Among amino acids, leucine is a potential signaling molecule to regulate cell growth and metabolism by activating mechanistic target of rapamycin complex 1 (mTORC1). To reveal the critical structures of leucine molecule to activate mTORC1, we examined the structure-activity relationships of leucine derivatives in HeLa S3 cells for cellular uptake and for the induction of phosphorylation of p70 ribosomal S6 kinase 1 (p70S6K), a downstream effector of mTORC1. The activation of mTORC1 by leucine and its derivatives was the consequence of two successive events: the cellular uptake by L-type amino acid transporter 1 (LAT1) responsible for leucine uptake in HeLa S3 cells and the activation of mTORC1 following the transport. The structural requirement for the recognition by LAT1 was to have carbonyl oxygen, alkoxy oxygen of carboxyl group, amino group and hydrophobic side chain. In contrast, the requirement for mTORC1 activation was more rigorous. It additionally required fixed distance between carbonyl oxygen and alkoxy oxygen of carboxyl group, and amino group positioned at α-carbon. L-Configuration in chirality and appropriate length of side chain with a terminal isopropyl group were also important. This confirmed that LAT1 itself is not a leucine sensor. Some specialized leucine sensing mechanism with rigorous requirement for agonistic structures should exist inside the cells because leucine derivatives not transported by LAT1 did not activate mTORC1. Because LAT1-mTOR axis is involved in the regulation of cell growth and cancer progression, the results from this study may provide a new insight into therapeutics targeting both LAT1 and leucine sensor.

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The enantioselective total synthesis of (+)-hexachlorosulfolipid, a cytotoxin found in the Adriatic mussel Mytilus galloprovincialis, is described. The unique chlorinated hydrocarbon motif of the lipid is successfully furnished by a series of dichlorination reactions of chiral epoxides with chlorophosphonium reagent generated in situ from Ph(3)P/NCS. The present total synthesis has allowed the confirmation of the absolute configuration of the natural cytotoxic (+)-hexachlorosulfolipid originally proposed by Fattorusso, Ciminiello, and co-workers.

Most Annonaceous acetogenins are characterized by between one and three THF ring(s) with one or two flanking hydroxyl group(s) in the center of a C32/34 fatty acid, and the terminal carboxylic acid is combined with a 2-propanol unit to form an α,β-unsaturated γ-lactone. While many studies have addressed the properties and synthesis of natural acetogenins due to their attractive biological activities and unique structural features, a number of analogues have also been described. This review covers the design, synthesis, and biological evaluation of acetogenin analogues.

A new heterocyclic compound, C(2)-symmetric bis-sulfoxide 1, has been found to be an efficient chiral auxiliary for asymmetric desymmetrization of cyclic meso-1,2-diols via diastereoselective acetal fission. Both (R,R)- and (S,S)-1 are readily synthesized with high optical purity via asymmetric oxidation of 1, 5-benzodithiepan-3-one (2). After acetalization of meso-1,2-diols 6a-e and a mono-TMS ether 6f with this chiral auxiliary 1, the resulting acetals 7a-f were subjected to base-promoted acetal fission upon treatment with potassium hexamethyldisilazide (KHMDS) followed by acetylation or benzylation to give the desymmetrized diol derivatives 8a-f with high diastereoselectivity. The chiral auxiliary 1 is readily removed by acid-promoted hydrolysis and can be recovered without a loss in enantiomeric excess.