Showing papers in "Letters in Drug Design & Discovery in 2011"

Synthesis of some coumarinyl chalcones and their antiproliferative activity against breast cancer cell lines

Abstract: A series of coumarinyl chalcones derivatives were synthesized and evaluated for their antiproliferative activities on three different breast cancer cell lines (MDA-MB231, MDA-MB468, MCF7) and one non-cancer breast epithelial cell line (184B5). The coumarinyl derivatives exhibited anticancer activity against breast cancer cell lines at a micromolar range. A structure-activity relationship (SAR) analysis was performed by studying the effect of substituents on their antiproliferative activities. One of the compound 3i bearing methoxy substitutions at the R1, R2 and R3 positions of the phenyl ring showed comparable potency to the reference drug cisplatin as well as a two-fold higher selectivity for the breast cancer cell lines than 184B5 cells.

Design, Synthesis and Anti Colon Cancer Activity Evaluation of Phosphorylated Derivatives of Lamivudine (3TC)

Abstract: The novel phosphorylated derivatives of Lamivudine (5a-5l) as potential anti colon cancer agents are synthe- sized. These title compounds are designed based on the basic pyrimidine derivative lamivudine as a starting compound and reacted with various phosphorodichloridates followed by the introduction of bioactive groups at the phosphorus. Their structures were characterized by IR, 1 H, 13 C, 31 P NMR and mass spectral analyses. All the compounds were evaluated for their anti colon cancer activity against COLO-205 cell lines in vitro studies. Among them 5a and 5b emerged as lead compounds with 0.003 μM and 0.0001 μM values.

Prediction of specificity and cross-reactivity of kinase inhibitors

Abstract: Designing kinase inhibitors is always an area of interest because kinases are involved in many diseases. In the last one decade a large number of kinase inhibitors have been launched successfully; six inhibitors have been approved by FDA and more are under clinical trials. Cross-reactivity or off-target is one of the major problems in designing inhibitors against protein kinases; as human, have more than 500 kinases with high sequence similarity. In this study an attempt has been made to develop a model for predicting specificity and cross-reactivity of kinase inhibitors. The dataset used for test- ing and training consists of binding affinities of 20 chemical kinase inhibitors with protein kinases. We developed QSAR based SVM models for predicting binding affinity of an inhibitor against protein kinases using most relevant 5,10 and 15 structure descriptors and achieving average correlation of 0.64, 0.488 and 0.442 respectively. In or- der to predict specificity and cross-reactivity of an inhibitor, we developed 16 QSAR based SVM models for 16 protein kinases; one model for each kinase. We achieved average correlation 0.719 between actual and predicted binding affinity using kinase specific models. Based on the above study a web server DMKPred has been developed for predicting binding affinity of a drug molecule with 16 kinases. The SVM based model used in this study can be used to predict kinase spe- cific inhibitors. This study will be useful for designing kinase specific inhibitors.

Discovery of BRM Targeted Therapies: Novel Reactivation of an Anti-cancer Gene

Abstract: Drug discovery in the field of oncology has been advanced mainly through the targeting of receptor tyrosine kinases. Both antibodies and small molecule inhibitors have been found to have successful applications in blocking the proliferative functions of these cell surface receptors. Based on these early successes, additional kinases within the cytoplasm have been found to promote cancer and, as such, have been recognized as feasible targets for additional modes of therapies. Unlike these oncogene targets, most tumor suppressors are irreversibly altered during cancer progression and therefore are not feasible targets for therapy. However, a subset of these genes is reversibly epigenetically suppressed. One such gene is BRM, and when it is re-expressed in cancer cells, this gene halts their growth. Moreover, as the key catalytic subunit of the SWI/SNF complex, BRM is centrally important to a host of anticancer pathways and cellular mechanisms, and its status may serve as a biomarker. Restoring its expression will both reconnect a number of growth-controlling pathways and affect cellular adhesion, DNA repair, and immune functions. For these reasons, restoring BRM expression is not only feasible, but potentially a potent form of anticancer therapy. To identify BRM-restoring compounds, we developed a cell-based luciferase assay. In this review, we discuss some of the challenges we encountered, issues related to this type of drug discovery, and our future ambitions. We hope this review will provide insight to this type of endeavor and lead to more investigations pursuing this type of drug research.

