Our laboratory is developing practical synthetic routes to families of chemically complex natural products that have been shown to inhibit the growth of human cancer cells. In this way, we are able to prepare large numbers of related structures (analogs) for evaluation as new chemotherapeutic agents, compounds with potentially improved properties that would be otherwise unavailable for study. The synthetic routes we are developing also allow us to prepare chemical probes that are useful for the identification of the cellular targets of the natural products families we study, which in many cases are not known. The dual impacts of this work, providing molecules for target binding and target identification, are of potentially great potential utility in the extraordinarily challenging problem of developing new cancer therapies. Indeed, many of our current front-line small-molecule therapies for cancer are natural products or were derived from natural products lead structures, and many important targets of cancer have been identified through the use of probes prepared by chemical modification of natural products. Among the classes of natural products we are studying are the cortistatins, a family of steroidal alkaloids isolated from a marine sponge that potently inhibit the proliferation of human umbilical vein endothelial cells;the daphniglaucins, unique plant-derived substances that have been shown to inhibit the growth of a lymphoma-derived cell line;the trioxacarcins, bacterial fermentation products with extremely potent inhibitory properties toward growing cancer cells and known to alkylate duplex DNA;salinosporamides, isolates from a marine bacterium that target the proteasome (also targeted by Velcade(R), an approved chemotherapeutic agent for multiple myeloma), and avrainvillamides, fungal natural products shown in our laboratory to target nucleophosmin, a protein whose mutation has been implicated in ~35% of all acute myelogenous lukemias (AMLs) and a novel target for chemotherapeutic intervention.

Public Health Relevance

Many current front-line small-molecule therapies for cancer are natural products, or were derived from natural products as lead structures, and many important targets of cancer have been identified through the use of probes that are structural analogs of natural products;our research seeks to develop highly convergent, highly flexible synthetic routes to five different classes of natural products so as to enable large numbers of analogs to be synthesized and explored as potential leads for cancer therapy. These compounds would not be available for study by any other means. We also seek to use the chemistry we develop to synthesize chemical probes for the identification of the cellular targets of the natural products families we study, in cases where their targets are not known.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA047148-25S1
Application #
8396561
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Ogunbiyi, Peter
Project Start
1988-04-01
Project End
2016-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
25
Fiscal Year
2012
Total Cost
$94,640
Indirect Cost
$38,640
Name
Harvard University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
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 α-methyl α-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-α,β-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
Simmons, Rebecca L; Yu, Robert T; Myers, Andrew G (2011) Storable arylpalladium(II) reagents for alkene labeling in aqueous media. J Am Chem Soc 133:15870-3

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