CYP1B1 is recognized as a new target in cancer prevention and therapy. Taking α-naphthoflavone as a lead, a series of 6,7,10-trimethoxy-α-naphthoflavones (4a-o) were synthesized and evaluated for their inhibitory potency against CYP1B1 and selectivity over CYP1A1 and 1A2. SAR analysis indicated that introducing methoxy groups at C(6), C(7), and C(10) on the naphthalene part and a fluoro atom at C(3') on the B-ring, could sharply increase the efficiency toward CYP1B1 inhibition. Among the prepared derivatives, compound 4c is the most potent and selective CYP1B1 inhibitor ever reported. More effort was taken to acquire water-soluble α-naphthoflavone derivatives for further cell-based study of overcoming anticancer drug-resistance. Finally, we obtained water-soluble naphthoflavone (11f) which could obviously eliminate the docetaxel-resistance caused by the enhanced expression of CYP1B1 in MCF-7/1B1 cells. It could be envisaged that the discovery of new α-naphthoflavones as CYP1B1 inhibitors is clinically important for overcoming CYP1B1-mediated drug-resistance in cancer therapeutics.

Since Human CYP1 enzymes catalyze the metabolic activation of procarcinogens and deactivation of certain anticancer drugs, the inhibition of these enzymes has been considered as an effective approach for chemoprevention and treatment of CYP1-mediated drug resistance. Recent knowledge relating to the enhanced expression of CYP1B1 in tumors also provided certain advantages in cancer therapy by the activation of prodrugs only in tumor cells. This review concentrates on the characterized CYP1 inhibitors and CYP1-activatied anticancer prodrugs. The mechanism for enzyme inhibition and activation of prodrugs, the cancer preventive/therapeutic potential of these chemicals and their related SARs are highlighted. According to their structural features, CYP1 inhibitors are divided into the following categories: flavonoids, trans-stilbenes, coumarins, terpenoids, alkaloids, quinones, isothiocyanates and synthetic aromatics. In the same way, CYP1-activatied prodrugs are categorized into four groups: benzothiazoles, flavonoids, stilbenes and alkylating agents. Almost all of these inhibitors and prodrugs are planar molecules with one aromatic ring and some have similarity with identified CYP1 substrates. CYP1 inhibitors could effectively block the procarcinogen-induced tumor initiation in animal models and benefit us with chemoprevention. The advent of Phortress and aminoflavone as clinical candidates shows promising perspectives in developing CYP1-mediated prodrugs as chemotherapeutic drugs that are specifically activated in tumors. All of these preclinical and clinical studies indicate that inhibitors and prodrugs target CYP1 are promising anticancer strategies.

The statefinder diagnosic is a useful method for distinguishing different dark energy models. In this paper, we investigate the new agegraphic dark energy model with interaction between dark energy and matter component by using statefinder parameter pair {r, s} and study its cosmological evolution.We plot the trajectories of the new agegraphic dark energy model for different interaction cases in the statefinder plane. As a result, the influence of the interaction on the evolution of the universe is shown in the statefinder diagrams.

The present work describes the syntheses of diverse triazole bridged flavonoid dimers and identifies potent, nontoxic, and highly selective BCRP inhibitors. A homodimer, Ac22­(Az8) 2 , with m-methoxycarbonylbenzyloxy substitution at C-3 of the flavone moieties and a bis-triazole-containing linker (21 atoms between the two flavones) showed low toxicity (IC50 toward L929, 3T3, and HFF-1 > 100 μM), potent BCRP-inhibitory activity (EC50 = 1–2 nM), and high BCRP selectivity (BCRP selectivity over MRP1 and P-gp > 455–909). Ac22­(Az8) 2 inhibits BCRP-ATPase activity, blocks the drug efflux activity of BCRP, elevates the intracellular drug accumulation, and finally restores the drug sensitivity of BCRP-overexpressing cells. It does not down-regulate the surface BCRP protein expression to enhance the drug retention. Therefore, Ac22­(Az8) 2 and similar flavonoid dimers appear to be promising candidates for further development into combination therapy to overcome MDR cancers with BCRP overexpression.

: COX-2, a key enzyme that catalyzed the rate-limiting steps in the conversion of arachidonic acid to prostaglandins, played a pivotal role in inflammatory process. Different from other family members, COX-2 was barely detectable in normal physiological conditions and highly inducible during acute inflammatory response of human bodies to injuries or infections. Therefore, the therapeutic utilization of selective COX-2 inhibitors has already been considered as an effective approach for the treatment of inflammation with diminished side effects. Currently, both traditional and newer NSAIDs are the commonly prescribed medications that treat inflammatory disease by targeting COX-2. However, due to the cardiovascular side-effects of the NSAIDs, finding reasonable alternatives for these frequently prescribed medicines are a hot spot in medicinal chemistry research. Naturally-occurring compounds have been reported to inhibit COX-2, thereby possessing beneficial effects against inflammation and certain cell injury. The review mainly concentrated on recently identified natural products and derivatives as COX-2 inhibitors, the characteristics of their structural core scaffolds, their anti-inflammatory effects, molecular mechanisms for enzymatic inhibition and related structure-activity relationships. According to the structural features, the natural COX-2 inhibitors were mainly divided into the following categories: natural phenols, flavonoids, stilbenes, terpenoids, quinones and alkaloids. Apart from the anti-inflammatory activities, a few dietary COX-2 inhibitors from nature origin also exhibited chemopreventive effects by targeting COX-2-mediated carcinogenesis. The utilization of these natural remedies in future cancer prevention was also discussed. In all, the survey on the characterized COX-2 inhibitors from natural sources paths the further development of more potent and selective COX-2 inhibitors in the future.