BackgroundRecent studies showed that moderate consumption of red or white wines increased the chances of breast cancer, while similar consumption of red wines, rich in trans-resveratrol (trans-R), decreased the rate of prostate cancer. This prompted us to explore the role of various forms of R in cancer proliferation.ResultsTrans-R was found to be the most potent antiproliferative agent. Cis-R demonstrated somewhat less potency compared to trans-R. Unlike cis-R and trans-R, dihydro-R exhibits moderate proliferative effect on androgen-independent prostate cancer cell lines PC-3 and DU-145 at picomolar concentrations. At higher concentrations, dihydro-R caused proliferation inhibition, similar to cis-R and trans-R. The proliferative effect of dihydro-R at low concentrations can be reversed by trans-R which acts as a partial antagonist in the presence of dihydro-R. Mixtures of dihydro-R and trans-R demonstrated complex non-monotonic cross-modulation activity patterns.ConclusionsDihydro-R exhibits proliferative effects in androgen-independent prostate cancer cells at picomolar and nanomolar concentrations. While the exact mechanism of these effects requires further evaluation, our preliminary results point to hormone receptor modulation activity. We also observed strong cross modulation between trans-R and dihydro-R at sub-picomolar concentrations. The role of dihydro-R in cancer proliferation related to moderate consumption of red wine remains an open question because dihydro-R has a very complex activity pattern in the presence of trans-R.
A new chemical series was identified via high-throughput screening as having antiproliferative activity on DU-145 human prostate carcinoma cell line (hit compound potency - 2.9 microM). Medicinal chemistry optimization of two peripheral diversity vectors of the hit molecule, independently, led to SAR generalizations and identification of the 'best' moieties. The latter were merged in a single compound that exhibited an over 100-fold better potency than the hit compound. For the most potent compounds it was confirmed that the observed antiproliferative potency was not associated with the compounds' non-specific cytotoxicity.
The combination of experimental (inhibition of colchicine binding) and computational (COMPARE, docking studies) data unequivocally identified diaryl 5-amino-1,2,4-oxadiazoles as potent tubulin inhibitors. Good correlation was observed between tubulin binding and cytostatic properties for all tested compounds with the notable exception of the lead candidate, 3-(3-methoxyphenyl)-5-(4-methoxyphenyl)amino-1,2,4-oxadiazole (DCP 10500078). This compound was found to be substantially more active in our in vitro experiments than the monofluorinated title compound, 3-(2-fluorophenyl)-5-(4-methoxyphenyl)amino-1,2,4-oxadiazole (DCP 10500067/NSC 757486), which in turn demonstrated slightly better tubulin binding activity. Comparative SAR analysis of twenty five diaryl 5-amino-1,2,4-oxadiazoles with other known tubulin inhibitors, such as combretastatin A-4 (CA-4) and colchicine, provides further insight into the specifics of their binding as well as the plausible mechanism of action.
We discovered a new chemical class of antiproliferative agents, 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides. SAR-guided optimization of the two distinct terminal fragments yielded a compound with 120 nM potency in an antiproliferative assay. Biological activity profile studies (COMPARE analysis) demonstrated that 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides act as tubulin inhibitors, and this conclusion was confirmed via biochemical assays with pure tubulin and demonstration of increased numbers of mitotic cells following treatment of a leukemia cell line.
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