[en] We report the efficient synthesis involving palladium-catalyzed reactions and biological evaluation of new naphthocarbazoles designed as potential anticancer agents. The use of 5- and 6-benzyloxyindoles generated three substitution sites which were successively exploited to introduce several hydrophilic side chains. The cytotoxicity of the newly designed compounds was evaluated on three cell lines. Several compounds showed a marked cytotoxicity with IC(50) values in the sub-micromolar range. This is the case for the 3-hydroxy-naphthopyrrolocarbazoledione 37, bearing a dimethylaminoethyl side chain, which is extremely cytotoxic to L1210 and DU145 cells (IC(50): 36 nM, 108 nM) and induces an accumulation of L1210 cells in the G2+M phases of the cell cycle. Some of the most cytotoxic compounds were tested for inhibition of CDK-5, GSK-3 and topoisomerase I, and their interaction with DNA was also evaluated. Interaction with DNA was detected, suggesting that nucleic acids represent a privileged target for these molecules.
Bailly C. Targetting DNA and Topoisomerase I with Indolocarbazole Antitumor Agents. In Small Molecule DNA and RNA Binders; Demeunynck, M.; Bailly, C.; Wilson, W., Eds.; Wiley-VCH: New York, 2003; Vol 2, pp 538-575.
Pines, J. Four-dimensional Control of the Cell Cycle. Nat. Cell. Biol. 1999, 1, E73-E79.
Morgan, D. O. Cyclin-dependent Kinases: Engines, Clocks, and Microprocessors. Annu. Rev. Cell. Dev. Biol. 1997, 13, 261-269.
Marschal, M.; Stein-Gerlach, M.; Freitag, M.; Kupfer, R.; Van den Bogaard, M.; Stamminger, T. Direct Targeting of Human Cytomegalovirus Protein Kinase pUL97 by Kinase Inhibitors is a Novel Principle for Antiviral Therapy. J. Gen. Virol. 2002, 83, 1013-1023.
Long, B. H.; Rose, W. C.; Vyas, D. M.; Matson, J. A.; Forenza, S. Discovery of Antitumor Indolocarbazoles: Rebeccamycin, NSC655649, and Fluoroindolocarbazoles. Curr. Med. Chem. Anti-Cancer Agents 2002, 2, 255, 265.
Yoshinari, T.; Ohkubo, M.; Fukasawa, K.; Egashira, S.; Hara, Y.; Matsumoto, M.; Nakai, K.; Arakawa, H.; Morishima, H.; Nishimura, S. Mode of Action of a New Indolocarbazole Anti-cancer Agent, J-107088, Targeting Topoisomerase I. Cancer Res. 1999, 59, 4271-4275.
Arakawa, H.; Morita, M.; Kodera, T.; Okura, A.; Ohkubo, M.; Morishima, H.; Nishimura, S. In vivo Anti-tumor Activity of a Novel Indolocarbazole Compound, J-107088, on Murine and Human Tumors Transplanted into Mice. Jpn. J. Cancer Res. 1999, 90, 1163-1170.
Balasubramanian, B. N.; St Laurent, D. R.; Saulnier, M. G.; Long, B. H.; Bachand, C.; Beaulieu, F.; Clarke, W.; Deshpande, M.; Eummer, J.; Fairchild, C. R.; Frennesson, D. B.; Kramer, R.; Lee, F. Y.; Mahler, M.; Martel, A.; Naidu, B. N.; Rose, W. C.; Russell, J.; Ruediger, E.; Solomon, C.; Stoffan, K. M.; Wong, H.; Zimmermann, K; Vyas, D. M. Design and Synthesis of a Fluoroindolocarbazole Series as Selective Topoisomerase I Active Agents. Discovery of Water-soluble 3,9-difluoro-12, 13-dihydro-13-[6-amino-β-D-glucopyranosyl]-5H,13H-benzo[b] -thienyl[2,3-a]-pyrrolo[3,4-c]carbazole-5,7(6H)-dione (BMS-251873) with Curative Antitumor Activity Against Prostate Carcinoma Xenograft Tumor Model. J. Med. Chem. 2004, 47, 1609-1612.
Akinaga, S.; Sugiyama, K.; Akiyama, T. (7-hydroxystaurosporine) and other Indolocarbazole Compounds: a New Generation of Anti-cancer Agents for the New Century? Anti-Cancer Drug Des. 2000, 15, 43-52.
Bailly, C.; Goossens, J.-F.; Laine, W.; Anizon, F.; Prudhomme, M.; Ren, J.; Chaires, J. B. Formaldehyde-Induced Alkylation of a 2′-Aminoglucose Rebeccamycin Derivative to Both A·T and G· C Base Pairs in DNA. J. Med. Chem. 2000, 43, 4711-4720.
