 v ' ' ' HH
3J = 6.9 Hz), 1.63 (4H, dd, CHH-C-carborane, 2J = 14.6 Hz,
HH 77 v ' ' ' HH
3J = 4.0 Hz).
HH 7
Pd complex of 5,10,15,20-tetra[p-2-hydroxy-3-(1'-o-carbo-ran-2'-yl)propyl]aminophenylporphyrin, 22. Yield 85 mg (77.0 %). Found: C, 48.21; H, 6.07; B, 27.64; N, 7.18 %. CДДДОPd
5 ' 5 ' 5 ' 5 64 96 40 8 4
requires C, 48.64; H, 6.12; B, 27.36; N, 7.09 %. m/z (MALDI): 1580 [M+]. IR (hexachloro-1,3-butadiene) vmax cm-1: 3340 (ОН, NH), 2592 (ВН). UV-vis (CHCl3) Xmax nm (lgT'e): 435 (4.89), 561 (3.87), 610 (3.45). 1Н NMR (CDCl3) Sppm: 9.40 (8Н, s, pyrrole-H), 8.68 (4Н, s, NH), 7.10 - 8.50 (16Н, m, Ph), 3.60 - 3.69 (4Н, m, CH), 3.15 (4H, br.s, carborane-H), 2.50 (4Н, br.s, ОН), 2.30 (4Н, dd, СЯН-N, 2J = 13.7 Hz, 3J = 3.8 Hz), 2.10 (4Н, dd, СНЯ-N, 2J = 13.6 Hz,
нн ' нн /5 v 5 5 ' нн
3J = 11.0 Hz), 2.05 (4Н, dd, СЯН-С-carborane, 2J = 14.8 Hz,
нн нн
3J = 6.6 Hz), 1.60 (4Н, dd, СНЯ-С-carborane, 2J = 14.8 Hz,
нн нн
3J = 4.1 Hz).
нн
General procedure of synthesis of carboranylporphyrins 23 and 24.
To the solution of 0.05 mmol of 15 or 16 in 10 ml of CHCl3 0.1 ml of trifluoroacetic acid was added and the reaction mixture was kept at 200 C with stirring for 2 h. The solvent was evaporated in vacuo. The residue was purified on a SiO2 (column 1x20 cm) using CHCl3 as eluent.
5,10,15-Triphenyl-20-[p-(1 '-o-carboranylphenyl-2 '-hydroxypropyl)aminophenylporphyrin, 23. Yield 40 mg (94.8%). Found: C 73.32, H 5.58, B 11.59, N 7.89 %. C55H51B10N5O requires C 72.90, H 5.67, B 11.93, N 7.73 %. m/z (MALDI): 904 [M+]. IR (hexachloro-1,3 -butadiene) vmax cm-1: 3379 (ОН, NH), 3061 (Ph), 2585 (ВН). UV-vis 85 (1нГсЫ, СЯН-С-carborane, J = 15.8 Hz, 3J = 7.3 Hz), 1.67 (1Н, dd, СНЯ-С-carborane, 2 J ="15.8 Hz
нн нн
lmax (CHCl3) nm (lg e): 421 (4.96), 553 (4.10), 597 (3.78). 1Н NMR (CDCl3) S ppm: 8.89 (2Н, s, pyrrole-H), 8.77 (6Н, s, pyrrole-H), 8.02 (1Н, s, NH), 6.96 - 7.93 (24Н, m, Ph), 3.70 - 3.80 (1Н, m, СН), 2.46 (1Н, br.s, ОН), 2.20 (1Н, dd, СЯН-N, J = 13.9 Hz, 3J = 4.0 Hz), 1.93 (1Н, dd, СНЯ-N, 2J = 13.9 Hz, 3J =н12.4 Hz), 1.,
нн нн нн
J = 3.8 Hz), -2.68 (2Н, br.s, pyrrole-NH).
