Initial evaluation of the antitumour activity of KGP94, a functionalized benzophenone thiosemicarbazone inhibitor of cathepsin L

Kinetic analysis of the mode of inhibition of cathepsin L by KGP94, a lead compound from a privileged library of functionalized benzophenone thiosemicarbazone derivatives, demonstrated that it is a time-dependent, reversible, and competitive inhibitor of the enzyme. These results are consistent with the formation of a transient covalent bond, and are supported by molecular modeling that places the thiocarbonyl of the inhibitor in proximity to the thiolate moiety of the enzyme active site Cys25. KGP94 significantly decreased the activity of cathepsin L toward human type I collagen, and impeded both migration and invasion of MDA-MB-231 human breast cancer cells. Growth retardation was achieved in vivo against both recently implanted and established tumours using a C3H mouse mammary carcinoma model

Design, synthesis, biochemical, and biological evaluation of nitrogen-containing trifluoro structural modifications of combretastatin A-4

A new trifluorinated amino-combretastatin analogue, (Z)-2-(4′-methoxy-3′-aminophenyl)-1-(3,4,5-trifluorophenyl)ethene, prepared by chemical synthesis, was found to be a potent inhibitor of tubulin assembly (IC50 = 2.9 μM), and cytotoxic against selected human cancer cell lines. This new lead compound is among the most active from a group of related structural modifications

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 (IC<sub>50</sub> < 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 (IC<sub>50</sub> > 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

19th international isotope society (UK group) symposium: synthesis & applications of labelled compounds 2010

The 19th annual symposium of the International Isotope Society’s United Kingdom Group took place at the Wellcome Genome Campus, Hinxton, Cambridge, UK on Thursday 14th October 2010. The meeting was attended by around 80 delegates from academia and industry, the life sciences, chemical, radiochemical and scientific instrument suppliers.The Harrowven contribution:Since Kekule ? first proposed his ouroboros-inspired structure for benzene in the mid-nineteenth century, it has been regarded as the archetypal aromatic compound – flat, with carbon-carbon bonds of equal length and bond angle.1 The viability of non-planar benzene rings has been known for many decades, with the first reported example of a boat-configured arene dating to the synthesis of [2.2]paracyclophane in 1949.2 However, it was arguably the isolation of (1)-cavicularin in 1996, and latterly of the haouamines and hirsutellones, that alerted the wider scientific community to the existence of biosynthetic pathways for the generation of such motifs in Nature (Figure 1).Through a combination of chemical synthesis (cavicularin,3,4 riccardin C3,4 and RP-664534), molecular modelling and data mining, we have strong evidence to suggest that boat-configured arenes are far more common in natural products than has been traditionally thought, spanning many classes including macrocyclic alkaloids, guaianolides, bisbibenzyls, peptides and biarylheptanoids. In addition, our work provides guidance for addressing the chemical synthesis of such targets