PYRROLO(1,4)BENZODIAZEPINE ANTITUMOR ANTIBIOTICS

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.