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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA035318-03
Application #
3172895
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1983-08-01
Project End
1986-07-31
Budget Start
1985-08-01
Budget End
1986-07-31
Support Year
3
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Type
Schools of Pharmacy
DUNS #
City
Austin
State
TX
Country
United States
Zip Code
78713