Rebeccamycin
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| Other names | 7,10-dichloro-8-(3,4-dihydroxy-6-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-2-yl)-8,9-dihydro-1H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-1,3(2H)-dione |
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| Formula | C27H21Cl2N3O7 |
| Molar mass | 570.38 g·mol−1 |
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Rebeccamycin (NSC 655649) is a weak topoisomerase I inhibitor isolated from Nocardia bacteria.[1][2] It is structurally similar to staurosporine, but does not show any inhibitory activity against protein kinases. It shows significant antitumor properties in vitro (IC50=480nM against mouse B16 melanoma cells and IC50=500nM against P388 leukemia cells). It is an antineoplastic antibiotic and an intercalating agent.
Becatecarin (BMS-181176) is a synthetic analog of rebeccamycin.[3]
Rebeccamycin and becatecarin have been tested in phase II clinical trials for the treatment of lung cancer, liver cancer, breast cancer, lymphoma, retinoblastoma, kidney cancer, and ovarian cancer.[4]
Biosynthesis
An early step in the biosynthesis is the reaction of 7-chloro-L-tryptophan with oxygen catalysed by 7-chloro-L-tryptophan oxidase (RebO):[5][6]
Dichlorochromopyrrolate synthase (RebD) couples two molecules of the intermediate 2-iminio-3-(7-chloroindol-3-yl)propionate to give dichlorochromopyrrolic acid:[7]
The enzyme dichloroarcyriaflavin A synthase is responsible for forming the new aromatic bond between the indole components of dichlorochromopyrrolic acid, making a six-membered ring.[8]
The reaction proceeds in two stages. A protein component, called RebP, is an oxidase which contains heme and uses oxygen and nicotinamide adenine dinucleotide (NADH) to link the rings. Then it acts with a flavin-dependent partner called RebC to remove the two carboxylic acid groups by oxidative decarboxylation.[9]
The penultimate step in rebeccamycin's biosynthesis is the addition of a sugar group to one of the indole nitrogens by 4'-demethylrebeccamycin synthase (RebG).[7]
The final methylation is carried out by demethylrebeccamycin-D-glucose O-methyltransferase (RebM) using S-adenosyl methionine as cofactor.[7]
References
- ^ Nettleton DE, Doyle TW, Krishnan B, Matsumoto GK, Clardy J (January 1985). "Isolation and structure of rebeccamycin-a new antitumor antibiotic from Nocardia aerocoligenes". Tetrahedron Letters. 26 (34): 4011–4014. doi:10.1016/S0040-4039(00)89280-1.
- ^ Bush JA, Long BH, Catino JJ, Bradner WT, Tomita K (May 1987). "Production and biological activity of rebeccamycin, a novel antitumor agent". The Journal of Antibiotics. 40 (5): 668–78. doi:10.7164/antibiotics.40.668. PMID 3112080.
- ^ Clinical trial number NCT00006017 at ClinicalTrials.gov
- ^ "2 Studies found for: BRN 4732638". Clinical Trials Gov.
- ^ Nishizawa T, Aldrich CC, Sherman DH (March 2005). "Molecular analysis of the rebeccamycin L-amino acid oxidase from Lechevalieria aerocolonigenes ATCC 39243". Journal of Bacteriology. 187 (6): 2084–92. doi:10.1128/JB.187.6.2084-2092.2005. PMC 1064027. PMID 15743957.
- ^ Howard-Jones AR, Walsh CT (December 2005). "Enzymatic genеration of the chromopyrrolic acid scaffold of rebeccamycin by the tandem action of RebO and RebD". Biochemistry. 44 (48): 15652–63. CiteSeerX 10.1.1.537.5773. doi:10.1021/bi051706e. PMID 16313168.
- ^ a b c Pommerehne, Kathrin; Walisko, Jana; Ebersbach, Anna; Krull, Rainer (2019). "The antitumor antibiotic rebeccamycin—challenges and advanced approaches in production processes". Applied Microbiology and Biotechnology. 103 (9): 3627–3636. doi:10.1007/s00253-019-09741-y. PMID 30888461.
- ^ Makino M, Sugimoto H, Shiro Y, Asamizu S, Onaka H, Nagano S (July 2007). "Crystal structures and catalytic mechanism of cytochrome P450 StaP that produces the indolocarbazole skeleton". Proceedings of the National Academy of Sciences of the United States of America. 104 (28): 11591–6. Bibcode:2007PNAS..10411591M. doi:10.1073/pnas.0702946104. PMC 1913897. PMID 17606921.
- ^ Howard-Jones AR, Walsh CT (September 2006). "Staurosporine and rebeccamycin aglycones are assembled by the oxidative action of StaP, StaC, and RebC on chromopyrrolic acid". Journal of the American Chemical Society. 128 (37): 12289–98. Bibcode:2006JAChS.12812289H. doi:10.1021/ja063898m. PMID 16967980.
Further reading
- Anizon F, Belin L, Moreau P, Sancelme M, Voldoire A, Prudhomme M, et al. (October 1997). "Syntheses and biological activities (topoisomerase inhibition and antitumor and antimicrobial properties) of rebeccamycin analogues bearing modified sugar moieties and substituted on the imide nitrogen with a methyl group". Journal of Medicinal Chemistry. 40 (21): 3456–65. doi:10.1021/jm9702084. PMID 9341921.
- Bailly C, Riou JF, Colson P, Houssier C, Rodrigues-Pereira E, Prudhomme M (April 1997). "DNA cleavage by topoisomerase I in the presence of indolocarbazole derivatives of rebeccamycin". Biochemistry. 36 (13): 3917–29. doi:10.1021/bi9624898. PMID 9092822.
- Bailly C, Qu X, Graves DE, Prudhomme M, Chaires JB (May 1999). "Calories from carbohydrates: energetic contribution of the carbohydrate moiety of rebeccamycin to DNA binding and the effect of its orientation on topoisomerase I inhibition". Chemistry & Biology. 6 (5): 277–86. doi:10.1016/S1074-5521(99)80073-8. PMID 10322124.