5550 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 17
Zhou et al.
Further, 6 shows low micromolar cytotoxicity in AR-positive
LNCaP, PCa 2b, 22Rv1, and C4-2B cells. Its cytotoxicity in
AR-negative PC-3 cells suggests 6 is a multitarget agent. The
possible additional target(s) of 6 is not clear at this stage, and
this is the subject of our further work. Taken together, 6 is a
lead compound to be further optimized as a novel antiandro-
gen for advanced prostate cancer.
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Experimental Section
General. All reagents for chemical syntheses were purchased
from Sigma-Aldrich (Oakville, ON, Canada). Hydroxyflutamide,
bicalutamide and DHT were purchased from Toronto Research
Chemicals (North York, ON, Canada). R5020 was purchased
from PerkinElmer Inc. (Woodbridge, ON, Canada). All the 1H
NMR spectra of compounds 1-5 and 7-11 were recorded on an
Avance Bruker NMR spectrometer operating at 500 MHz on
proton. The NMR spectra of compound 6 were recorded on an
Avance Bruker NMR spectrometer operating at 600.17 MHz on
proton and 150.93 MHz on carbon-13. Mass measurements
were performed on a LC-MSD-TOF instrument from Agilent
Technologies in positive electrospray mode. Purity was deter-
mined by HPLC (Waters Alliance 2695-2996) and purity of
compound 1-11 was g95%.
General Procedure for the Synthesis of Compounds 6-11.
Diketone 1 (0.25 mmol, 92 mg) and 4-hydroxy-3-methoxyben-
zaldehyde (0.3 mmol, 47 mg) were dissolved in 6 mL of
methanol. After adding piperidine (25 μL), the mixture was
stirred for 48 h at room temperature. The solvent was distilled
off, and the crude product was purified by silica gel column
chromatography (elutant: EtOAc/hexane, 1:2) to afford com-
pound 6. Yellow solid (26 mg, 21%). ESI-TOF MS m/z 503.24
[M þ H]þ. The 1H and 13C NMR analyses for both cis and trans
isomers of compound 6 were summarized in Tables S1 and S2
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Biology. Details of antiproliferative assays in five prostate
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porting Information.
Acknowledgment. We thank Dr. Gerald Batist for his
insightful comments of the manuscript. We thank Dr.
Liang-Nian Song (Columbia University), Dr. S Srivastava
(Uniformed Services University), and Dr. Osmu Ogawa
(Kyoto University, Japan) for providing AR expressing
plasmids. This work was supported by the Canadian Institute
of Health Research via an operating grant to J.H.W. (grant
number: MOP-74741). J.H.W. is a FRSQ investigator.
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Supporting Information Available: Syntheses of (E)-6-(2,6,6-
trimethylcyclohex-1-enyl)-hex-5-ene-2,4-dione and diketones
1-5, the predicted binding modes of compounds 6-11, NMR
and MS analyses, biological assays details, and molecular
modeling methods. This material is available free of charge via