5,10,15-Triphenyl-20-[p-(1'-o-carboranyl-2'-hydroxypropyl)aminophenylporphyrin, 24. Yield 0.40 mg (93.5%). Found: C 70.58, H 5.78, B 13.36, N 8.61 %. C49H47B10N5O requires C 70.90, H 5.71, B 13.02, N 8.44 %. m/z (MALDI): 828 [M+]. IR (hexachloro-1,3-butadiene) vmax cm-1: 3403 (ОН, NH), 3059 (Ph), 2585 (ВН). UV-vis (CHCl3) f^ nm (lg e): 422 (4.98), 555 (4.15), 596 (3.86). 1Н NMR (CDCl3) S 'ppm: 9.01 (2Н, s, pyrrole-H), 8.94 (6Н, s, pyrrole-H), 8.66 (1Н, s, NH), 6.93 - 7.87 (19Н, m, Ph), 4.12 (1Н, br.s, carborane-H), 3.63 - 3.77 (1Н, m, СН), 2.75 (1Н, dd, СЯН-N, 2J = 13.2 Hz, 3J = 3.5 Hz), 2.43 (1Н, dd, СНЯ-N,
нн нн
J = 13.2 Hz, ^„„=12.7 Hz), 2.42 (1Н, br.s, ОН), 1.96 (1Н, dd, СЯН-С-carborane, 2J = 16.7 Hz, 3J = 6.9 Hz), 1.58 (1Н, dd,
нн нн
СНЯ-С-carborane, 2J = 16.7 Hz, 3J = 3.8 Hz), -2.75 (2Н, br.s,
нн нн
pyrrole-NH),
General procedure of synthesis of carboranylporphyrins 25, 26.
To the solution of 0.03 mmol of 19 or 20 in 10 ml of CHCl3 0.1 ml of trifluoroacetic acid was added and reaction mixture was kept at 200 C with stirring for 2 h. The solvent was evaporated in vacuo. The residue was purified on a SiO2 (column 1x20 cm) using CHCl3:CH3OH (14:1 v/v) as eluent.
5,10,15,20-Tetra[p-2-hydroxy-3-(1 '-o-phenylcarboran-2 '-yl) propyl]aminophenylporphyrin, 25. Yield 50 mg (95.0%). Found: C 59.04, H 6.37, B 24.57, N 6.38 %. C88H114B40N8O4 requires C 59.37, H 6.45, B 24.29, N 6.29 %. m/z (MALDI): 1780 [M+]. IR (hexachloro-1,3-butadiene) vmax cm-1: 3416 (ОН, NH), 2586 (ВН). UV-vis (CHCl3) lmax nm (lg e): 423 (4.92), 553 (3.83), 599 (3.43). 1Н NMR (CDCl3) Sppm: 9.65 (8Н, s, pyrrole-H). 8.93 (4Н, s, NH), 7.36 - 8.65 (36Н, m, Ph), 3.71 - 3.82 (4Н, m, СН), 2.60 (4Н, br.s, ОН), 2.35 (4Н, dd, СЯН-N, 2J = 13.9 Hz, 3J = 3.9 Hz), 2.18
нн нн
(4Н, dd, СНЯ-N, 2J = 13.9 Hz, 3J = 12.3 Hz), 2.08 (4Н, dd,
нн нн
СЯН-С-carborane, 2J = 16.2 Hz, 3J = 6.9 Hz), 1.64 (4Н, dd,
нн нн
СНЯ-С-carborane, 2J = 16.2 Hz, 3J = 3.9 Hz), -2.63 (2Н, br.s,
нн нн
pyrrole-NH).
