(Principal Investigator's) A detailed study of CC-1065 and the duocarmycins, exceptionally potent antitumor antibiotics, are described. CC-1065 and the duocarmycins derive their biological properties through a sequence selective alkylation of duplex DNA which proceeds by reversible, stereoelectronically-controlled adenine N3 addition to the least substituted carbon of the activated cyclopropane within minor groove 5 or 3.5 base pair AT-rich sites, respectively. Further studies to define the characteristics of the alkylation reaction, to determine the origin of the DNA alkylation selectivity and the source of catalysis, and to define fundamental principles underlying the relationships between structure, chemical or functional reactivity, DNA alkylation properties, and biological activity are detailed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA041986-15
Application #
6172049
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Lees, Robert G
Project Start
1991-02-01
Project End
2002-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
15
Fiscal Year
2000
Total Cost
$314,095
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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