Abstract

This proposal outlines a comprehensive research program directed toward the synthesis of compounds of demonstrated or potential importance in cancer research/treatment. The synthetic component of this effort emphasizes the development of new methods and strategies for many-membered ring synthesis, fused-ring synthesis, and cannabinoid synthesis. A continuation of our olefin metathesis studies is designed to provide a general solution to the synthesis of germacradienes, a natural product class membered by various antitumor agents. The viability of a macro-expansion method designed to service the antitumor lankacidins and lathyranes will also be evaluated. An expansion/fragmentation method for many-membered ring synthesis will be directed initially at a methymycin synthesis. A continuation of our studies on the olefin metathesis/transannular ene method for fused ring synthesis will be directed at the synthesis of the cytotoxic agents warburganal and muzigadial. Intramolecular homo-Diels-Alder and arene-olefin cycloadditions will be studied in connection with syntheses of antitumor pseudoguaianes. The latter method will also be explored in connection with syntheses in the pentalenolactone and coriolin series including the antitumor agent coriolin. A new enolate chemistry will be developed in connection with a general approach to cannabinoid synthesis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA031845-07
Application #
3169956
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1981-07-01
Project End
1991-03-31
Budget Start
1987-04-01
Budget End
1988-03-31
Support Year
7
Fiscal Year
1987
Total Cost
Indirect Cost

  Institution

Name
Stanford University
Department
Type
Schools of Arts and Sciences
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305

  Publications

McKinlay, Colin J; Benner, Nancy L; Haabeth, Ole A et al. (2018) Enhanced mRNA delivery into lymphocytes enabled by lipid-varied libraries of charge-altering releasable transporters. Proc Natl Acad Sci U S A 115:E5859-E5866
Fernandes-Cunha, Gabriella M; McKinlay, Colin J; Vargas, Jessica R et al. (2018) Delivery of Inorganic Polyphosphate into Cells Using Amphipathic Oligocarbonate Transporters. ACS Cent Sci 4:1394-1402
Yang, Hao; Staveness, Daryl; Ryckbosch, Steven M et al. (2018) REDOR NMR Reveals Multiple Conformers for a Protein Kinase C Ligand in a Membrane Environment. ACS Cent Sci 4:89-96
Haabeth, Ole A W; Blake, Timothy R; McKinlay, Colin J et al. (2018) mRNA vaccination with charge-altering releasable transporters elicits human T cell responses and cures established tumors in mice. Proc Natl Acad Sci U S A 115:E9153-E9161
Khan, Tapan K; Wender, Paul A; Alkon, Daniel L (2018) Bryostatin and its synthetic analog, picolog rescue dermal fibroblasts from prolonged stress and contribute to survival and rejuvenation of human skin equivalents. J Cell Physiol 233:1523-1534
Marsden, Matthew D; Wu, Xiaomeng; Navab, Sara M et al. (2018) Characterization of designed, synthetically accessible bryostatin analog HIV latency reversing agents. Virology 520:83-93
Albert, Brice J; Niu, Austin; Ramani, Rashmi et al. (2017) Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation. Sci Rep 7:7456
Ryckbosch, Steven M; Wender, Paul A; Pande, Vijay S (2017) Molecular dynamics simulations reveal ligand-controlled positioning of a peripheral protein complex in membranes. Nat Commun 8:6
McKinlay, Colin J; Vargas, Jessica R; Blake, Timothy R et al. (2017) Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals. Proc Natl Acad Sci U S A 114:E448-E456
Wender, Paul A; Hardman, Clayton T; Ho, Stephen et al. (2017) Scalable synthesis of bryostatin 1 and analogs, adjuvant leads against latent HIV. Science 358:218-223

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