5,10,15,20-Tetra[p-2-hydroxy-3-(1 '-o-carboran-2 '-yl) propyl]aminophenylporphyrin, 26. Yield 42 mg (93.5%). Found: C 52.39, H 6.72, B 29.03, N 7.46 %. C64H98B40N8O4 requires C, 52.08; H, 6.69; B, 29.30; N, 7.59 %. m/z (MALDI): 1477 [M+]. IR (hexachloro-1,3-butadiene) vmax cm-1: 3410 (ОН, NH), 2602 (ВН). UV-vis (CHCl 3) lmax nm (lg e):433 (4.93), 563 (3.95), 612 (3.62). 1Н NMR (CDCl3) S ppm: 9.60 (8Н, s, pyrrole-H), 8.90 (4Н, s, NH), 7.40 - 8.70 (16Н, m, Ph), 3.70 - 3.87 (4Н, m, CH ), 3.25 (4H, br.s, carborane-H), 2.58 (4Н, br.s, ОН), 2.30 (4Н, dd, СЯН-N, J = 14.0 Hz, 3J = 4.0 Hz), 2.20 (4Н, dd, СНЯ-N, 2J = 13.6 Hz, J1"1 =
нн нн нн
12.0 Hz), 2.04 (4Н, dd, СЯН-С-carborane, 2J = 16.0 Hz, 3J = 7.0
нн нн
Hz), 1.60 (4Н, dd, СНЯ-С-carborane, 2J = 16.0 Hz, 3J = 3.8 Hz),
нн нн
-2.60 (2Н, br.s,pyrrole-NH).
General procedure of synthesis of carboranylporphyrins 30-32.
To the solution of porphyrin 1 (0.08 mmol) in 10 ml of toluene 0.16 mmol of corresponding isocyanato carborane (27, 28 or 29) was added, and the reaction mixture was refluxed for 8-48 h. The toluene was evaporated in vacuo, and the residue was purified on SiO2 (column 1x20 cm) using CH2Cl2-hexane mixture (7:2 v/v) as eluent.
5-[4-(o-Carboran-1-yl)aminocarbonylaminophenyl]-10,15,20-triphenylporphyrin, 30. Yield 57 mg (87.7%). Found: C 68.79, H 5.22, B 13.54, N 10.43 %. C47H42B10N6O requires C 69.27, H 5.19, B 13.27, N 10.31 %. m/z (MALDI): 816 [M+]. IR (KBr) vmax cm-1: 3411 (NH), 2598 (ВН), 1628 (С=О). UV-vis (CHCl3) Xmax nm (lg e): 418 (4.94), 522 (4.07), 555 (3.79), 646 (3.08). 1Н NMR (CDCl3) S ppm: 8.89 (8Н, s, pyrrole-H), 7.35 - 8.20 (19Н, m, Ph), 5.23 (2H, s, КН), 3.64 (1Н, br.s, carborane-Н), -2.14 (2H, br.s, pyrrole-NH).
5-[4-(o-Carboran-9-yl)aminocarbonylaminophenyl]-10,15,20-triphenylporphyrin, 31. Yield 38 mg (58.5%). Found: C 68.92, H 5.16, B 13.41, N 10.36 %. C47H42B10N6O requires C 69.27, H 5.19, B 13.27, N 10.31 %. m/z (MALDI): 816 [M+]. IR (KBr) vmax cm-1: 3389 (NH), 2593 (ВН), 1631 (С=О). UV-vis (CHCl3) Xmsx nm (lg e): 420 (4.92), 522 (4.03), 552 (3.78), 647 (3.04). 1Н NMR (CDCl3) S ppm: 8.76 (8Н, s, pyrrole-H), 7.20 - 8.10 (19Н, m, Ph), 5.12 (2H, s, МН), 3.44 (1Н, br.s, carborane-Н), -2.20 (2H, br.s, pyrrole-NH).
5-[4-(m-Carboran-9-yl)aminocarbonylaminophenyl]-10,15, 20-triphenylporphyrin, 32. Yield 43 mg (66.2%). Found: C 68.92, H 5.14, B 13.44, N 10.40 %. C47H42B10N6O requires C 69.27, H 5.19, B 13.27, N 10.31 %. m/z (MALDI): 816 [M+]. IR (KBr) vmax cm-1: 3387 (NH), 2596 (ВН), 1629 (С=О). UV-vis (CHCl3) lmax nm(lg e): 425 (4.93), 525 (4.02), 560 (3.78), 649 (3.00). 1Н NMR(CDCl3) S ppm: 8.89 (8Н, s,pyrrole-H), 7.45 - 8.32 (19Н, m, Ph), 5.27 (2H, s, N^, 3.61 (1Н, br.s, carborane-Н), -2.03 (2H, br.s,pyrrole-NH).
