Identification of a selective inhibitor of human monocarboxylate transporter 4.

The human monocarboxylate transporters (hMCTs/SLC16As) mediate the uptake of various monocarboxylates. Several isoforms of hMCTs are expressed in cancerous tissue as well as in normal tissue. In cancerous tissue, hypoxia induces the expression of hMCT4, which transports the energetic metabolite l-lactate across the plasma membrane. Since hMCT4 is involved in pH regulation and the transport of l-lactate in cancer cells, an hMCT4 inhibitor could function as an anticancer agent. Although several non specific hMCT inhibitors have been developed, a selective hMCT4 inhibitor has not yet been identified. The aim of this study was therefore to identify a selective hMCT4 inhibitor for use as a pharmacological tool for studying hMCT4. The heterologous expression system of the Xenopus oocyte was used to assess the effects of test compounds on hMCT4, whereupon isobutyrate derivatives, fibrates, and bindarit (2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropanoic acid) were demonstrated to exhibit selective inhibitory effects against this transporter. It is suggested that the structure formed from the joining of an isobutyrate moiety and two aromatic rings by appropriate linkers is important for acquiring the selective hMCT4-inhibiting activity. These findings provide novel insights into the ligand recognition of hMCT4, and contribute to the development of novel anticancer agents.

Antidiarrheal Thymol Derivatives from Ageratina glabrata. Structure and Absolute Configuration of 10-Benzoyloxy-8,9-epoxy-6-hydroxythymol Isobutyrate.

Chemical investigation of the leaves from Ageratina glabrata yielded four new thymol derivatives, namely: 10-benzoyloxy-8,9-dehydro-6-hydroxythymol isobutyrate (4), 10-benzoyloxy-8,9-dehydrothymol (5), 10-benzoyloxythymol (6) and 10-benzoyloxy-6,8-dihydroxy-9-isobutyryl-oxythymol (7). In addition, (8S)-10-benzoyloxy-8,9-epoxy-6-hydroxythymol isobutyrate (1), together with other two already known thymol derivatives identified as 10-benzoyloxy-8,9-epoxy-6-methoxythymol isobutyrate (2) and 10-benzoyloxy-8,9-epoxythymol isobutyrate (3) were also obtained. In this paper, we report the structures and complete assignments of the ¹H and (13)C-NMR data of compounds 1-7, and the absolute configuration for compound 1, unambiguously established by single crystal X-ray diffraction, and evaluation of the Flack parameter. The in vitro antiprotozoal assay showed that compound 1 and its derivative 1a were the most potent antiamoebic and antigiardial compounds. Both compounds showed selectivity and good antiamoebic activity comparable to emetine and metronidazole, respectively, two antiprotozoal drugs used as positive controls. In relation to anti-propulsive effect, compound 1 and 1a showed inhibitory activity, with activities comparable to quercetin and compound 9, two natural antipropulsive compounds used as positive controls. These data suggest that compound 1 may play an important role in antidiarrheal properties of Ageratina glabrata.

Synthesis and properties of novel biomimetic and thermo-responsive dextran-based biohybrids.

A new class of biodegradable, biomimetic and thermo-responsive dextran/synthetic glycopolymer biohybrids (dextran-graft-poly(lactobionamidoethyl methacrylate)-block-poly(di(ethylene glycol) methyl ether methacrylate), dextran-g-(PLAMA-b-PDEGMA)), was synthesized by the direct atom transfer radical polymerization (ATRP) of unprotected lactobionamidoethyl methacrylate (LAMA) glycomonomer and di(ethylene glycol) methyl ether methacrylate (DEGMA) monomer. The dextran macroinitiator for ATRP was prepared by partial esterification of the hydroxyl groups of the polysaccharide with 2-bromo-2-methylpropionic acid (BrMPA). The biohybrids containing PDEGMA segments exhibited a lower critical solution temperature (LCST) behavior, which changed from unimers to aggregates in solutions. Moreover, it was demonstrated that these biohybrids had specific biomolecular recognition with ricinus communis agglutinin 120 (RCA120) in comparison with bovine serum albumin (BSA). Furthermore, these biohybrids showed good biocompatibility in the cytotoxicity assays. This hopefully provides a platform for targeted drug delivery and studying the biomolecular recognition between sugar and lectin.