Abstract

The design, synthesis, and evaluation of functional analogs of the potent antitumor antibiotic (+)-CC-1065 are detailed. A primary objective of the studies is the definition of the structural origin of the agents DNA alkylation selectivity. Concurrent with these efforts, the evaluation of analogs bearing deep seated structural changes continue to help define the relationship between their DNA alkylation properties and biological properties, provide key partial structures and fundamental new agents for evaluation, and have resulted in the preparation of a class of potentially useful antitumor agents. These studies will be fully developed in the current grant period.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA041986-11
Application #
2090530
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1991-02-01
Project End
1996-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
11
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Wolfe, Amanda L; Duncan, Katharine K; Lajiness, James P et al. (2013) A fundamental relationship between hydrophobic properties and biological activity for the duocarmycin class of DNA-alkylating antitumor drugs: hydrophobic-binding-driven bonding. J Med Chem 56:6845-57
Wolfe, Amanda L; Duncan, Katharine K; Parelkar, Nikhil K et al. (2013) Efficacious cyclic N-acyl O-amino phenol duocarmycin prodrugs. J Med Chem 56:4104-15
Wolfe, Amanda L; Duncan, Katharine K; Parelkar, Nikhil K et al. (2012) A novel, unusually efficacious duocarmycin carbamate prodrug that releases no residual byproduct. J Med Chem 55:5878-86
Lajiness, James P; Boger, Dale L (2011) Asymmetric synthesis of 1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI). J Org Chem 76:583-7
Lajiness, James P; Boger, Dale L (2010) Synthesis and characterization of a cyclobutane duocarmycin derivative incorporating the 1,2,10,11-tetrahydro-9H-cyclobuta[c]benzo[e]indol-4-one (CbBI) alkylation subunit. J Am Chem Soc 132:13936-40
Boyle, Kristopher E; MacMillan, Karen S; Ellis, David A et al. (2010) Synthesis and evaluation of duocarmycin SA analogs incorporating the methyl 1,2,8,8a-tetrahydrocyclopropa[c]oxazolo[2,3-e]indol-4-one-6-carboxylate (COI) alkylation subunit. Bioorg Med Chem Lett 20:1854-7
Robertson, William M; Kastrinsky, David B; Hwang, Inkyu et al. (2010) Synthesis and evaluation of a series of C5'-substituted duocarmycin SA analogs. Bioorg Med Chem Lett 20:2722-5
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
Lajiness, James P; Robertson, William M; Dunwiddie, Irene et al. (2010) Design, synthesis, and evaluation of duocarmycin O-amino phenol prodrugs subject to tunable reductive activation. J Med Chem 53:7731-8
MacMillan, Karen S; Lajiness, James P; Cara, Carlota Lopez et al. (2009) Synthesis and evaluation of a thio analogue of duocarmycin SA. Bioorg Med Chem Lett 19:6962-5

Showing the most recent 10 out of 62 publications