Yoji Umezawa

CH/π hydrogen bonds in organic and organometallic chemistry

This treatise is an update to a preceding highlight (CH/π hydrogen bonds in crystals) published in this journal 5 years ago (M. Nishio, CrystEngComm, 2004, 6, 130–156). After the introductory part (sections 1 and 2), we survey recent results (mostly since 2004) relevant to the CH/π hydrogen bond: crystal conformation, packing and host/guest chemistry (section 3). Section 4 summarizes the results obtained by crystallographic database (CSD and PDB) analyses. In section 5, several topics in related fields (selectivity in organic reactions, surface chemistry, structural biology, drug design and high-level ab initio calculations of protein/substrate complexes and natural organic compounds) are introduced, and in the final part we comment on the prospects of this emerging field of chemistry.

Synthesis of boronic acid derivatives of tyropeptin : Proteasome inhibitors

Boronic acid derivatives of tyropeptin were synthesized with TP-110 as the lead compound. Due to the lability of the aminoboronic acid moiety, careful design of the deprotection and coupling sequence was required. Liquid-liquid partition chromatography was found to be a powerful tool for purification of compounds of this class. The obtained derivatives showed potent inhibitory activities against the human 20S proteasome in vitro.

Total synthesis of deglyco-bleomycin A2

Abstract Deglyco-bleomycin A2, the aglycon of bleomycin A2, has been synthesized for the first time.

Structure-activity relationship and rational design of 3,4-dephostatin derivatives as protein tyrosine phosphatase inhibitors

Several alkyl- and O-methylated-3,4-dephostatin were synthesized and evaluated for their inhibitory activity toward protein tyrosine phosphatase. Alkyl chains with a length up to that of the pentyl group gave tolerable inhibition, whereas methylation of hydroxyl groups resulted in a decrease in the activity. Based on the structure–activity relationship and X-ray crystallographic analysis of C215S PTP1B–phosphotyrosine containing peptide complex, the mode of binding of 3,4-dephostatins to the active site was speculated with the aid of calculation. Several hydrogen bonds and CH/π interactions were suggested to be important for inhibition of PTPase. A novel nitroso-free methoxime compound was designed so that all the attractive interactions were maintained. The methoxime compound was synthesized and shown to inhibit PTP1B.

Stereoselective synthesis of (2s,3s,4r)-4-amino-3-hydroxy-2-methyl-pentanoic acid, an amino acid constituent of bleomycin, by aldold condensation)☆

Abstract (2S,3S,4R)-4-Amino-3-hydroxy-2-methylpentanoic acid, a novel amino acid constituent of bleomycin, has been synthesized stereoselectively through aldol condensation of (R)-2-aminopropionaldehyde derivatives and E-vinyloxyboranes.

CC bond formation from schiff base and vinyloxyborane: Synthesis of β-amino acid derivatives

Abstract An efficient methodology for the preparation of β-amino acid derivatives ( 3 ) by CC bond formation from Schiff bases ( 1 ) and vinyloxyborane ( 2 ) and their utilization in the synthesis of the pyrimidine moiety ( 3f ) of bleomycin are described.

Novel pyrrole- and 1,2,3-triazole-based 2,3-oxidosqualene cyclase inhibitors.

Pyrrole- and 1,2,3-triazole-based 2,3-oxidosqualene cyclase (OSC) inhibitors 3 and 4 were discovered by conducting a virtual screening, a docking study based on the crystallographic structure of OSC, and biological assays. The hit rate of the assays was increased by establishing appropriate substructural filters in the virtual screening stage. Amide derivatives of 8 and 12 preserved the inhibitory activity of parent compound 3, which provided a reasonable starting point for further structure-activity-relationship (SAR) studies on related compounds.

Synthesis and Activity of Tyropeptin A Derivatives as Potent and Selective Inhibitors of Mammalian 20S Proteasome

Tyropeptin A, a potent proteasome inhibitor, was isolated from the culture broth of Kitasatospora sp. MK993-dF2. We synthesized the derivatives of tyropeptin A to enhance its inhibitory potency. Among the synthesized derivatives, the most potent compound, TP-104, exhibited a 20-fold inhibitory potency enhancement for chymotrypsin-like activity of 20S proteasome compared to tyropeptin A. Additionally, TP-110 specifically inhibited the chymotrypsin-like activity, but did not inhibit the post-glutamyl-peptide hydrolyzing (PGPH) and the trypsin-like activities of 20S proteasome. In vitro TP-110 strongly inhibited the growth of various cell lines.

Vanoxonin, a new inhibitor of thymidylate synthetase.

Vanoxonin, a new inhibitor of thymidylate synthetase, was found in cultured broths of the strain MG245-CF2 classified as Saccharopolyspora hirsuta. Vanoxonin, C18H25N3O9, was obtained as colorless powder. Vanoxonin forms a vanadium complex which exhibits a strong inhibition against thymidylate synthetase. The concentration for 50% inhibition of the enzyme (IC50) was 0.7 micrograms/ml.

A new synthesis of deglyco-bleomycin A2 aiming at the total synthesis of bleomycin

Abstract An improved route to synthesize deglyco-bleomycin A2, the aglycon of bleomycin A2, aiming at the total synthesis of bleomycin is described. The new route is characterized by the stepwise elongation of the amino acid constituents and the use of a thiol ester obtained by aldol condensation.