Abstract

The objective of this program is to synthesize and study the mechanism of action of the recently discovered anti-tumor antibiotic FR-900482. This substance is a natural product isolated from the fermentation extracts of Streptomyces sandaensis No. 6897 at Fujisawa Pharmaceutical Co. in Japan. FR-900482 and its derived triacetate FK973 display potent cytotoxic and anti-tumor activity against murine and human tumors in vitro and in vivo. Structurally related to the well-known mitomycin C anti-tumor antibiotic, these new compounds are exciting due to their unique, demonstrated ability to cross-link double-stranded DNA and also form DNA-protein cross-links. Unlike mitomycin C and most other antitumor drugs, FK 973 does not cause oxidative damage to DNA. FK 973, now in advanced clinical trials in Japan, is significantly less toxic than mitomycin C and is three-fold more potent. The purpose of this investigation is to synthesize FR-900482 and some simple analogs to probe the unique mechanism of DNA-DNA and DNA-protein cross-link formation by this important new drug.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA051875-02
Application #
3196584
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1992-04-01
Project End
1996-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
Colorado State University-Fort Collins
Department
Type
Schools of Arts and Sciences
DUNS #
112617480
City
Fort Collins
State
CO
Country
United States
Zip Code
80523

  Publications

Bass, Phillip D; Gubler, Daniel A; Judd, Ted C et al. (2013) Mitomycinoid alkaloids: mechanism of action, biosynthesis, total syntheses, and synthetic approaches. Chem Rev 113:6816-63
Williams, Robert M (2011) Natural products synthesis: enabling tools to penetrate Nature's secrets of biogenesis and biomechanism. J Org Chem 76:4221-59
Williams, Robert M; Stille, J; Echavarren, A et al. (2011) Discussion Addendum for: 4-Methoxy-4'-nitrophenyl. Recent Advances in the Stille Biaryl Coupling Reaction and Applications in Complex Natural Products Synthesis. Organic Synth 88:197-201
Subramanian, Vidya; Williams, Robert M; Boger, Dale L et al. (2010) Methods to characterize the effect of DNA-modifying compounds on nucleosomal DNA. Methods Mol Biol 613:173-92
Chamberland, Stephen; Grüschow, Sabine; Sherman, David H et al. (2009) Synthesis of potential early-stage intermediates in the biosynthesis of FR900482 and mitomycin C. Org Lett 11:791-4
Gubler, Daniel A; Williams, Robert M (2009) Synthetic Studies Towards the Mitomycins: Construction of the Tetracyclic Core via a Reductive Aminocyclization Reaction. Tetrahedron Lett 50:4265-4267
Namiki, Hidenori; Chamberland, Stephen; Gubler, Daniel A et al. (2007) Synthetic and biosynthetic studies on FR900482 and mitomycin C: an efficient and stereoselective hydroxymethylation of an advanced benzazocane intermediate. Org Lett 9:5341-4
Subramanian, Vidya; Ducept, Pascal; Williams, Robert M et al. (2007) Effects of photochemically activated alkylating agents of the FR900482 family on chromatin. Chem Biol 14:553-63
Judd, Ted C; Williams, Robert M (2004) A concise total synthesis of (+)-FR900482 and (+)-FR66979. J Org Chem 69:2825-30
Williams, Robert M; Ducept, Pascal (2003) Interstrand cross-linking of DNA by FK317 and its deacetylated metabolites FR70496 and FR157471. Biochemistry 42:14696-701

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