The primary focus of our research continues to be the synthesis and study of complex molecules with proven or potential anti-cancer activity. Efficient laboratory synthetic routes are developed that provide access to new materials with potentially improved properties for study and biological evaluation. The elucidation of the detailed chemical processes that underlie the biological (antiproliferative) activity of the agents we study is a principal goal of our research. Specific synthetic targets include the natural antiproliferative agents avrainvillamide, stephacidin B, salinosporamides, quinocarcin, N1999A2, kedarcidin chromophore, and maduropeptin chromophore. In addition, we will execute a solid-phase split-pool synthesis of a library of ~1,000 saframycin analogs, a small library (-200compounds) of molecules bearing the 3-alkylidene3-H- indole-1-oxide function, a novel class of potential enzyme (protease) inhibitors, and a number of structural analogs of quinocarcin, avrainvillamide, and stephacidin B. We will synthesize a large number of analogs of the natural proteasomal inhibitor and antiproliferative agent salinosporamide. By design, the synthetic route under development incorporates three sites of structural variability; the route is also notably short and efficient. A major effort is underway in our laboratory to elucidate the molecular target(s) of the saframycins and, separately, the new class of natural antiproliferative agents represented by avrainvillamide and stephacidin B. We will continue to pursue studies designed to elucidate the details of the interaction of the protein target glyceraldehyde 3-phosphate dehydrogenase (GAPDH) with binary complexes of duplex DMA and saframycins, and the role this interaction may play in the antiproliferative activity of saframycins.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA047148-23
Application #
7840495
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
1988-04-01
Project End
2011-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
23
Fiscal Year
2010
Total Cost
$711,965
Indirect Cost
Name
Harvard University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Andresen, Vibeke; Erikstein, Bjarte S; Mukherjee, Herschel et al. (2016) Anti-proliferative activity of the NPM1 interacting natural product avrainvillamide in acute myeloid leukemia. Cell Death Dis 7:e2497
Mukherjee, Herschel; Chan, Kok-Ping; Andresen, Vibeke et al. (2015) Interactions of the natural product (+)-avrainvillamide with nucleophosmin and exportin-1 Mediate the cellular localization of nucleophosmin and its AML-associated mutants. ACS Chem Biol 10:855-63
Blasdel, Landy K; Lee, DongEun; Sun, Binyuan et al. (2013) (S)-4-Trimethylsilyl-3-butyn-2-ol as an auxiliary for stereocontrolled synthesis of salinosporamide analogs with modifications at positions C2 and C5. Bioorg Med Chem Lett 23:6905-10
Magauer, Thomas; Smaltz, Daniel J; Myers, Andrew G (2013) Component-based syntheses of trioxacarcin A, DC-45-A1 and structural analogues. Nat Chem 5:886-93
Hugelshofer, Cedric L; Mellem, Kevin T; Myers, Andrew G (2013) Synthesis of quaternary ?-methyl ?-amino acids by asymmetric alkylation of pseudoephenamine alaninamide pivaldimine. Org Lett 15:3134-7
Mellem, Kevin T; Myers, Andrew G (2013) A simple, scalable synthetic route to (+)- and (-)-pseudoephenamine. Org Lett 15:5594-7
Morales, Marvin R; Mellem, Kevin T; Myers, Andrew G (2012) Pseudoephenamine: a practical chiral auxiliary for asymmetric synthesis. Angew Chem Int Ed Engl 51:4568-71
Smaltz, Daniel J; Švenda, Jakub; Myers, Andrew G (2012) Diastereoselective additions of allylmetal reagents to free and protected syn-?,?-dihydroxyketones enable efficient synthetic routes to methyl trioxacarcinoside A. Org Lett 14:1812-5
Svenda, Jakub; Hill, Nicholas; Myers, Andrew G (2011) A multiply convergent platform for the synthesis of trioxacarcins. Proc Natl Acad Sci U S A 108:6709-14
Si, Chong; Myers, Andrew G (2011) A versatile synthesis of substituted isoquinolines. Angew Chem Int Ed Engl 50:10409-13

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