Antitumor agents 290. Design, synthesis, and biological evaluation of new LNCaP and PC-3 cytotoxic curcumin analogs conjugated with anti-androgens.
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.
Natural Products Research Laboratories, UNC Eshelmen School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA. qshi1@email.unc.edu
Qian
Q
Shi
Koji
K
Wada
Emika
E
Ohkoshi
Li
L
Lin
Rong
R
Huang
Susan L
SL
Morris-Natschke
Masuo
M
Goto
Kuo-Hsiung
KH
Lee
D000726:Androgen Antagonists / Q000737:chemistry*; D000813:Anilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use / Q000633:toxicity; D015195:Drug Design; D005485:Flutamide / Q000737:chemistry; D006801:Humans; D008297:Male; D009570:Nitriles / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011554:Pseudopodia / Q000187:drug effects; D013329:Structure-Activity Relationship; D014105:Tosyl Compounds / Q000737:chemistry
D000726:Androgen Antagonists; D000813:Anilides; D000970:Antineoplastic Agents; C575503:N-(4-nitro-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamidomethylcurcumin; D009570:Nitriles; D014105:Tosyl Compounds; D005485:Flutamide; C053541:bicalutamide; D003474:Curcumin