RATIONAL BASIS FOR THE DESIGN OF CC-1066 ANALOGS

Project: Research project

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

Fingerprint

CC 1065
DNA
DNA adducts
antineoplastic agents
pins
research projects
DNA damage
toxicity
nucleotide sequences
gene expression
synthesis
Antineoplastic Agents
Proteins
Poisons
Microinjections
Streptomyces
Immunoprecipitation
Anura
Oocytes
Electrophoresis

ASJC

  • Medicine(all)