Document Detail


Antitumor agents 290. Design, synthesis, and biological evaluation of new LNCaP and PC-3 cytotoxic curcumin analogs conjugated with anti-androgens.
MedLine Citation:
PMID:  22672984     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In our continuing study of curcumin analogs as potential anti-prostate cancer drug candidates, 15 new curcumin analogs were designed, synthesized and evaluated for cytotoxicity against two human prostate cancer cell lines, androgen-dependent LNCaP and androgen-independent PC-3. Twelve analogs (5-12, 15, 16, 19, and 20) are conjugates of curcumin (1) or methyl curcumin (2) with a flutamide- or bicalutamide-like moiety. Two compounds (22 and 23) are C4-mono- and difluoro-substituted analogs of dimethyl curcumin (DMC, 21). Among the newly synthesized conjugates compound 15, a conjugate of 2 with a partial bicalutamide moiety, was more potent than bicalutamide alone and essentially equipotent with 1 and 2 against both prostate tumor cell lines with IC(50) values of 41.8 μM (for LNCaP) and 39.1 μM (for PC-3). A cell morphology study revealed that the cytotoxicity of curcumin analogs or curcumin-anti-androgen conjugates detected from both prostate cancer cell lines might be due to the suppression of pseudopodia formation. A molecular intrinsic fluorescence experiment showed that 1 accumulated mainly in the nuclei, while conjugate 6 was distributed in the cytosol. At the tested conditions, anti-androgens suppressed pseudopodia formation in PC-3 cells, but not in LNCaP cells. The evidence suggests that distinguishable target proteins are involved, resulting in the different outcomes toward pseudopodia suppression.
Authors:
Qian Shi; Koji Wada; Emika Ohkoshi; Li Lin; Rong Huang; Susan L Morris-Natschke; Masuo Goto; Kuo-Hsiung Lee
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-05-15
Journal Detail:
Title:  Bioorganic & medicinal chemistry     Volume:  20     ISSN:  1464-3391     ISO Abbreviation:  Bioorg. Med. Chem.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-06-15     Completed Date:  2012-10-11     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  9413298     Medline TA:  Bioorg Med Chem     Country:  England    
Other Details:
Languages:  eng     Pagination:  4020-31     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Ltd. All rights reserved.
Affiliation:
Natural Products Research Laboratories, UNC Eshelmen School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA. qshi1@email.unc.edu
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MeSH Terms
Descriptor/Qualifier:
Androgen Antagonists / chemistry*
Anilides / chemical synthesis*,  chemistry,  therapeutic use,  toxicity
Antineoplastic Agents / chemical synthesis*,  therapeutic use,  toxicity
Cell Line, Tumor
Cell Survival / drug effects
Curcumin / analogs & derivatives*,  chemical synthesis,  therapeutic use,  toxicity
Drug Design*
Flutamide / chemistry
Humans
Male
Nitriles / chemistry
Prostatic Neoplasms / drug therapy
Pseudopodia / drug effects
Structure-Activity Relationship
Tosyl Compounds / chemistry
Grant Support
ID/Acronym/Agency:
CA-17625-32/CA/NCI NIH HHS; R01 CA017625/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Androgen Antagonists; 0/Anilides; 0/Antineoplastic Agents; 0/N-(4-nitro-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamidomethylcurcumin; 0/Nitriles; 0/Tosyl Compounds; 13311-84-7/Flutamide; 458-37-7/Curcumin; 90357-06-5/bicalutamide
Comments/Corrections

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