Rebeccamycin

Rebeccamycin
Clinical data
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
ATC code	none;
Identifiers
	IUPAC name 1,11-dichloro-12-(4-O-methyl-β-D-glucopyranosyl)-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione;
CAS Number	93908-02-2 [CAS?];
PubChem CID	73110;
ChemSpider	65891 ;
UNII	Y96MQM21V9;
ChEBI	CHEBI:135511 ;
ChEMBL	ChEMBL370100 ;
CompTox Dashboard (EPA)	DTXSID70239880 ;
Chemical and physical data
Formula	C27H21Cl2N3O7
Molar mass	570.38 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CO[C@@H]1[C@H](O[C@H]([C@@H]([C@H]1O)O)N2C3=C(C=CC=C3Cl)C4=C5C(=C6C7=C(C(=CC=C7)Cl)NC6=C42)C(=O)NC5=O)CO;
	InChI InChI=1S/C27H21Cl2N3O7/c1-38-24-13(8-33)39-27(23(35)22(24)34)32-20-10(5-3-7-12(20)29)15-17-16(25(36)31-26(17)37)14-9-4-2-6-11(28)18(9)30-19(14)21(15)32/h2-7,13,22-24,27,30,33-35H,8H2,1H3,(H,31,36,37)/t13-,22-,23-,24-,27-/m1/s1 ; Key:QEHOIJJIZXRMAN-QZQSLCQPSA-N ;

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:^[5]^[6]

2D representation of the chemical structure of Q27120774.

7-chloro-L-tryptophan

O₂

H₂O₂

Reversible left-right reaction arrow with minor forward substrate(s) from top left, minor forward product(s) to top right, minor reverse substrate(s) from bottom right and minor reverse product(s) to bottom left

O₂

H₂O₂

2D representation of the chemical structure of Q27126524.

2-iminio-3-(7-chloroindol-3-yl)propionate

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.

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.

[1] 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.

[2] 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.

[3] Clinical trial number NCT00006017 at ClinicalTrials.gov

[4] "2 Studies found for: BRN 4732638". Clinical Trials Gov.

[5] 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.

[6] 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.

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Biosynthesis

References

Further reading