Ohe, Y.; Tanigawara, Y.; Jujii, H.; Ohtsu, T.; Wakita, H.; Igarashi, T.; Minami, H.; Eguchi, K.; Shinkai, T.; Tamura, T.; Kunotoh, H.; Saijo, N.; Okada, K.; Ogino, H.; Sasaki, Y. Phase I and Pharmacology Study of 5-days infusion of NB-506. Proc. Am. Soc. Clin. Oncol. 1997, 16, 199a.
Dowlati, A.; Remick, S. C.; Majka, S.; Ingalis, S.; Hoppel, C.; Spiro, T.; Gerson, S.; Willson, J. K. V. A phase I Clinical and Pharmacocinetic Study of Rebeccamycin Analogue (NCS655649) given Daily for 5 Consecutive Days. Proc. Am. Soc. Clin. Oncol. 1999, 18, 181a.
Long, B. H.; Balasubramanian, B. N. Non Camptothecin Topoisomerase I Active Compounds as Potential Anticancer Agents. Expert Opin. Ther. Pat. 2000, 10, 635-666.
Routier, S.; Ayerbe, N.; Mérour, J. Y.; Coudert, G.; Bailly, C.; Pierré, A.; Pfeiffer, B.; Caignard, D. H.; Renard, P. Synthesis and Biological Activity of 7-Azaindolocarbazoles. Tetrahedron 2002, 68, 6621-6630.
Marminon, C.; Pierré, A.; Pfeiffer, B.; Pérez, V.; Léonce, S.; Renard P.; Prudhomme, M.; Syntheses and Antiproliferative Activities of Rebeccamycin Analogues Bearing two 7-Aazaindole Moieties. Bioorg. Med. Chem. 2003, 11, 679-687.
Marminon, C.; Pierré, A.; Pfeiffer, B.; Pérez, V.; Léonce, S.; Joubert, A.; Bailly, C.; Renard, P.; Hickman, J.; Prudhomme M. Syntheses and Antiproliferative Activities of 7-Azarebeccamycin Analogues Bearing One 7-Azaindole Moiety. J. Med. Chem. 2003, 46, 609-622.
Zhang, H.-C.; White, K. B.; Ye, H.; McComsey, D. F.; Derian, C. K; Addo, M. F.; Andrade-Gordon, P.; Eckardt, A. J.; Conway, B. R.; Westover, L.; Xu, J. Z.; Look, R.; Demarest, K. T.; Emanueland, S.; Maryanoff, B. E. Macrocyclic Bisindolylmaleimides as Inhibitors of Protein Kinase C and Glycogen Synthase Kinase-3. Bioorg. Med. Chem. Lett. 2003, 13, 3049-3053.
Kuo, G.-H.; Prouty, C.; DeAngelis, A.; Shen, L.; O'Neill, D. J.; Shah, C.; Connolly, P. J.; Murray, W. V.; Conway, B. R.; Cheung, P.; Westover, L.; Xu, J. Z.; Look, R. A.; Demarest, K. T.; Emanuel, S.; Middleton, S. A.; Jolliffe, L.; Pat Beavers, M.; Chen X. Synthesis and Discovery of Macrocyclic Polyoxygenated Bis-7-azaindolylmaleimides as a Novel Series of Potent and Highly Selective Glycogen Synthase Kinase- β3 Inhibitors. J. Med. Chem. 2003, 46, 4021-4031.
Zhu, G.; Conner, S. E.; Zhou, X.; Shih, C.; Li, T.; Anderson, B. D.; Brooks, H. B.; Campbell, R. M.; Considine, E.; Dempsey, J. A.; Faul, M. M.; Ogg, C.; Patel, B.; Schultz, R. M.; Spencer, C. D.; Teicher, B.; Watkins, S. A. Synthesis, Structure-Activity Relationship, and Biological Studies of Indolocarbazoles as Potent Cyclin D1-CDK4 Inhibitors. J. Med. Chem. 2003, 46, 2027-2030.
Gingrich, D. E.; Reddy, D. R.; Iqbal, M. A.; Singh, J.; Aimone, L. D.; Angeles, T. S.; Albom, M.; Yang, S.; Ator, M. A.; Meyer, S. L.; Robinson, C.; Ruggeri, B. A.; Dionne, C. A.; Vaught, J. L.; Mallamo, J. P.; Hudkins R. L. A New Class of Potent Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors: Structure-Activity Relationships for a Series of 9-Alkoxy-methyl-12-(3-hydroxyprpyl)indeno[2,1-a]pyrrolo[3,4-c]carbazole-5-one and the Identification of CEP-5214 and Its Dimethylglycine Ester Prodrug Clinical Candidate CEP-7055. J. Med. Chem. 2003, 46, 5375-5388.
