Medicinal Chemistry

Due to the increasingly larger and more interdisciplinary nature of scientific reporting, it is becoming more difficult to identify all the potentially relevant, citeable articles in reference lists of publications such as scientific papers, reports, grant proposals and patent applications. Authors may miss and/or give inaccurate citations, potentially hindering progress in a discipline and on a personal level, and change the importance and impact of an investigator’s work. Given the emphasis on quantitative means for assessing productivity, including the number of literature citations, efforts are needed to assist authors in the identification of potentially relevant articles to cite. Prior work has analyzed citation network structure and characteristic features and correlated these with other variables, such as country of origin, journal impact factor and open access status. As a result, problems have been revealed, such as underrepresentation of third-world countries, a high incidence of self-citation, and unsystematic quotation habits in review articles. With the exception of gross plagiarism detection software, however, no attempt has been made to develop a practical solution to identifying potentially relevant, citeable articles that may have been missed. Here, we use statistical methods to help in the retrieval of relevant literature from existing publications. Specifically, we exploit the fact that publications reporting specific findings are typically quoted together as grouped-co-citations in their respective contexts. Our approach can automatically construct rules for co-citation by automatically extracting co-citation overrepresentations in manuscripts. This approach should help authors and reviewers identify potentially relevant, citeable articles.

Drug usefulnessis frequently obstructed by the incidence of the multidrug resistance (MDR) phenotype and severe adverse effects. Exploiting collateral sensitive(CS)agents (in this case also called MDR-selective agents), which selectively target only MDR cells, is an emerging and novel approach to overcome MDR in cancer treatment. In prior studies, we found that 4’-methyl-6,6,8-triethyldesmosdumotin B (4’-Me-TEDB, 2) is an MDR-selective synthetic flavonoid with significant in vitro anticancer activity against a MDR cell line (KB-Vin) but without activity against the parent cells (KB) as well as other non-MDR tumor cells. Our recent results suggest the absolute MDR-selectivity varies depending on the cell-line system. In order to explore this further and to better understand the critical pharmacophores, we have synthesized nine novel analogues of 2, which contain heteroaromatic as well ascycloalkyl B-rings. The new compounds were evaluated for cytotoxicity to explore the effect of B-ring modifications on MDR-selectivity. All analogues, except 7, 9 and 10, were identified as significant MDR-selective compounds. This observation solidifies the importance of the 5-hydroxy-6,8,8-trialkyl-4H-chromene-4,7(8H)-dione skeleton (AC-ring system) for the pharmacological activity and establishes the B-ring as less critical for the broader spectrum MDR-selectivity. Notably, 3-furanyl (3)and 2-thiophenyl (6)analogues displayed substantial MDR–selectivity with KB/KB-Vin ratios of >12 and 16, respectively. Furthermore, 3 and 6 also exhibited MDR–selectivity in a second set of paired cell lines, theMDR/non-MDR hepatoma-cell system. Interestingly, a cyclohexyl analogue (11) showed moderate inhibition of A549, DU145, and PC-3 cell growth, while the other compoundswere inactive.These new findings are discussed in terms of current understanding of mechanism and structure–activity relationship (SAR) of our novel MDR-selective flavonoids.

Eight halogenated N,N´-diphenethylethylenediamines were synthesized, characterized and evaluated for ?1 receptor binding affinity in vitro. Measurements of lipophilicity also were obtained. The substitution pattern on one of the aromatic rings remained constant as 3,4-dichloro, while the substituents on the other aromatic ring were varied to include fluorine, bromine or iodine in either the 2-, 3- or 4- positions. Two main structure activity relationships were observed. First, halogen substitution on the 3- or 4-positions of the aromatic ring conferred higher binding affinities (Ki values 6.35 - 15.82 nM) than the corresponding substitutions at the 2-position (Ki values 12.08 - 43.15 nM). Second, derivatives containing either a bromo or fluoro substituent at a given position showed higher ?1 receptor binding affinities than derivatives with a corresponding iodo substituent. The data indicate that ?1 receptor affinity for this structural series is sensitive to steric bulk at the 2-position. Log k´w measurements for the halogenated N,N´- diphenethylethylenediamines were determined by high performance liquid chromatography, and varied from 2.54 - 3.71. In particular, the 3-fluoro analog exhibited a log k´w = 2.54 accompanied by a ?1 receptor Ki = 7.8 nM. These novel N,N´-diphenethylethylenediamines warrant further investigation in behavioral assays, and radiolabeled versions may prove suitable for in vivo studies of ?1 receptors.

In the present study, olive leaves of eight varieties were investigated for the total phenol and flavonoid content, for the major compound and for the in vitro antioxidant properties. The different varieties showed a high content of polyphenol and flavonoid. Oleuropein was the major compound of the leaf extract for all varieties. Also, olive leaves extract exhibited a good antioxidant activity and a reduced power, each variety showed its own feature. A significant negative correlation between anti-radical activities and oleuropein content was observed only for four varieties (r = - 0.94). The high oleuropein content and the important antioxidant activities of olive leaves extract could be useful sources for industrial extraction and pharmacological application in the promotion of health and prevention of damages caused by radicals.

Poly (maleic anhydride-co-vinyl acetate) (MAVA) copolymer was synthesized by free-radical copolymerization in methyl ethyl ketone (MEK) at 80ºC, using benzoyl peroxide (BPO) as the initiator. The radical chain copolymerization was confirmed by Fourier Transform Infrared (FTIR) and Nuclear Magnetic Resonance (1H-NMR) spectra. Copolymer surface morphology was visualized by scanning electron microscopy (SEM). After these characterization studies, the amoebicidal effect of MAVA was investigated on E.histolytica trophozoites using differing copolymer concentrations and periods of time. Results indicated that MAVA killed all the trophozoites at 32 mg/mL concentration in 3 h.

A series of novel flavonoids derivatives containing sulfhydryl groups have been designed, designing for potential FAK inhibitors. Docking simulation was performed to position these compounds into the FAK active site to determine the probable binding model. Simulation results showed that 5-hydroxy-3-(4-hydroxyphenyl)-7-mercapto-4H-chromen- 4-one(4a),7-mercapto-3-(4-methoxyphenyl)-4H-chromen-4-one(4b) and 5-hydroxy-7-mercapto- 2-phenyl- 4H- chromen- 4-one(4c) displayed the most potent biological activity. So the three compounds have been synthesized. Antiproliferative assay results demonstrated that the three compounds own fairly good antiproliferative activity .Therefore compounds 4a, 4b and 4c would be potential anticancer agents.