Based on continuing success and promising results in the previous grant period, the overall goal of the proposed research is to discover novel anticancer drugs from selected medicinal plants that have been chosen either for their therapeutic use to treat cancer(s) or for their novelty. Lead compounds will be isolated and identified based on cytotoxicity (human tissue culture cell line panel), mechanistic (DNA topoisomerase assays), and molecular target-based screening (androgen/androgen receptor target based assays). The identification and development of clinical trial candidates are overall goals of our program. The following specific studies will be carried out to accomplish these goals: 1) The Natural Products Laboratory (NPL) will use analytical instrumental chromatography to isolate and identify the active principles found in anticancer bioassays) termed bioactivity-directed fractionation and isolation, BDFI). The structural characterization of new active leads will be carried out by physical and spectral techniques. 2) Certain leads will be selected for structural modification and synthesis of analogs in order to elucidate their structure-activity relationships and mechanism of action as well as to improve their pharmacological profiles. Conventional structure activity relationship (SAR) studies, molecular modeling approaches, and combinatorial chemistry techniques are used by the NPL to aid lead generation and optimization. Current classes of primary interest include fluorinated phenyl quinolones, dithiophene and epipodophyllotoxin-camptothecin conjugates. 3) Promising compounds and their synthetic analogs will be submitted to the National Institutes of Health (NIH) at the National Cancer Institute (NCI) for additional in vitro and in vivo antitumor studies. Our previous program has been augmented by participation in the NCI Natural Product Repository Program (NCI-NPRP) for the study of promising cytotoxic rainforest species, and by the collaboration of Dr. C. S. Chang, University of Rochester Medical School, who has unique expertise in screening for prostate cancer targets. Our program continues to have the advantages of 1) an excellent supply of highly active lead compounds, (2) a focus on the structural modification of these new leads as clinical trials candidates, and (3) excellent productivity and a superior prospect for the successful development of a clinically useful drugs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA017625-24
Application #
6258493
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Fu, Yali
Project Start
1978-06-01
Project End
2005-01-31
Budget Start
2001-02-09
Budget End
2002-01-31
Support Year
24
Fiscal Year
2001
Total Cost
$240,737
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Lu, Yan; Li, Yu-Quan; Liu, Yi-Nan et al. (2013) Cytotoxic and potential anticancer constituents from the stems of Schisandra pubescens. Pharm Biol 51:1204-7
Wang, Xiao-Feng; Wang, Sheng-Biao; Ohkoshi, Emika et al. (2013) N-aryl-6-methoxy-1,2,3,4-tetrahydroquinolines: a novel class of antitumor agents targeting the colchicine site on tubulin. Eur J Med Chem 67:196-207
Wang, Xiao-Feng; Ohkoshi, Emika; Wang, Sheng-Biao et al. (2013) Synthesis and biological evaluation of N-alkyl-N-(4-methoxyphenyl)pyridin-2-amines as a new class of tubulin polymerization inhibitors. Bioorg Med Chem 21:632-42
Chen, Min; Xu, Xiumei; Xu, Bing et al. (2013) Neglschisandrins E-F: two new lignans and related cytotoxic lignans from Schisandra neglecta. Molecules 18:2297-306
Wang, Qi; Chen, Tzu-Hsuan; Bastow, Kenneth F et al. (2013) Songaricalarins A-E, Cytotoxic Oplopane Sesquiterpenes from Ligularia songarica. J Nat Prod 76:305-10
Ye, Deyong; Shi, Qian; Leung, Chung-Hang et al. (2012) Antitumor agents 294. Novel E-ring-modified camptothecin-4?-anilino-4'-O-demethyl-epipodophyllotoxin conjugates as DNA topoisomerase I inhibitors and cytotoxic agents. Bioorg Med Chem 20:4489-94
Chen, Ying; Liu, Hong-Rui; Liu, Hong-Shan et al. (2012) Antitumor agents 292. Design, synthesis and pharmacological study of S- and O-substituted 7-mercapto- or hydroxy-coumarins and chromones as potent cytotoxic agents. Eur J Med Chem 49:74-85
Hung, Hsin-Yi; Nakagawa-Goto, Kyoko; Tokuda, Harukuni et al. (2012) Cancer preventive agents 11. Novel analogs of dimethyl dicarboxylate biphenyl as potent cancer chemopreventive agents(†). Pharm Biol 50:18-24
Shi, Qian; Wada, Koji; Ohkoshi, Emika et al. (2012) Antitumor agents 290. Design, synthesis, and biological evaluation of new LNCaP and PC-3 cytotoxic curcumin analogs conjugated with anti-androgens. Bioorg Med Chem 20:4020-31
Dong, Yizhou; Nakagawa-Goto, Kyoko; Lai, Chin-Yu et al. (2012) Antitumor agents. 289. Design, synthesis, and anti-breast cancer activity in vivo of 4-amino-2H-benzo[h]chromen-2-one and 4-amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one analogues with improved water solubility. J Nat Prod 75:370-7

Showing the most recent 10 out of 282 publications