Piers, E.; Britton, R.; Andersen, R. J. Improved Synthesis of Isogranulatimide, a G2 Checkpoint Inhibitor. Syntheses of Didemnimide C, Isodidemnimide A, Neodidemnimide A, 17-Methylgranulatimide, and Isogranulatimides A-C. J. Org. Chem. 2000, 65, 530-535.
Ugon, B.; Pfeiffer, B.; Renard P.; Prudhomme M. Synthesis of Granulatimide Analogues Bearing a Maleimide Instead of an Imidazole Heterocycle. Tetrahedron Lett. 2003, 44, 3935-3937.
Terpin, A.; Winklhofer, C.; Schumann, S.; Steglich, W. Synthesis and Cyclisation of Didemnimide C and its Imidazol-1-yl Isomer. Tetrahedron 1998, 54, 1745-1752.
Hugon, B.; Pfeiffer, B.; Renard P.; Prudhomme M. Synthesis of Isogranulatimide Analogues Possessing a Pyrrole Moiety Instead of an Imidazole Heterocycle. Tetrahedron Lett. 2003, 44, 3927-3930.
Routier, S.; Coudert, G.; Mérour, J. Y. Synthesis of Naphthopyrrolo[3,4-c]carbazoles. Tetrahedron Lett. 2001, 42, 7025-7028.
Sanchez-Martinez, C.; Faul, M. M.; Shih, C.; Sullivan, K. A.; Grutsch, J. L. Cooper, J. T.; Kolis, S. P. Synthesis of Aryl- and Heteroaryl[a]pyrrolo[3,4- c]carbazoles. J. Org. Chem. 2003, 68, 8008-8014.
Sanchez-Martinez, C.; Shih, C.; Faul, M. M.; Zhu, G.; Paal, M.; Somoza, C.; Li, T.; Kumrich, C. A.; Winneroski, L. L.; Xun, Z.; Brooks, H. B.; Patel, B. K. R.; Schultz, R. M.; DeHahn, T. B.; Spencer, C. D.; Watkins, S. A.; Considine, E.; Dempsey, J. A.; Ogg, C. A.; Campbell, R. M.; Anderson B. A.; Wagner J. Aryl-[a]pyrrolo[3,4-c]carbazoles as Selective Cyclin D1-CDK4 Inhibitors. Bioorg. Med. Chem. Lett. 2003, 13, 3835-3839.
Zhu, G.; Conner, S.; Zhou, X.; Shih, C.; Brooks, H. B.; Considine, E.; Dempsey, J. A.; Ogg, C.; Patel, B.; Schultz, R. M.; Spencer, C. D.; Teicher B.; Watkins, S. A. Synthesis of Quinolinyl/isoquinolinyl[a]pyrrolo [3, 4-c] carbazoles as Cyclin D1/CDK4 Inhibitors. Bioorg. Med. Chem. Lett. 2003, 13, 1231-123.
Engler, T. A.; Furness, K.; Malhotra, S.; Sanchez-Martinez, C.; Shih, C.; Xie, W.; Zhu, G.; Zhou, X.; Conner, S.; Faul, M. M.; Sullivan, K. A.; Kolis, S. P.; Brooks, H. B.; Patel, B.; Schultz, R. M.; DeHahn, T. B.; Kirmani, K.; Spencer, C. D.; Watkins, S. A.; Considine, E. L.; Dempsey, J. A.; Ogg, C. A.; Stamm, N. B.; Anderson, B. D.; Campbell, R. M.; Vasudevan V.; Lytle M. L. Novel, Potent and Selective Cyclin D1/CDK4 Inhibitors: Indolo-[6,7-a]pyrrolo[3,4-c] carbazoles. Biorg Med Chem. Lett. 2003, 13, 2261-2267.
Knölker, H.-J., Reddy, K. R. Isolation and Synthesis of Biologically Active Carbazole Alkaloids. Chem. Rev. 2002, 102, 4303-4427.
Faul, M. M.; Engler, T. A.; Sullivan, K. A.; Grutsch, J. L.; Clayton, M. T.; Martinelli, M. J.; Pawlak, J. M.; LeTourneau, M.; Coffey, D. S.; Pedersen, S. W.; Kolis, S. P.; Furness, K.; Malhotra, S.; Al-awar, R. S.; Ray, J. E. Synthetic Approaches to Indolo[6,7-a]pyrrolo[3, 4-c]carbazoles: Potent Cyclin D1/CDK4 Inhibitors. J. Org. Chem. 2004, 69, 2967-2975.
