A Covalent Inhibitor for Glutathione S-Transferase Pi (GSTP ) in Human Cells.

Glutathione S-transferase π (GSTP ) is overexpressed in many types of cancer and is involved in drug resistance. Therefore, GSTP is an important target in cancer therapy, and many GST inhibitors have been reported. We had previously developed an irreversible inhibitor, GS-ESF, as an effective GST inhibitor; however, its cellular permeability was too low for it to be used in inhibiting intracellular GST.

A covalent G-site inhibitor for glutathione S-transferase Pi (GSTP).

We herein report the first covalent G-site-binding inhibitor for GST, GS-ESF (1), which irreversibly inhibited the GSTP function. LC-MS/MS and X-ray structure analyses of the covalently linked GST-inhibitor complex suggested that 1 reacted with Tyr108 of GSTP. The mechanism of covalent bond formation was discussed based on MD simulation results.

Biarylmethane and Fused Heterocyclic Arene Synthesis via in Situ Generated o- and/or p-Naphthoquinone Methides.

o- and/or p-naphthoquinone methides (NQMs) can be selectively prepared by the ring opening of 1-(siloxymethyl)-1,4-epoxy-1,4-dihydronaphthalene derivatives based on a substituent effect at the 4 position of the substrates. The 4-alkyl- or silyl-substituted 1-(siloxymethyl)-1,4-epoxy-1,4-dihydronaphthalene was transformed to o-NQM (1-naphthoquinone-2-methide), which underwent Friedel-Crafts 1,4-addition of the α,β-unsaturated carbonyl moiety to provide the 2-benzyl-1-naphthol as the biarylmethane and [4 + 2]-cycloaddition with a dienophile to give the fused heterocyclic arene. Meanwhile, the 4-unsubstituted 1-(siloxymethyl)-1,4-epoxy-1,4-dihydronaphthalene could be converted to the corresponding 4-benzyl-1-naphthol by the Friedel-Crafts 1,6-addition of p-NQM (1-naphthoquinone-4-methide) generated by the site-selective ring opening of the 1,4-epoxy moiety.

Chemoselective and direct functionalization of methyl benzyl ethers and unsymmetrical dibenzyl ethers by using iron trichloride.

Methyl and benzyl ethers are widely utilized as protected alcohols due to their chemical stability, such as the low reactivity of the methoxy and benzyloxy groups as leaving groups under nucleophilic conditions. We have established the direct azidation of chemically stable methyl and benzyl ethers derived from secondary and tertiary benzyl alcohols. The present azidation chemoselectively proceeds at the secondary or tertiary benzylic positions of methyl benzyl ethers or unsymmetrical dibenzyl ethers and is also applicable to direct allylation, alkynylation, and cyanation reactions, as well as the azidation.

Iron-catalyzed Friedel-Crafts benzylation with benzyl TMS ethers at room temperature.

Friedel-Crafts benzylations between unactivated arenes and benzyl alcohol derivatives are clean and straightforward processes to construct biologically useful di- and tri-arylmethanes. We have established an efficient iron-catalyzed Friedel-Crafts benzylation method at room temperature that uses benzyl TMS ethers as substrates, which are poorly reactive under common nucleophilic substitution conditions. The reaction seems to progress through iron-catalyzed self-condensation of the benzyl TMS ether to the corresponding dibenzylic ether.