General method of synthesis of carboranylporphyrins
33-35.
To the solution of 2 (0.075 mmol) in the mixture of 10 ml of toluene and 10 ml of acetonitrile 0.6 mmol of the corresponding isocyanato carborane (27, 28 or 29) was added, and the reaction mixture was refluxed for 8-48 h. The solvents were evaporated in vacuo, and the product was isolated by column chromatography (column 1x20 cm) with CH2Cl2-CH3OH mixture (10:1 v/v) as eluent.
5,10,15,20-Tetra[4-(o-carboran-1-yl)aminocarbonylamino-phenyl]porphyrin, 33. Yield 95 mg (90.5%). Found: C 47.88, H 5.43, B 30.07, N 11.96 %. C56H78B40N12O4 requires C 47.51, H 5.55, B 30.55, N 11.87 %. m/z (MALDI): 1418 [M+]. IR (KBr) vmax cm-1: 3416 (NH), 2605 (ВН), 1627 (С=О). UV-vis (CH3CN) if nm (lg e): 419 (4.95), 520 (4.10), 557 (3.84), 647 (3.11). 1Н NN MR (CD 3CN) S ppm: 8.82 (8Н, s, pyrrole-H), 7.40 - 8.33 (16Н, m, Ph), 5.40 (8H, s, N^, 3.76 (4Н, br.s, carborane-Н), -2.05 (2H, br.s,pyrrole-NH).
5,10,15,20-Tetra[4-(o-carboran-9-yl)aminocarbonylamino-phenyl]porphyrin, 34. Yield 68 mg (64.8%). Found: C 47.93, H 5.50, B 29.98, N 11.89 %. C56H78B40N12O4 requires C 47.51, H 5.55,
B 30.55, N 11.87 %. m/z (MALDI): 1418 [M+]. IR (KBr) vmax cm-1: 3385 (NH), 2586 (ВН), 1630 (С=О). UV-vis (CH3CN) ^Jnm (lg s): 420 (4.94), 517 (4.13), 560 (3.87), 645 (3.08). 1H NMRm(CD3CN) S ppm: 8.85 (8H, s,pyrrole-H), 7.30 - 8.30 (16H, m, Ph), 5.61 (8H, s, NH), 3.70 (4H, br.s, carborane-H), -2.10 (2H, br.s,pyrrole-NH).
5,10,15,20-Tetra[4-(m-carboran-9-yl)aminocarbonylamino-phenyl]porphyrin, 35. Yield 74 mg (70.5%). Found: C 47.94, H 5.66, B 30.12, N 12.04 %. C56H78B40N12O4 requires C 47.51, H 5.55, B 30.55, N 11.87 %. m/z (MALDI): 1418 [M+]. IR (KBr) vmax cm-1: 3390 (NH), 2592 (BH), 1628 (С=О). UV-vis (CH3CN) Г^ nm (lgs): 420 (4.94), 517 (4.12), 560 (3.87), 645 (3.07). 1H "nMR (CD3CN) S ppm: 8.96 (8H, s,pyrrole-H), 7.35 - 8.18 (16H, m, Ph), 5.54 (8H, s, NH), 3.67 (4H, br.s, carborane-H), -2.18 (2H, br.s, pyrrole-NH).
Results and Discussion
Carboranylmethylation of Porphyrins 1 and 2 with Carboranylmethyl Triflates
Previously we have synthesized 1-trifluoromethane sulfonylmethyl-o-carborane (3)[9] and 1-trifluoromethane sulfonylmethyl-1-carba-closo-dodecaborate cesium (4).[10] These compounds were efficient in the reactions of alkylation of aminoethyl group in chlorophyll а derivatives.[3,10-11] In contrast to aryl- and vinyl triflates widely used in chemical modifications of aromatic compounds,[12] the reactions of carboranyltriflates 3 and 4 with nucleophiles remain poorly investigated. We took advantage of the fact that triflates 3 and 4 are highly reactive with Ж-nucleophiles and conjugated the carborane polyhedra with porphyrins 1 and 2 (Scheme 1).
