Shigetoshi Tsubotani

A new anti-MRSA dipeptide, TAN-1057 A

Abstract The chemical structure of a new dipeptide antibiotic, TAN-1057 A, isolated from the broth filtrate of Flexibacter sp. PK-74 was determined to be (3′S, 5S)-5-[N-methyl-N-(3′-amino-6′-guanidinohexanoyl)amino]5,6-dihydro-2-ureido-4(1H)-pyrimidone. The antibiotic was specifically active against staphylococcus species including methicillin-resistant strains.

Structure of lactivicin, an antibiotic having a new nucleus and similar biological activities to β-lactam antibiotics

Abstract The structure of a new antibiotic, lactivicin, was determined to be [4S]-2-(4-acetylamino-3-oxo-2-isoxazolidinyl)-5-oxo-tetrahydrofuran-2-carboxylic acid.

Discovery of a 3-Pyridylacetic Acid Derivative (TAK-100) as a Potent, Selective and Orally Active Dipeptidyl Peptidase IV (DPP-4) Inhibitor

Inhibition of dipeptidyl peptidase IV (DPP-4) is an exciting new approach for the treatment of diabetes. To date there has been no DPP-4 chemotype possessing a carboxy group that has progressed into clinical trials. Originating from the discovery of the structurally novel quinoline derivative 1, we designed novel pyridine derivatives containing a carboxy group. In our design, the carboxy group interacted with the targeted amino acid residues around the catalytic region and thereby increased the inhibitory activity. After further optimization, we identified a hydrate of [5-(aminomethyl)-6-(2,2-dimethylpropyl)-2-ethyl-4-(4-methylphenyl)pyridin-3-yl]acetic acid (30c) as a potent and selective DPP-4 inhibitor. The desired interactions with the critical active-site residues, such as a salt-bridge interaction with Arg125, were confirmed by X-ray cocrystal structure analysis. In addition, compound 30c showed a desired preclinical safety profile, and it was encoded as TAK-100.

Chemistry of a new antibiotic: lactivicin

Abstract A novel antibiotic, lactivicin (LTV), was isolated from the culture filtrates of two bacterial strains by various types of chromatography. LTV exists in aqueous solution as an equilibrium mixture of two epimers in a ratio of about 1:1. The chemical structure of LTV (C 10 H 12 N 2 O 7 ) was determined to be 2-(4S-acetylamino-3-oxo-2-isoxazolidinyl)-5-oxo-tetrahydrofuran-2-carboxylic acid. The absolute configuration at the C-6 position was elucidated from the CD spectral data and X-ray crystallographic analysis of 4-amino-lactivinic acid obtained by the iminoether method. This compound is useful as a starting material for chemical modification. LTV showed antibacterial activity against Gram-positive and negative bacteria, susceptibility to β-lactamases, and affinity for penicillin-binding proteins. We therefore concluded that LTV is a novel skeleton antibiotic having β-lactam-like activities.

A novel amino acid antibiotic tan-950

Abstract A novel antifungal antibiotic, TAN-950 A, was isolated from the culture filtrate of Streptomyces platensis A-136. Its structure was determined to be (S)-2-amino-3-(isoxazolin-5-on-4-yl)-propanoic acid. Minor components, TAN-950 B, C, D and E, were found to be present in an equilibrium mixture containing TAN-950 A. Their structures were determined from spectral analyses. X-ray crystallographic analysis and synthesis from L-glutamic acid.

Identification of 3-aminomethyl-1,2-dihydro-4-phenyl-1-isoquinolones: a new class of potent, selective, and orally active non-peptide dipeptidyl peptidase IV inhibitors that form a unique interaction with Lys554.

