Discovery of new low-molecular-weight p53-Mdmx disruptors and their anti-cancer activities.

Although several p53-Mdm2-binding disruptors have been identified to date, few studies have been published on p53-Mdmx-interaction inhibitors. In the present study, we demonstrated that o-aminothiophenol derivatives with molecular weights of 200-300 selectively inhibited the p53-Mdmx interaction. S-2-Isobutyramidophenyl 2-methylpropanethioate (K-178) (1c) activated p53, up-regulated the expression of its downstream genes such as p21 and Mdm2, and preferentially inhibited the growth of cancer cells with wild-type p53 over those with mutant p53. Furthermore, we found that the S-isobutyryl-deprotected forms 1b and 3b of 1c and S-2-benzamidophenyl 2-methylpropanethioate (K-181) (3c) preferentially inhibited the p53-Mdmx interaction over the p53-Mdm2 interaction, respectively, by using a Flag-p53 and glutathione S-transferase (GST)-fused protein complex (Mdm2, Mdmx, DAPK1, or PPID). In addition, the interaction of p53 with Mdmx was lost by replacing a sulfur atom with an oxygen atom in 1b and 1c. These results suggest that sulfides such as 1b, 3b, 4b, and 5b interfere with the binding of p53-Mdmx, resulting in the dissociation of the two proteins. Furthermore, the results of oral administration experiments using xenografts in nude mice indicated that 1c reduced the volume of tumor masses to 49.0% and 36.6% that of the control at 100 mg/kg and 150 mg/kg, respectively, in 40 days.

Total Synthesis of the Sesquiterpene (-)-Merrillianin.

The first total synthesis of (-)-merrillianin (1), which is a natural sesquiterpene with a tricyclic structure having a cyclopentane ring and five- and seven-membered lactone parts, is demonstrated. This asymmetric total synthesis enabled the absolute stereostructure determination of naturally occurring (-)-1.

Design, synthesis and evaluations of spiro-fused benzoxaborin derivatives as novel boron-containing compounds.

Drug design using boron-containing heterocycles has attracted a great deal of attention because these compounds are believed to possess high biological activity. However, information on the synthetic methodology and pharmacokinetic profiling of boron-containing compounds is limited. In this study, we provide a new synthetic route for preparation of spiro-fused benzoxaborin derivatives and investigate their in vitro pharmacokinetic properties. Our efforts led to the successful construction of a chemical library of spiro-fused benzoxaborin derivatives with appropriate physicochemical and in vitro pharmacokinetic properties for oral drugs. These results indicate that the synthesized boron-containing compounds are therefore eligible for classification in a novel chemical library.

Total synthesis of buergerinin F via effective construction of the asymmetric quaternary carbons using an enantioselective aldol reaction.

An efficient method for the synthesis of (+)-buergerinin F is established via the enantioselective aldol reaction of a tetra-substituted ketene silyl acetal with crotonaldehyde, followed by intramolecular Wacker-type ketalization.

Enantioselective synthesis of the optically active alpha-methylene-beta-hydroxy esters, equivalent compounds to Morita-Baylis-Hillman adducts, using successive asymmetric aldol reaction and oxidative deselenization.

[Chemical reaction: See text] The asymmetric aldol reaction of a tetra-substituted ketene silyl acetal including an alkylseleno group with aldehydes has been developed by the promotion of Sn(OTf)2 coordinated with a chiral diamine to afford the corresponding aldols having chiral quaternary centers at the alpha-positions. The facile oxidative deselenization of these aldol compounds produces optically active alpha-methylene-beta-hydroxy esters which correspond to adducts prepared by the asymmetric Morita-Baylis-Hillman reaction.

Enantioselective total synthesis of octalactin a using asymmetric aldol reactions and a rapid lactonization to form a medium-sized ring.

Octalactin A, an antitumor agent containing an eight-membered lactone moiety, has been stereoselectively prepared by means of enantioselective aldol reactions of selected silyl enolates with achiral aldehydes, promoted by a chiral Sn(II) complex. The medium-sized lactone part was effectively constructed by way of a new and rapid mixed-anhydride lactonization using 2-methyl-6-nitrobenzoic anhydride (MNBA) with a catalytic amount of 4-(dimethylamino)pyridine (DMAP) or 4-(dimethylamino)pyridine 1-oxide (DMAPO). The use of only 5 mol % of DMAP or 2 mol % of DMAPO rapidly promoted formation of the medium-sized ring of the octalactin, demonstrating the remarkable efficiency of the new lactonization protocol.