Alkylation of amino groups in 1 and 2 with carboranyltriflates 3 and 4 in the presence of sodium acetate in acetonitrile produced mono- and tetracarborane substituted porphyrins (5-8) with quantitative yields (Scheme 1). Importantly, 6 and 8 that contain anionic closo-monocarba-dodecaboranyl group were soluble in water, making these compounds perspective for practical use.
A structurally close compound in which three o-carborane polyhedra were linked to the porphyrin macrocycle through the aminomethylene group[13] has been synthesized by sequential transformations of 5,10,15-tris(4-nitrophenyl)-20-phenylporphyrin into the respective amino derivative after reduction in SnCl2-HCl. Then the amino derivative reacted with 1-formyl-o-carborane and ultimately the prepared imino derivative was reduced with NaBH4 to produce 5,10,15-tris[(carboranylaminomethyl)phenyl]-20-phenylporphyrin. In our method structurally similar compounds can be synthesized in one step with high yields.
Aminolysis of Carboranylepoxides porphyrins 1 and 2
with Amino-
Another approach for direct introduction of boron polyhedra into aminoporphyrins 1 and 2 is based on the reaction of aminolysis of 1,2-carboranylepoxides.[14-15] Aminolysis of epoxides is efficient for preparation of p-aminoalcohols, the important intermediates in the synthetic procedures to obtain biologically active compounds. However, it remained unknown whether aminoporphyrins 1 and 2 react with organic epoxides. To functionalize the amino groups in 1 and 2 with carborane epoxides 9-10[16] we used the catalytic activity of zinc chloride in the opening of the epoxide ring with nucleophiles.[17] However, zinc chloride might react with porphyrins to form metal complexes. Therefore, we first obtained Zn (11, 13) and Pd (12, 14) complexes of 1 и 2,[18-19] and these metal complexes were put into the reactions with carborane epoxides. We found that the catalytic opening of the epoxide ring in carboranes 9-10 by amino groups of metal containing porphyrins (11-14) easily occurred in boiling acetonitrile or THF in the presence of 1-3 mol% ZnCl2. These reactions resulted in boronated metal porphyrins 15-22 in which the aminoalcohol spacer linked the carborane polyhedron with the porphyrin macrocycle (Scheme 2). All compounds were obtained in high yields.
h2n-
J \
nh2
-nh n-
-n nh-
//VJ
-nh2
r/^0s02cf3 (3-4)
NaOAc
MeCN
t°
nh2
7 r = r1
8 R = R2 • = С or CH
о = BH
Scheme 1.
11 M=Zn
12 M = Pd
О (9-10)
ZnCI2 ТГФ t?
19 M = Zn, R = R1
20 M = Zn, R = R2
21 M = Pd, R = R1
22 M = Pd, R= R2
Scheme 2.
15-16 or 19-20
25 r = r1
26 r = r2
Scheme 3.
Demetallation of the products of aminolysis of 15-16 and 19-20 with trifluoroacetic acid in methylene chloride1201 allowed us to obtain boronated p-aminoalcohol derivatives of porphyrins 23-26 in good yields (Scheme 3).
Interestingly, only one regioisomer was formed in this reaction. It seems likely that the attack by amine nucleophile takes place exclusively at the less hindered position, namely at the methylene group of epoxyde ring. Compounds 15-26 possess the asymmetric carbon atom, and presumably two enantiomeres can be formed. The reactions of carboranyle-poxides 9, 10 with free base porphyrins 1 and 2 generated
very low yields (<3%) of resulting products, probably, because of the deficit of the catalyst due to preferential formation of metal porphyrin complexes.
Amidation of Porphyrins 1 and 2 with Carboranyl-isocynates
To introduce the carborane polyhedra into 1 and 2 we used 1-isocyanato-o-carborane (27),[21] 9-isocyanato-o-and 9-isocyanato-m-carboranes (28, 29)[22] in which the isocyanate group is hydrolytically stable and can react with
1 or 2
R-N=C=0 (27 - 29)
toluene/CH3CN, t°
• = C or CH O = B or BH
Scheme 4.
primary and secondary amines. The reactions of 1 and 2 with isocyanates 27-29 in boiling toluene smoothly produced stable boron containing conjugates 30-35 (Scheme 4).
