Chemistry:Rebeccamycin
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]
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Dichlorochromopyrrolate synthase (RebD) couples two molecules of the intermediate 2-iminio-3-(7-chloroindol-3-yl)propionate to give dichlorochromopyrrolic acid:[7]
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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]
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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]
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The final methylation is carried out by demethylrebeccamycin-D-glucose O-methyltransferase (RebM) using S-adenosyl methionine as cofactor.[7]
References
- ↑ "Isolation and structure of rebeccamycin-a new antitumor antibiotic from Nocardia aerocoligenes.". Tetrahedron Letters 26 (34): 4011–4014. January 1985. doi:10.1016/S0040-4039(00)89280-1.
- ↑ "Production and biological activity of rebeccamycin, a novel antitumor agent". The Journal of Antibiotics 40 (5): 668–678. May 1987. doi:10.7164/antibiotics.40.668. PMID 3112080.
- ↑ Clinical trial number NCT00006017 for "Two Rebeccamycin Analogue Regimens in Treating Patients With Advanced or Recurrent Non-small Cell Lung Cancer" at ClinicalTrials.gov
- ↑ "2 Studies found for: BRN 4732638". Clinical Trials Gov. https://clinicaltrials.gov/ct2/results?term=BRN+4732638.
- ↑ "Molecular analysis of the rebeccamycin L-amino acid oxidase from Lechevalieria aerocolonigenes ATCC 39243". Journal of Bacteriology 187 (6): 2084–2092. March 2005. doi:10.1128/JB.187.6.2084-2092.2005. PMID 15743957.
- ↑ "Enzymatic genеration of the chromopyrrolic acid scaffold of rebeccamycin by the tandem action of RebO and RebD". Biochemistry 44 (48): 15652–15663. December 2005. doi:10.1021/bi051706e. PMID 16313168.
- ↑ 7.0 7.1 7.2 "The antitumor antibiotic rebeccamycin-challenges and advanced approaches in production processes". Applied Microbiology and Biotechnology 103 (9): 3627–3636. May 2019. doi:10.1007/s00253-019-09741-y. PMID 30888461.
- ↑ "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): 11591–11596. July 2007. doi:10.1073/pnas.0702946104. PMID 17606921. Bibcode: 2007PNAS..10411591M.
- ↑ "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): 12289–12298. September 2006. doi:10.1021/ja063898m. PMID 16967980. Bibcode: 2006JAChS.12812289H.
Further reading
- "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): 3456–3465. October 1997. doi:10.1021/jm9702084. PMID 9341921.
- "DNA cleavage by topoisomerase I in the presence of indolocarbazole derivatives of rebeccamycin". Biochemistry 36 (13): 3917–3929. April 1997. doi:10.1021/bi9624898. PMID 9092822.
- "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): 277–286. May 1999. doi:10.1016/S1074-5521(99)80073-8. PMID 10322124.
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