Abstract

Mitomycin C is a clinically useful antineoplastic antibiotic compound. This drug is considered the archetypa, example of bioreductive alkylation reagents. The mechanism of action of the mitomycins is poorly understood. In this proposal an integrated approach has been outlined for the elucidation of how both the drug and the receptpr site, DNA, function. Emphasis has been placed on delineating the energetics of key steps in the reaction. The information obtained should be useful in elaborating the pathways of action for the remaining members of this class if medicinal agents. This knowledge may provide the molecular basis for subsequent research in cancer chemotherapy and allow future general drug design to proceed on a less empirical basis. A select series of modified mitomycins are proposed as potential candidates for future pharmacological evaluation. These compounds are expected to have increased activity and decreased toxicity.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA029756-05
Application #
3168858
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1981-05-01
Project End
1987-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
5
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
University of Houston
Department
Type
Schools of Arts and Sciences
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77204

  Publications

Lee, Sang Hyup; Kohn, Harold (2009) Nucleophilic activation of a tetra-substituted mitomycin cyclic bis-disulfide. Chem Pharm Bull (Tokyo) 57:149-57
Lee, Sang Hyup; Kohn, Harold (2005) 7-N,7'-N'-(1"",2""-Dithianyl-3"",6""-dimethylenyl)bismitomycin C: synthesis and nucleophilic activation of a dimeric mitomycin. Org Biomol Chem 3:471-82
Lee, Sang Hyup; Kohn, Harold (2004) Cyclic disulfide C8 iminoporfiromycin: nucleophilic activation of a porfiromycin. J Am Chem Soc 126:4281-92
Na, Younghwa; Wang, Shuang; Kohn, Harold (2002) 7-N-(mercaptoalkyl)mitomycins: implications of cyclization for drug function. J Am Chem Soc 124:4666-77
Lee, Sang Hyup; Kohn, Harold (2002) Efficient synthesis of medium-sized cyclic ether diamines. J Org Chem 67:1692-5
Zewail-Foote, M; Li, V S; Kohn, H et al. (2001) The inefficiency of incisions of ecteinascidin 743-DNA adducts by the UvrABC nuclease and the unique structural feature of the DNA adducts can be used to explain the repair-dependent toxicities of this antitumor agent. Chem Biol 8:1033-49
Li, V S; Tang, M S; Kohn, H (2001) The effect of C(5) cytosine methylation at CpG sequences on mitomycin-DNA bonding profiles. Bioorg Med Chem 9:863-73
Na, Y; Li, V S; Nakanishi, Y et al. (2001) Synthesis, DNA cross-linking activity, and cytotoxicity of dimeric mitomycins. J Med Chem 44:3453-62
Li, V S; Reed, M; Zheng, Y et al. (2000) C5 cytosine methylation at CpG sites enhances sequence selectivity of mitomycin C-DNA bonding. Biochemistry 39:2612-8
Wang, S; Kohn, H (1999) Studies on the mode of action of mitomycin C(7) aminoethylene disulfides (BMS-181174 and KW-2149): reactivity of 7-N-(mercaptoethyl)mitomycin C. J Med Chem 42:788-90

Showing the most recent 10 out of 13 publications