In this regard, we have recently reported the chemical synthesis and CYP1A1 inhibitory profile of a new series of hybrid resveratrol-salicylate analogues with promising chemopreventive activity (38); after we re-examined the chemical structures of these derivatives, we acknowledged a potentially useful pattern: by replacing the central methylene group in NSC14778 for the ethylene (CH=CH) moiety present in stilbenes. modulation of the estrogen receptor (10), and chemopreventive activity (11). In this regard, resveratrol possesses a stylish chemopreventive profile, because it inhibits the proliferation of cancer cells without exerting significant cytotoxicity to normal cells (12) ; it induces cancer cell apoptosis in several cell lines from different tissue types (13C15), and it significantly decreases tumor size using different cancer cells in xenograft models of rodents (16, 17). The mechanisms of action associated with the chemopreventive profile of resveratrol are varied and rather complex. In accordance with the current paradigm involving the design of multi-target drugs, and the relatively new concept known as polypharmacology (18), there is evidence supporting the multi-target profile of resveratrol. In this regard, resveratrol downregulates the expression or inhibits the activity of key enzymes and transcription factors involved in carcinogenesis, including (but not limited to) cyclooxygenase (COX) enzymes, inducible nitric oxide synthase (evaluation of more than 26,000 compounds from the National Malignancy Institute (NCI) database on DNMT enzymes. In that paper, authors reported a series of small molecules with relatively high biochemical selectivity towards individual human DNMT enzymes. Using a multistep docking approach of lead-like compounds with a homology model of the catalytic site of DNMT1, followed by experimental testing, authors identified seven new molecules with detectable DNMT1 inhibitory activity. The molecules identified in this study had diverse scaffolds, some of them not previously reported as DNMT inhibitors, such as a series of methylenedisalicylic acids, among which, the compound NSC 14778 (Physique 1) was one of the most potent compounds tested on DNMT1 and DNMT3B enzymes (37). By analysing the chemical structure of the scaffold present in methylenedisalicylic acids, and compare it to that of our recently reported resveratrol-salicylate analogues, in which we added a carboxylic acid group to one of GGTI-2418 the aromatic rings present in the polyphenol (38), we hypothesized that, in addition to the CYP1A1 inhibitory activity reported previously, these hybrid drugs could also inhibit the enzymatic activity of DNMT (Physique 1). To the best of our knowledge, there are no reports in the literature describing the direct inhibitory effect of resveratrol on DNMT enzymes, and the only report we could find on this regard, was that published by Qin et al., who reported the effects of resveratrol around the expression of DNMT enzymes (39). As part of an ongoing research work aimed at developing new cancer chemopreventive brokers, we now report biological evaluation and the molecular modeling (docking) studies of a new series of resveratrol-salicylate derivatives with DNMT inhibitory activity. Our hypothesis was based on the idea that this addition of a carboxylic GGTI-2418 acid or its methyl ester, attached to one of the phenol groups present in hydroxystilbenes, GGTI-2418 might confer resveratrol with a novel DNMT inhibitory profile, similar to that exerted by methylenedisalicylic acids described above. In this report, we identified compound 10 as the most active analogue which showed greater than four-fold potency compared to resveratrol in inhibiting the DNMT3A enzyme. Additionally, compound 10 exerted cell proliferation inhibition on Rabbit Polyclonal to CXCR3 three different human malignancy cell lines (HT-29, HepG2, and SK-BR-3), suggesting that this chemical compound GGTI-2418 was GGTI-2418 more effective than the parent resveratrol under the same experimental conditions. MATERIALS AND METHODS Chemistry We carried out the synthesis of hybrid resveratrol-salicylate derivatives 3C12 as.