The design, synthesis, and evaluation of a series of CC-1065 and duocarmycin analogues are described in efforts to define fundamental relationships between structure, reactivity, and biological properties. These include deep-seated structural changes in the DMAalkylation subunits, the exploration of a novel series of alkylation subunit DMAcross-linking analogues, and an examination of altered DMAbinding subunits. Each of these modifications or approaches is used to address a specific question or concept relating structure and function (structure-reactivity or structure-activity). Central to these studies is the use of organic synthesis and fundamental physical organic principles to define the underlying recognition features responsible for the sequence selective DMAalkylation reaction and its source of catalysis. Through these studies, we hope to fully characterize the first well-defined example of a new mechanism of in situ activation of a DMA alkylating antitumor agent and the first example of activation at and by the biological target. The introduction and continued development of new techniques for establishing DMAbinding selectivity and affinity promises to facilitate these and related studies and are being extended to include the inhibiton of aberrant gene transcription. Public Health Relevance: New drugs for the treatment of cancer will be explored and new general concepts of drug design may emerge from the investigations.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA041986-24
Application #
8005500
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
1991-02-01
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2012-12-31
Support Year
24
Fiscal Year
2011
Total Cost
$396,544
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
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
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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; Boger, Dale L (2009) Fundamental relationships between structure, reactivity, and biological activity for the duocarmycins and CC-1065. J Med Chem 52:5771-80

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