Polymorphisms of extrinsic death receptor apoptotic genes (FAS -670 G>A, FASL -844 T>C) in coronary artery disease.

Apoptosis plays an important role in atherogenesis and rupture of vulnerable plaques in coronary artery disease. FAS and FAS ligand (FASL) induce apoptosis when FAS binds to FAS-L. However sFas blocks apoptosis by binding to FAS and FASL or sFasL. The present study is sought to examine the role of extrinsic apoptotic genes (FAS, FASL) polymorphism and serum levels of FAS, FASL in the pathogenesis and susceptibility to CAD in south Indian population. The study included 300 CAD patients and 300 healthy controls. Lipid profiles, sFas, sFasL were estimated by commercially available kits. FAS -670 G>A, FASL -844 T>C genotypes were analyzed by PCR-RFLP. Secondary structures of pre mRNA were analyzed by the Vienna RNA webserver and gene-gene and gene-environment interactions were determined by MDR analysis. Total cholesterol, triglyceride and LDL levels were significantly high in CAD patients compared to the controls. Molecular analysis revealed that the frequency of the AA genotype of FAS (54% vs 27%) and CC genotypes of FASL (10.3% vs 1.3%) were high in CAD patients compared to controls. Secondary structure analysis of FAS and FASL confirmed our molecular analysis. sFas levels were low while serum sFasL were high in CAD patients. MDR analysis revealed synergistic effects of gene polymorphisms and additive effects of epidemiological factors on risk of CAD. Polymorphisms of FAS (-670 G/A), FASL (-844 T/C) and their circulating levels play an important role in the pathology of CAD.

Synthesis and biochemical evaluation of benzoylbenzophenone thiosemicarbazone analogues as potent and selective inhibitors of cathepsin L.

Upregulation of cathepsin L in a variety of tumors and its ability to promote cancer cell invasion and migration through degradation of the extracellular matrix suggest that cathepsin L is a promising biological target for the development of anti-metastatic agents. Based on encouraging results from studies on benzophenone thiosemicarbazone cathepsin inhibitors, a series of fourteen benzoylbenzophenone thiosemicarbazone analogues were designed, synthesized, and evaluated for their inhibitory activity against cathepsins L and B. Thiosemicarbazone inhibitors 3-benzoylbenzophenone thiosemicarbazone 1, 1,3-bis(4-fluorobenzoyl)benzene thiosemicarbazone 8, and 1,3-bis(2-fluorobenzoyl)-5-bromobenzene thiosemicarbazone 32 displayed the greatest potency against cathepsin L with low IC50 values of 9.9 nM, 14.4 nM, and 8.1 nM, respectively. The benzoylbenzophenone thiosemicarbazone analogues evaluated were selective in their inhibition of cathepsin L compared to cathepsin B. Thiosemicarbazone analogue 32 inhibited invasion through Matrigel of MDA-MB-231 breast cancer cells by 70% at 10 µM. Thiosemicarbazone analogue 8 significantly inhibited the invasive potential of PC-3ML prostate cancer cells by 92% at 5 µM. The most active cathepsin L inhibitors from this benzoylbenzophenone thiosemicarbazone series (1, 8, and 32) displayed low cytotoxicity toward normal primary cells [in this case human umbilical vein endothelial cells (HUVECs)]. In an initial in vivo study, 3-benzoylbenzophenone thiosemicarbazone (1) was well-tolerated in a CDF1 mouse model bearing an implanted C3H mammary carcinoma, and showed efficacy in tumor growth delay. Low cytotoxicity, inhibition of cell invasion, and in vivo tolerability are desirable characteristics for anti-metastatic agents functioning through an inhibition of cathepsin L. Active members of this structurally diverse group of benzoylbenzophenone thiosemicarbazone cathepsin L inhibitors show promise as potential anti-metastatic, pre-clinical drug candidates.

Synthesis and evaluation of macrocyclic diarylether heptanoid natural products and their analogs.

The macrocyclic diarylether heptanoid (MDEH) natural products have been used in folk medicine for centuries. MDEHs are reported to exert anti-tumor properties by inhibiting the activation of NF-κB. Here we report the synthesis of a small MDEH library (first reported synthesis of racemic platycarynol) using a Grubbs cross metathesis/Ullmann cyclization strategy. Evaluation of the library led to the identification of MDEH 9b which sensitizes pancreatic cancer cells to gemcitabine mediated growth inhibition and apoptosis.

Design, synthesis, and biological evaluation of potent thiosemicarbazone based cathepsin L inhibitors.

A small library of 36 functionalized benzophenone thiosemicarbazone analogs has been prepared by chemical synthesis and evaluated for their ability to inhibit the cysteine proteases cathepsin L and cathepsin B. Inhibitors of cathepsins L and B have the potential to limit or arrest cancer metastasis. The six most active inhibitors of cathepsin L (IC50<85 nM) in this series incorporate a meta-bromo substituent in one aryl ring along with a variety of functional groups in the second aryl ring. These six analogs are selective for their inhibition of cathepsin L versus cathepsin B (IC50>10,000 nM). The most active analog in the series, 3-bromophenyl-2'-fluorophenyl thiosemicarbazone 1, also efficiently inhibits cell invasion of the DU-145 human prostate cancer cell line.

A facile, catalytic, and environmentally benign method for selective deprotection of tert-butyldimethylsilyl ether mediated by phosphomolybdic acid supported on silica gel.

An environmentally benign PMA supported on SiO(2) is found to be an efficient catalyst for the chemoselective deprotection of TBDMS ethers under very mild conditions. Various labile functional groups such as isopropylidene acetal, OTBDPS, OTHP, Oallyl, OBn, alkene, alkyne, OAc, OBz, N-Boc, N-Cbz, N-Fmoc, mesylate, and azide are found to be stable under the reaction conditions. This "truly catalytic" heterogeneous reaction does not require aqueous workup, and the supported catalyst and the solvent can be readily recovered and recycled.