As in the past the very vigorous and sharply focused objective of the continuation research will be the accelerated discovery and preclinical development of new and structurally unique anticancer drug candidates for the U.S. National Cancer Institute. Emphasis will continue to be devoted to small molecule anticancer constituents isolated from terrestrial arthropods, marine organisms, microorganisms and plants followed by structural determinations, syntheses and/or structural modifications. Special emphasis will be placed on new antineoplastic substances either isolated based on molecular target bioassays or subsequently displaying such potent antiangiogenesis, cancer vascular targeting, tubulin and/or various cancer-implicated kinase (cyclin-dependent, protein kinase C, tyrosine kinase and telomerase) properties as well as exceptionally strong antineoplastic activity. Additional emphasis will be placed on further research necessary to advance the expanding and vitally important clinical trials of the auristatins, bryostatin 1, the dolastatins, and others discovered in our laboratory such as the powerful cancer antiangiogenesis and vascular targeting drugs in the combretastatin (CA4P, CA1P) and other series. Only those leads from confirmed active extracts of arthropods, marine invertebrates, marine and terrestrial plants, and marine as well as terrestrial microorganisms that give maximum promise of yielding new drugs with potential clinical activity will be pursued. The proposed continuation research will provide great assistance to the DCTD/NCI in selecting new anticancer drug candidates and speeding their development toward clinical trials. In summary, the proposed research will be sharply aimed at the discovery and very rapid development of new anticancer drugs for the NCI programs directed at improving human cancer treatments.

Public Health Relevance

In the coming year approximately 600,000 people will die of cancer in the United States alone. The discovery and development of more effective and curative anticancer drugs is a vital component in the global effort to address this devastating health problem. The goal of this project is the discovery and development of novel small molecules from terrestrial arthropods, marine organisms, microorganisms, and plants with sufficient antineoplastic activity to offer the potential for ultimate clinical activity against human cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090441-08
Application #
7905973
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fu, Yali
Project Start
2001-04-01
Project End
2011-09-30
Budget Start
2010-09-01
Budget End
2011-09-30
Support Year
8
Fiscal Year
2010
Total Cost
$381,250
Indirect Cost
Name
Arizona State University-Tempe Campus
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
943360412
City
Tempe
State
AZ
Country
United States
Zip Code
85287
Pettit, George R; Searcy, Justin D; Tan, Rui et al. (2016) Antineoplastic Agents. 585. Isolation of Bridelia ferruginea Anticancer Podophyllotoxins and Synthesis of 4-Aza-podophyllotoxin Structural Modifications. J Nat Prod 79:507-18
Pettit, George R; Smith, Thomas H; Arce, Pablo M et al. (2015) Antineoplastic agents. 599. Total synthesis of dolastatin 16. J Nat Prod 78:476-85
Pettit, George R; Xu, Jun-Ping; Chapuis, Jean-Charles et al. (2015) The Cephalostatins. 24. Isolation, Structure, and Cancer Cell Growth Inhibition of Cephalostatin 20. J Nat Prod 78:1446-50
Pettit, George R; Moser, Bryan R; Herald, Delbert L et al. (2015) The Cephalostatins. 23. Conversion of Hecogenin to a Steroidal 1,6-Dioxaspiro[5.5]nonane Analogue for Cephalostatin 11. J Nat Prod 78:1067-72
Pettit, George R; Arce, Pablo M; Chapuis, Jean-Charles et al. (2015) Antineoplastic agents. 600. From the South Pacific Ocean to the silstatins. J Nat Prod 78:510-23
Pettit, George R; Melody, Noeleen; Hempenstall, Frank et al. (2014) Antineoplastic agents. 595. Structural modifications of betulin and the X-ray crystal structure of an unusual betulin amine dimer. J Nat Prod 77:863-72
Pettit, George R; Tang, Yuping; Zhang, Qingwen et al. (2013) Isolation and structures of axistatins 1-3 from the Republic of Palau marine sponge Agelas axifera Hentschel . J Nat Prod 76:420-4
Lubahn, Cheri; Schaller, Jill A; Shewmacker, Eric et al. (2012) Preclinical efficacy of sodium narcistatin to reduce inflammation and joint destruction in rats with adjuvant-induced arthritis. Rheumatol Int 32:3751-60
Pettit, George R; Moser, Bryan R; Mendonça, Ricardo F et al. (2012) The cephalostatins. 22. synthesis of bis-steroidal pyrazine pyrones (1). J Nat Prod 75:1063-9
Pettit, George R; Tan, Rui; Bao, Guan-Hu et al. (2012) Antineoplastic agents. 587. Isolation and structure of 3-epipancratistatin from Narcissus cv. Ice Follies. J Nat Prod 75:771-3

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