pterostilbene and Neoplasms

Natural polyphenols are organic chemicals which contain phenol units in their structures. They show antitumor properties. However, a key problem is their short half-life and low bioavailability under in vivo conditions. Still, definitively demonstrating the human benefits of isolated polyphenolic compounds (alone or in combination) using modern scientific methodology has proved challenging. The most common discrepancy between experimental and clinical observations is the use of nonphysiologically relevant concentrations of polyphenols in mechanistic studies. Thus, it remains highly controversial how applicable underlying mechanisms are with bioavailable concentrations and biological half-life. The present Perspective analyses proposed antitumor mechanisms, in vivo reported antitumor effects, and possible mechanisms that may explain discrepancies between bioavailability and bioefficacy. Polyphenol metabolism and possible toxic side effects are also considered. Our main conclusion emphasizes that these natural molecules (and their chemical derivatives) indeed can be very useful, not only as cancer chemopreventive agents but also in oncotherapy.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Biological Availability; Drug Delivery Systems; Humans; Neoplasms; Phytochemicals; Polyphenols

A series of new resveratrol analogues were designed and synthesized and their inhibitory activities against aromatase were evaluated. The crystal structure of human aromatase (PDB 3eqm) was used to rationalize the mechanism of action of the aromatase inhibitor 32 (IC50 0.59 microM) through docking, molecular mechanics energy minimization, and computer graphics molecular modeling, and the information was utilized to design several very potent inhibitors, including compounds 82 (IC50 70 nM) and 84 (IC50 36 nM). The aromatase inhibitory activities of these compounds are much more potent than that for the lead compound resveratrol, which has an IC50 of 80 microM. In addition to aromatase inhibitory activity, compounds 32 and 44 also displayed potent QR2 inhibitory activity (IC50 1.7 microM and 0.27 microM, respectively) and the high-resolution X-ray structures of QR2 in complex with these two compounds provide insight into their mechanism of QR2 inhibition. The aromatase and quinone reductase inhibitors resulting from these studies have potential value in the treatment and prevention of cancer.

Topics: Anticarcinogenic Agents; Aromatase; Aromatase Inhibitors; Chemoprevention; Crystallography, X-Ray; Humans; Models, Molecular; Neoplasms; Quinone Reductases; Resveratrol; Stilbenes; Veratrum