The position of the isocyanate group in the carborane significantly influenced the rate of the reaction and the yields of carboranylporphyrins 30-35. As expected, the ability of isocyanate 27 to react with amino groups in 1 and 2 was higher than that of isocyanates 28, 29. This difference can be explained by a nonuniform distribution of electron density on skeletal atoms of carborane polyhedra[23] that gives rise to various electronic effects of carboranyl groups as substituents. Therefore, the same functional groups linked to the skeletal atoms would show differential activity. In compound 27 the N=C=O group is linked to the electron-withdrawing 1-o-carboranyl group (< = + 0.38)[24-25] whereas in compounds 28 and 29 the N=C=O groups are located at electron-donating 9-o- (<< = -0.23) and 9-m- (< = -0.12)[24-25] carboranyl groups, thereby making the nucleophilic conjugation of aminoporphyrins 1 and 2 more difficult. In the resulting carboranylporphyrins 30-35 the carboranes are linked to the porphyrin macrocycle via stable amide bonds. One may anticipate that 30-35 will fit the requirements for BNCT since the conjugation of boron polyhedra to dendrim-ers via the amide bonds of a similar nature has been shown to produce efficient agents.[26-27]
The spectral data (UV-, IR-, 'H NMR- and mass-spectra) confirmed the structure of compounds 5-8, 15-26 and 30-35. IR spectra of novel boronated porphyrins exhibit intense bands at 2585-2600 cm-1 (6, 9, 15-26, 30-35) and 2530-2534 cm-1 (5, 7) corresponding to the stretching vibrational modes of BH groups of neutral and anionic
closo--carborane polyhedra, respectively. In all IR spectra of novel carboranylporphyrins there are bands at 3400 cm-1 assigned to the vibrational modes of NH groups. It is worth-noting that in compounds 15-26 the bands of NH groups overlap with those of OH groups of amino alcohol spacer lying in the spectral region of 3200-3600 cm-1. In 30 - 35 the bands at about 1630 cm-1 are attributed to amide C=O groups.
In the NMR 1H spectra of 5-8, 15-26, 30-35 the singlet signals at 8 = 4.30-5.40 ppm corresponded to the protons of spacer's amino groups. In 5-8 the singlet signals at 8 = 1.80 ppm reflected the protons in methylene groups, thereby confirming the conjugation of carborane polyhedra with porphyrin macrocycles. According to 1H NMR spectra the protons of methylene groups in 15-26 are magnetically non-equivalent and manifested themselves as the doublets of doublets signals.
Conclusions
In summary, we developed a simple and efficient synthetic approaches to carboranyl substituted amino-porphyrin derivatives based on the one stage reactions of amino derivatives of 5,10,15,20-tetraphenylporphyrins with carboranylmethyl triflates or carboranyl isocyanates. We found that the ZnCl2-catalyzed aminolysis of carborane epoxides with aminophenylporphyrins were of importance only in a case of metal complexes of tetrapyrrole macrocycles. These reactions were highly regioselective. Demetallation of zinc complexes produced free base boro-nated porphyrin amino alcohols in high yields.
Acknowledgements. This work was supported by grants of Russian Foundation for Basic Research (Projects 09-04-97511-r-centre-a, 08-03-99084-r_ofi) and Analytical Department Target Program, Project № 2.1.1/2889.
References
1. Renner M.W., Miura M., Easson M.W., Vicente M.G.H. AntiCancer Agents in Med. Chem. 2006, 6, 145-157.
2. Ratajski M., Osterloh J., Gabel D. Anti-Cancer Agents in Med. Chem. 2006, 6, 159-166.
3. Olshevskaya V.A., Zaitsev A.V., Savchenko A.N., Shtil A.A., Cheong C.S., Kalinin V.N. Bull. Korean Chem. Soc. 2007, 28, 1910-1916.
4. Soloway A.H., Tjarks W., Barnum B.A., Rong F.G., Barth R.F., Codogni I.M., Wilson J. G. Chem. Rev. 1998, 98, 1515-1562.
