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 Y[CAS?];
PubChem CID	73110;
ChemSpider	65891 Y;
UNII	Y96MQM21V9;
KEGG	C19701;
ChEBI	CHEBI:135511 Y;
ChEMBL	ChEMBL370100 Y;
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 Y; Key:QEHOIJJIZXRMAN-QZQSLCQPSA-N Y;

Rebeccamycin (NSC 655649) is a weak topoisomerase I inhibitor isolated from Nocardia bacteria.¹² 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):⁵⁶

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

Dichlorochromopyrrolate synthase (RebD) couples two molecules of the intermediate 2-iminio-3-(7-chloroindol-3-yl)propionate to give dichlorochromopyrrolic acid:⁷

4

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

O₂

2 H₂O

Rightward reaction arrow with minor substrate(s) from top left and minor product(s) to top right

2

2D representation of the chemical structure of Q27095865.

dichlorochromopyrrolic acid

+ 2 NH₃

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

dichlorochromopyrrolic acid

+ 4 NADH
+ 4 H⁺

4 O₂

2 CO₂

2D representation of the chemical structure of Q27225728.

dichloroarcyriaflavin A

+ 4 NAD⁺
+ 6 H₂O

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

dichloroarcyriaflavin A

+

2D representation of the chemical structure of Q23905968.

glucose

H₂O

Rightward reaction arrow with minor product(s) to top right

2D representation of the chemical structure of Q27105177.

4'-demethylrebeccamycin

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): 668–678. 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.
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): 2084–2092. 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): 15652–15663. CiteSeerX 10.1.1.537.5773. doi:10.1021/bi051706e. PMID 16313168.
Pommerehne K, Walisko J, Ebersbach A, Krull R (May 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): 11591–11596. 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): 12289–12298. Bibcode:2006JAChS.12812289H. doi:10.1021/ja063898m. PMID 16967980.

Biosynthesis

References

Further reading