Pyrrolo benzodiazepines antitumor

The carbinolamine-containing pyrrolo[2,l-c][l,4]benzodiazepine family of antitumor antibiotics is produced by various Streptomyces species well-known members include abthramy-cine, tomay mycine, and DC-81,138 Various approaches to the synthesis of these compounds have been investigated over past years reductive cyclization of suitably substituted nitroaldehydes is the frequently used method (Eq. 10.81).139... 

The C(2)-C(3) olefin of a l,4-benzodiazepin-5-one regiospecifically captured an alkyl radical intramolecularly in a 5-f vo-/r/g-proccss that is the critical step in an approach to the constmction of the fused tricyclic system found in the pyrrolo[2,l-f][l,4]benzodiazepine class of antitumor antibiotic. Treatment of the alkyl bromide 46 with Bu3SnH afforded the tricyclic product 47 in 90% yield, a reaction that proceeded with equal efficiency with the alkoxy aryl ring substituents found in the naturally occurring ( )DC-81 (Scheme 18) <19990L1835>. 

In earlier investigations by the authors (2,3), noncrosslinking pyrrolo[2,l-c][l,4] benzodiazepine hybrid derivatives, (II) and (IH), respectively, were prepared having significant DNA binding ability and antitumor activity and used in treating proliferative disorders. 

INDOLMYCIN (20) is formed from pyruvate, and two enzymes active in initial stages of Its biosynthesis have been studied. They are a transaminase and aC-methyltransferase. The hypothetical route to indolmycin is by indole pyruvate, 3-methyl-indolepyruvate, indolmycenic acid (reduced alpha oxo group) and finally indolmycin which probably takes its amidine group from an arginine molecule 79. The closely related [pyrrolo (1,4) benzodiazepines] 80>81,82 antitumor antibiotics, anthramycin, tomaymycin and sibiromycin are formed from tryptophan (via the kynurenine pathway ), tyrosine and methionine-derived methyl groups 80.si.sz. 

A series of sulfamide benzodiazepines 204 have been prepared and their p5 3-murine double minute 2 (MDM2) inhibitory activity and in vitro antitumor activity were evaluated (14MI15741). These heterocycles demonstrated moderate inhibition of p53 MDM2 protein—protein interaction. Intramolecular 1,3-dipolar cycloaddition of a l-(azidoarylsulfonyl)-2-alke-nyl pyrrolidine yielded aziridino-fused pyrrolo[l,2,5]benzothiadiazepine 205 as the only isolable product this system and other henzodiazepines are under investigation for antitumor and antibiotic potential (14MOL16737). 

There is a group of antibiotics that possess the pyrrolo[l,4]benzodiazepine skeleton and show antimicrobial activity against Gram-positive bacteria, along with antiviral, antiphage, and antitumor activities. Anthramycin and tomaymycin are typical alkaloids in this group. 

Figure 13.30 Biocatalytic azide reduction-cyclization sequence for the synthesis of various pyrrolo[2,l-c][l,4]benzodiazepines, potential antitumor antibiotics.

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