The overall objective of this proposal is to synthesize a rationally designed population of pyrrolo(1,4)benzodiazepine antitumor agents. Based primarily upon investigations in the P.I.'s laboratory sufficient information exists on the manner in which pyrrolo(1,4)benzodiazepine antibiotics, such as anthramycin, react with DNA, so that new DNA reactive compounds can be designed that will answer specific biochemical/biological questions such as: What structural features of these antibiotics are responsible for the high DNA sequence specificity of these drugs?, Can drugs which have high DNA sequence specificity direct genetic events such as retrovirus insertion of oncogenes and conversely their deletion?, Is the cardiotoxicity of sibiromycin and athramycin due to formation of quinone-imines?, Do the synthetic pyrrolo(1,4)benzodiazepines prepared during this study have improved therapeutic potential as antitumor agents? The successful completion of this project requires a problematic synthesis of a carbinolamine contained in a pyrrolo(1,4)benzodiazepine nucleus. Based upon our learned understanding of the factors which control the extent of hydride reduction of a lactam to form the carbinolamine, tertiary amine or acyclic amino alcohol we have established a biomimetic synthesis of these antibiotics and their derivatives in the pyrrolo(1,4)benzodiazepine group. This application is a logical extention of our overall research program on the development of the anthramycins, which will lead to important information on the molecular basis for antitumor activity of this group of compounds as well as potentially therapeutically improved anticancer agents in this series.
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|Hertzberg, R P; Hecht, S M; Reynolds, V L et al. (1986) DNA sequence specificity of the pyrrolo[1,4]benzodiazepine antitumor antibiotics. Methidiumpropyl-EDTA-iron(II) footprinting analysis of DNA binding sites for anthramycin and related drugs. Biochemistry 25:1249-58|
|Hurley, L H; Needham-VanDevanter, D R (1986) Sequence specificity and biological consequences of drugs that bind covalently in the minor groove of DNA. Basic Life Sci 38:203-10|