The design, synthesis, and structure-activity relationships of a new class of potent and orally active non-peptide dipeptidyl peptidase IV (DPP-4) inhibitors, 3-aminomethyl-1,2-dihydro-4-phenyl-1-isoquinolones, are described. We hypothesized that the 4-phenyl group of the isoquinolone occupies the S1 pocket of the enzyme, the 3-aminomethyl group forms an electrostatic interaction with the S2 pocket, and the introduction of a hydrogen bond donor onto the 6- or 7-substituent provides interaction with the hydrophilic region of the enzyme. Based on this hypothesis, intensive research focused on developing new non-peptide DPP-4 inhibitors has been carried out. Among the compounds designed in this study, we identified 2-[(3-aminomethyl-2-(2-methylpropyl)-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)oxy]acetamide (35a) as a potent, selective, and orally bioavailable DPP-4 inhibitor, which exhibited in vivo efficacy in diabetic model rats. Finally, X-ray crystallography of 35a in a complex with the enzyme validated our hypothesized binding mode and identified Lys554 as a new target-binding site available for DPP-4 inhibitors.

STRUCTURE DETERMINATION OF INDOLOCARBAZOLE ALKALOIDS BY NMR SPECTROSCOPY

Abstract The structures of two indolocarbazole alkaloids with macrophage-activating properties, TAN-1030 A and TAN-999, were determined based on NMR spectral analysis.

Design and synthesis of 3-pyridylacetamide derivatives as dipeptidyl peptidase IV (DPP-4) inhibitors targeting a bidentate interaction with Arg125

We have previously discovered nicotinic acid derivative 1 as a structurally novel dipeptidyl peptidase IV (DPP-4) inhibitor. In this study, we obtained the X-ray co-crystal structure between nicotinic acid derivative 1 and DPP-4. From these X-ray co-crystallography results, to achieve more potent inhibitory activity, we targeted Arg125 as a potential amino acid residue because it was located near the pyridine core, and some known DPP-4 inhibitors were reported to interact with this residue. We hypothesized that the guanidino group of Arg125 could interact with two hydrogen-bond acceptors in a bidentate manner. Therefore, we designed a series of 3-pyridylacetamide derivatives possessing an additional hydrogen-bond acceptor that could have the desired bidentate interaction with Arg125. We discovered the dihydrochloride of 1-{[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-(2-methylpropyl)pyridin-3-yl]acetyl}-l-prolinamide (13j) to be a potent and selective DPP-4 inhibitor that could interact with the guanidino group of Arg125 in a unique bidentate manner.

Discovery of potent, selective, and orally bioavailable quinoline-based dipeptidyl peptidase IV inhibitors targeting Lys554.

Dipeptidyl peptidase IV (DPP-4) inhibition is a validated therapeutic option for type 2 diabetes, exhibiting multiple antidiabetic effects with little or no risk of hypoglycemia. In our studies involving non-covalent DPP-4 inhibitors, a novel series of quinoline-based inhibitors were designed based on the co-crystal structure of isoquinolone 2 in complex with DPP-4 to target the side chain of Lys554. Synthesis and evaluation of designed compounds revealed 1-[3-(aminomethyl)-4-(4-methylphenyl)-2-(2-methylpropyl)quinolin-6-yl]piperazine-2,5-dione (1) as a potent, selective, and orally active DPP-4 inhibitor (IC₅₀=1.3 nM) with long-lasting ex vivo activity in dogs and excellent antihyperglycemic effects in rats. A docking study of compound 1 revealed a hydrogen-bonding interaction with the side chain of Lys554, suggesting this residue as a potential target site useful for enhancing DPP-4 inhibition.

Stereo-chemical studies on the sulfoxide of 5,6-cis-carbapenem antibiotics, C-19393 components

Abstract The absolute configuration at the sulfoxide of 5,6- cis -carbapenem antibiotics is discussed on the basis of chemical reactions and the CD spectral data. Some stereoisomers at the side chain were synthesized from C-19393 H 2 by the combination of hydrogenation, oxidation and Z,E -isomerization. The CD spectral studies revealed that the Cotton effects of stereoisomers at the sulfoxide indicated clear opposite signs at both 260–275 and 280–300 nm regions. Further CD spectral studies on the derivatives elucidated that these Cotton effects may reflect two chromophores; for the former region and for the latter. In conclusion, these naturally occurring 5,6- cis -carbapenem antibiotics have been shown to possess the R -configuration at the sulfoxide.