RATIONAL BASIS FOR THE DESIGN OF CC-1066 ANALOGS

Project: Research project

Project Details

Description

The long range objective of this research project is to provide a rational
basis for the design of new CC-1065 analogs with improved chemotherapeutic
potential as antitumor agents. Collaborative studies carried out
concurrently at Austin (UT) and Kalamazoo (Upjohn) have provided structural
information on the CC-1065-DNA adduct as well as insight into the
biochemical response to the DNA damage produced by CC-1065. Taken together
these results suggest three alternative ways in which CC-1065 may exert its
considerable potency as an antitumor agent. During the next project
period, we propose to pin-point the molecular basis for the antitumor
activity of CC-1065. Our strategy will involve correlation of biological
(antitumor) and biochemical activities with structural alterations in the
CC-1065-analog-DNA adducts. The three dimensional structural characterization of the CC-1065-DNA adduct
and analog complexes will rely upon 1H-NMR (and possibly X-ray
crystallographic analysis) studies on the defined CC-1065-oligodeoxyduplex
adduct. Biochemical parameters monitored in response to CC-1065-DNA damage
include DNA sequence specificity, tele-stability effects, DNA repair
consequences and possibly the effects of CC-1065 on gene expression using
SV40 DNA. The synthesis of CC-1065 analogs, and their biological
evaluation for antitumor activity and toxicity will be conducted in a
separate effort funded by The Upjohn Company. The results of this
investigation will not only provide a rational basis for the design of new
CC-1065 analogs with improved chemotherapeutic properties, but will provide
considerable insight into the mechanisms whereby specific chemical
modifications of DNA effect its structure and function.
StatusFinished
Effective start/end date7/1/8111/30/89

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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