5. Wellum G.R., Tolpin E. I., Soloway A. H., Kaczmarczyk A. Inorg. Chem. 1977, 16, 2120-2122.
6. Tolpin E.I., Wellum G.R., Berley S.A. Inorg. Chem. 1978, 17, 2867-2873.
7. Kruper W.J., Chamberlin T.A., Kochanny M. J. Org. Chem. Soc. 1989, 54, 2753-2756.
8. Semeikin A.S., Koifman O.I., Berezin B.D. Chem. Heterocycl. Comp. 1982, 18, 1046-1047.
9. Kalinin V.N., Ol'shevskaya V.A., Rys E.G., Tyutyunov A.A., Starikova Z.A., Korlyukov A.A., Sung D.D., Ponomaryov A.B., Petrovskii P.V., Hey-Hawkins E. Dalton Trans. 2005, 903-908.
10. Ol'shevskaya V.A., Savchenko A.N., Zaitsev A.V., Kononova E.G., Petrovskii P.V., Ramonova A.A., Tatarskiy V.V., Moisenovich M.M., Kalinin V.N., Shtil A.A. J. Organomet. Chem. 2009, 694, 1632-1637.
11. Ol'shevskaya V.A., Nikitina R.G., Savchenko A.N., Malshakova M.V., Vinogradov A.M., Golovina G.V., Belykh
D.V., Kutchin A .V., Kaplan M.A., Kalinin V.N., Kuzmin V.A., Shtil A.A. Bioorg. Med. Chem. 2009, 17, 1297-1306.
12. Barazhenok L., Nenajdenko V.G., Balenkova E. S. Tetrahedron 2000, 56, 3077-3119.
13. Luguya R., Jaquinod L., Fronczek F.R., Vicente M.G.H., Smith K.M., Tetrahedron 2004, 60, 2757-2763.
14. Zakharkin L.I., Kenzhetaeva V.D., Zhigareva G.G. Russ. Chem. Bull. 1975, 24, 521-526.
15. Zakharkin L.I., Zhigareva G.G., Kenzhetaeva V.D. Russ. Chem. Bull. 1975, 24, 527-529.
16. Kenzhetaeva V.D., Kazantsev A.V., Zakharkin L.I. Zh. Obsch. Khim. 1974, 46, 340-342 (in Russ.).
17. Pachon L.D., Games P., van Brussel J.J.M., Reedijk J. Tetrahedron Lett. 2003, 44, 6025-6027.
18. Fleischer E.B., Shachter A.M. Inorg. Chem. 1991, 30, 37633769.
19. Adler A.D., Longo F.R., Kampas F., Kim J. J. Inorg. Nucl. Chem. 1970, 32, 2443-2445.
20. Miura M., Gabel D., Oenbrink G., Fairchied R.G. Tetrahedron Lett. 1990, 31, 2247-2250.
21. Kalinin V.N., Astakhin A.V., Kazantsev A.V., Zakharkin L. I. Russ. Chem. Bull. 1984, 33, 1508-1510.
22. Ol'shevskaya V.A., Zaitsev A.V., Ayub R., Petrovskii P.V., Kononova E.G., Tatarskii V.V., Shtil A.A., Kalinin V.N. Doklady Chemistry 2005, 405, 230-234.
23. Kalinin V.N., Ol'shevskaya V.A. Russ. Chem. Bull. 2008, 57, 815-836.
24. Zakharkin L.I., Kalinin V.N., Snyakin A.P., Kvasov B.A. J. Organometal. Chem. 1969, 18, 19-26.
25. Zakharkin L.I., Kovredov A.I., Ol'shevskaya V.A. Russ. Chem. Bull. 1981, 1775-1777.
26. Barth R.F., Adams D.M., Soloway A.H., Alam F., Darby M.V. Bioconjug. Chem. 1994, 5, 58-66.
27. Liu L., Barth R.F., Adams D.M., Soloway A.H., Reisfeld R.A. Anticancer Res. 1996, 16, 2581-2588.
Received 16.09.2009 Accepted 17.10.2009