Effects of honey against the accumulation of adipose tissue and the increased blood pressure on carbohydrate-induced obesity in rat

Abstract: This study was designed to assess the effect of honey supplementation and sugar-based hypercaloric regimen on weight gain and blood pressure (BP) in Wistar rats. Animals were fed for 8 weeks with standard diet (S-free) or a hypercaloric diet (standard chow and 30% sugar in drinking water), (SF), or standard chow supplemented with fat and honey and 10% sugar in drinking water (HF). Overall weight gain and body fat levels were significantly higher in SF and HF than in S-free. Fat cells were significantly larger in SF compared with HF. Compared with SF and S-free, HF had higher glucose, but triglycerides, and LDLc levels were not different. BP was significantly higher in SF but not in HF compared to S-free. These observations indicate that honey may afford a protection against increase in BP and in fat cell size resulting from a hypercaloric diet. © 2011 Bentham Science Publishers Ltd.

Antiviral Activity of 3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol and its Derivatives Against Influenza A(H1N1)2009 Virus

Abstract: A number of new derivatives of monoterpenoid with a para-menthane framework 3-methyl-6-(prop-1-en-2- yl)cyclohex-3-ene-1,2-diol (-)-3 were synthesized. The antiviral activity of (-)-3 and its derivatives against the pandemic influenza virus A/California/07/09 (H1N1)v was studied in vitro. Compound (-)-3 was found to be active against this vi- rus (selectivity index 7.5); for mononicotinate (+)-6 the selectivity index was 17. The absolute configuration of compound 6 was shown to be critical for its antiviral activity.

Synthesis and Biological Evaluation of Ezetimibe Analogs as Possible Cholesterol Absorption Inhibitors

Abstract: In order to investigate the SAR of Ezetimibe analogs for cholesterol absorption inhibitions, amide group and electron-deficient pyridine ring were introduced to the C-(3) carbon chain of Ezetimibe. Eight new derivatives of the 2-azetidinone cholesterol absorption inhibitors have been synthesized, and all of them were enantiomerically pure. All the new compounds were evaluated for their activity to inhibit cholesterol absorption in hamsters, and most of them showed comparable effects in lowering the levels of total cholesterol in the serum.

The Antiangiogenic and Antitumoral Activity of Titanocene Y* In Vivo

Abstract: The 4-diethylaminomethylbenzyl-substituted titanocene dichloride (Titanocene Y*), which is completely water- soluble and showed nanomolar activity against the human renal cancer cells CAKI-1, was tested in vitro in an antiangiogenesis assay against human umbilical vein endothelial cells, HUVEC, delivering an IC50 value of 23 +/- 17 {Mu}M. Titanocene Y* was then given at 25, 50 and 75 mg/kg/d, on five consecutive days per week for up to three weeks to one cohort of six CAKI-1 tumor-bearing female NMRI:nu/nu mice, while a further cohort was treated with solvent only. At the two higher dosages Titanocene Y* showed high toxicity leading to mortality, while the titanocene-treated mouse cohort treated with the lowest dosage showed a moderate but statistically significant tumor growth reduction with respect to the solvent-treated control group, with an optimal T/C value of 76% at the end of the experiment. Immunohistological analysis revealed that the expression of the proliferation marker Ki-67 was reduced by 21%. Furthermore, anti-angiogenic activity was identified by CD31 staining; the number of micro vessels in a defined tumor area decreased by 23% due to Titanocene Y* treatment. The substance caused dose-dependent body weight loss but did not reduce the number of white blood cells at doses of 25 and 50 mg/kg/d.

Characterization of Carbonic Anhydrase Isozyme Specific Inhibition by Sulfamated 2-Ethylestra Compounds

Abstract: This work was supported by NIH Grant GM25154 and by grants from the Medical Research Council of South Africa (AG374, AK076), the Cancer Association of South Africa (AK246), the Struwig-Germeshuysen Cancer Research Trust of South Africa (AJ038) and RESCOM University of Pretoria (A0R984).