Rebeccamycin

Chemical compound From Wikipedia, the free encyclopedia

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.

Other names7,10-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
CAS Number
PubChem CID
Quick facts Clinical data, Other names ...
Rebeccamycin
Clinical data
Other names7,10-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
  • 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
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC27H21Cl2N3O7
Molar mass570.38 g·mol−1
3D model (JSmol)
  • 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=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 checkY
  • Key:QEHOIJJIZXRMAN-QZQSLCQPSA-N checkY
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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]

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
 
2D representation of the chemical structure of Q27126524.
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]

2D representation of the chemical structure of Q27095865.
dichlorochromopyrrolic acid
+ 4 NADH
+ 4 H+
 
 
4 O2
2 CO2
Rightward reaction arrow with minor substrate(s) from top left and minor product(s) to top right
 
 
 
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]

2D representation of the chemical structure of Q27225728.
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

Further reading

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