Quinocarcin (1) and a newly discovered, related natural product tetrazomine (2), naphthyridinomycin (3) and the recently discovered bioxalomycins (4) are potent anti-tumor antibiotics that have demonstrated potency against a range of human tumor cell lines. Most significantly, quinocarcin has excellent in vivo activity against human mammary MX-1 carcinoma with all tumors cured at i.v. doses of 4.4 mg/kg/day and p.o. doses of 262 mg/kg/day given daily for 7 days. It is the purpose of this program to exploit the mechanistic knowledge that has been uncovered during the first grant cycle in designing and synthesizing more potent and selective anti-tumor antibiotics. The primary hypothesis to be explored concerns separately evaluating, via chemical synthesis, the efficacy of quinocarcin (1), tetrazomine (2), naphthyridinomycin (3) and bioxalomycin (4) derivatives that lack the capacity to cause non-specific oxidative damage to cellular macromolecules but retain the enhanced capacity to alkylate DNA. As with many other anti-tumor antibiotics that display multiple modes of action, quinocarcin has the demonstrated capacity to both aIkylate DNA and, through the slow generation of superoxide, mediate Fenton-type oxidative damage to DNA and other cellular components in a non-specific fashion. It is the generation of the non-specific oxidative species derived from superoxide that is likely responsible for high levels of host toxicity that have made it so difficult for many promising anti- tumor drug candidates to successfully pass phase three human clinical trials and toxicological scrutiny. This program will endeavor to chemically attenuate or obviate an entire mechanistic manifold (superoxide release) exhibited by this class of compounds while at the same time, enhancing a complementary manifold (DNA alkylation). The efficient chemical synthesis of tetrazomine, naphthyridinomycin and the bioxalomycins is proposed as well as efficient chemical syntheses of several mechanism-based analogs of these potent anti-tumor antibiotics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA043969-07A2
Application #
2091336
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1987-01-01
Project End
1998-02-28
Budget Start
1995-03-17
Budget End
1996-02-29
Support Year
7
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
112617480
City
Fort Collins
State
CO
Country
United States
Zip Code
80523