Bergman, J.; Koch, E., Pelcman, B. Coupling Reactions of Indole-3-acetic Acid Derivatives. Synthesis of Arcyriaflavin A. J. Chem. Soc., Perkin trans 1 2000, 2609-2614.
Bit, R. A.; Crackett, P. H.; Harris, W.; Hill, C. H. Synthesis and Cyclisation of Didemnimide C and its Imidazol-1-yl Isomer. Tetrahedron Lett. 1993, 34, 5623-5626.
Lowinger, T. B.; Chu, J.; Spence, P. L. The Total Synthesis of (±)K252a. Tetrahedron Lett. 1995, 36, 8383-8686.
Adeva, M.; Buono, F.; Caballero, E.; Medarde, M.; Tomé, F. New Synthetic Approach to Arcyriaflavin-A and Unsymmetrical Analogs. Synlett 2000, 832-834.
Wood, J. L.; Petsch, D. T.; Stoltz, B. M.; Hawkins, E. M.; Elbaum, D.; Stover, D.R. Total Synthesis and Protein Kinase Activity of C(7) methyl Derivatives of K252. Synthesis 1999, 1529-1533.
Pindur, U.; Kim, Y.-S.; Schollmeyer, D. Cyclization Reactions of 2,2′-bis-N-methylindolyl to Potential Protein Kinase C Inhibitors. Heterocycles 1994, 38, 2267-2276.
Steglich, W.; Steffan, B.; Kopanski, L.; Eckhardt, G. E. Fungus Pigments; 36. Indole Pigments from the Fruit of the Slime Fungus Arcyria Denudata. Angew. Chem., Int. Ed. Engl. 1980, 19, 459.
Brenner, M.; Rexhausen, H.; Steffan, B.; Steglich, W. Synthesis of Arcyriarubin B and Related Bisindolylmaleimides. Tetrahedron 1988, 44, 2887-2892.
Faul, M. M.; Sullivan, K. A.; Winneroski, L. L. A General Approach to the Synthesis of Bisindolylmaleimides: Synthesis of Staurosporine Aglycone. Synthesis 1995, 1511-1516.
Ohkubo, M.; Nishimura, T.; Homna, T.; Morishima, H. Practical Synthesis of Indolopyrrolocarbazoles. Tetrahedron 1996, 52, 8099-8112.
Wang, J.; Rosingana, M.; Watson, D. J.; Dowdy, E. D.; Discordia, R. P.; Soundarajan, N.; Li, W. S. Practical Synthesis of the Rebeccamycin Aglycone and Related Analogs by Oxidative Cyclization of Bisindolylmaleimides with a Wacker-type Catalytic System. Tetrahedron Lett. 2001, 42, 8935-8937.
McCort, G.; Duclos, O.; Cadilhac, C.; Guilpain, E. A Versatile New Synthesis of 4-Aryl- and Heteroaryl-[3,4-c]pyrrolocarbazoles by [4+2] Cycloaddition Followed by Palladium Catalysed Cross Coupling. Tetrahedron Lett. 1999, 40, 6211-6215.
Neel, D. A.; Jirousek, M. R.; McDonald, J. H., III. Synthesis of Bisindolylmaleimides using a Palladium Catalyzed Cross-coupling Reaction. Bioorg. Med. Chem. Lett. 1998, 8, 47-50.
Nakano, Y.; Imai, D. Synthesis of 5-Substituted Quinolin-8-ols. Synthesis 1997, 1425-1428.
Yasuhara, A.; Sakamoto, T. Deprotection of N-sulfonyl nitrogen-heteroaromatics with tetrabutylammonium fluoride. Tetrahedron Lett. 1998, 39, 595-596.
Mettey, Y.; Compel, M.; Thomas, V.; Garnier, M.; Leost, M.; Ceballos-Picot, I.; Noble,M.; Endicott, J.; Vierfond, J.-M.; Meijer, L. Aloisines, a New Family of CDK/GSK-3 Inhibitors. SAR Study, Crystal Structure in Complex with CDK2, Enzyme Selectivity, and Cellular Effects. J. Med. Chem. 2003, 46, 222-236.
Léonce, S.; Pérez, V.; Casabianca-Pignède, M. R.; Anstatt, M.; Bisagni, E.; Atassi, G. In vitro Cytotoxicity of S16020-2, a New Olivacine Derivative. Invest. New Drugs 1998, 14, 169-180.
Bailly, C. DNA Relaxation and Cleavage assays to Study Topoisomerase I Inhibitors. Methods Enzymol. 2001, 340, 610-623.