This renewal involves integrated synthetic, mechanistic, mode of action, computer modeling, biochemical, imaging and preclinical studies directed at the design, synthesis and advancement of fundamentally new leads and strategies for the treatment of cancer, HIV/AIDS and potentially other therapeutic indications. These studies focus on understanding the molecular basis for cellular signaling through protein kinase C (PKC) and related pathways relevant to cancer treatment and other indications;on the development of novel synthetic approaches to promising therapeutic leads, especially those that exhibit unique activity relevant to cancer;on the development of drug and probe transporters, including new linker methodology;and on a promising strategy for using transporters to overcome Pgp based cancer resistance. Section D.1 describes continuing studies on the synthesis and biological evaluation of gnidimacrin and its analogs, the former a potent anticancer lead with in vitro and in vivo activity and a novel mode of action putatively involving selective PKC ?-II regulation;at the elucidation of the structural basis for this novel activity and mode of action;and at the design of simplified and potentially clinically superior candidates. Section D.2 is directed at the synthesis of synaptolepis factor K7, kirkinine and related functional analogs - the former two being potent anti-leukemic leads;at elucidation of the structural basis for their activity;and at the design of simplified and more effective candidates for advancing research on and potential clinical use of these novel leads. Section D.3 is directed at the synthesis of prostratin and its functional analogs, the former an active constituent in a medicinal tea used by healers in Samoa and now in preclinical development for eradicating HIV/AIDS virus through latent virus activation, and at evaluation of the promising anticancer activity of the analogs, their role in PKC signaling, and their ability to purge the latent virus from HIV infected cells as a clinical approach to HIV eradication. Section D.4 is directed at the development of methodology for the synthesis of new releasable drug-transporter conjugates designed to evade cellular Pgp efflux pumps in drug-resistant cancer cell lines and release free drug upon cell entry, providing a potentially general strategy to overcome Pgp-based resistant cancer and more specifically an approach to treating resistant ovarian cancer. Section D.5 is directed at the development of novel oligomerization strategies for the synthesis of new molecular transporters for drug/probe delivery and evaluation of their performance in transfected cells and transgenic animals. Collectively, this program provides for the first synthetic access to several designed and natural compounds with unique activities, including promising therapeutic leads and two leads in preclinical development, one designed to overcome Pgp-based resistance in ovarian cancer and a second targeting HIV/AIDS latent virus and thus a potential adjuvant for virus eradication.

Public Health Relevance

This project involves integrated synthetic, mechanistic, computer modeling, biochemical mode of action and preclinical studies directed at several promising anticancer leads including one that is also a clinical candidate for eradicating HIV/AIDS virus through latent virus activation, at the preclinical advancement of a novel strategy for overcoming resistant cancer, potentially applicable to ovarian cancer, and at the study of new drug delivery systems with potentially broad fundamental and clinical utility in cancer therapy and disease detection. The project seeks to advance our ability to synthesize molecules, at the same time to uncover new modes of action and strategies that are relevant to cancer therapy as well as other therapeutic indications, and to introduce new drug or probe delivery strategies for disease diagnosis and treatment. The project provides for the creation of fundamental knowledge of broad potential utility and at the same time new approaches and agents to address unmet clinical needs in cancer, HIV/AIDS and other diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA031841-33
Application #
8450909
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Misra, Raj N
Project Start
1981-07-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
33
Fiscal Year
2013
Total Cost
$305,768
Indirect Cost
$112,683
Name
Stanford University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
McKinlay, Colin J; Waymouth, Robert M; Wender, Paul A (2016) Cell-Penetrating, Guanidinium-Rich Oligophosphoesters: Effective and Versatile Molecular Transporters for Drug and Probe Delivery. J Am Chem Soc 138:3510-7
Staveness, Daryl; Abdelnabi, Rana; Near, Katherine E et al. (2016) Inhibition of Chikungunya Virus-Induced Cell Death by Salicylate-Derived Bryostatin Analogues Provides Additional Evidence for a PKC-Independent Pathway. J Nat Prod 79:680-4
Staveness, Daryl; Abdelnabi, Rana; Schrier, Adam J et al. (2016) Simplified Bryostatin Analogues Protect Cells from Chikungunya Virus-Induced Cell Death. J Nat Prod 79:675-9
Hsu, Hsiao-Tieh; Trantow, Brian M; Waymouth, Robert M et al. (2016) Bioorthogonal Catalysis: A General Method To Evaluate Metal-Catalyzed Reactions in Real Time in Living Systems Using a Cellular Luciferase Reporter System. Bioconjug Chem 27:376-82
Pavlovic, Igor; Thakor, Divyeshsinh T; Vargas, Jessica R et al. (2016) Cellular delivery and photochemical release of a caged inositol-pyrophosphate induces PH-domain translocation in cellulo. Nat Commun 7:10622
Wender, Paul A; Huttner, Melanie A; Staveness, Daryl et al. (2015) Guanidinium-rich, glycerol-derived oligocarbonates: a new class of cell-penetrating molecular transporters that complex, deliver, and release siRNA. Mol Pharm 12:742-50
Loy, Brian A; Lesser, Adam B; Staveness, Daryl et al. (2015) Toward a biorelevant structure of protein kinase C bound modulators: design, synthesis, and evaluation of labeled bryostatin analogues for analysis with rotational echo double resonance NMR spectroscopy. J Am Chem Soc 137:3678-85
Wender, Paul A; Jeffreys, Matthew S; Raub, Andrew G (2015) Tetramethyleneethane Equivalents: Recursive Reagents for Serialized Cycloadditions. J Am Chem Soc 137:9088-93
Wender, Paul A; Quiroz, Ryan V; Stevens, Matthew C (2015) Function through synthesis-informed design. Acc Chem Res 48:752-60
Vargas, Jessica R; Stanzl, Erika Geihe; Teng, Nelson N H et al. (2014) Cell-penetrating, guanidinium-rich molecular transporters for overcoming efflux-mediated multidrug resistance. Mol Pharm 11:2553-65

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