Toshio Otani

Structure and cycloaromatization of a novel enediyne, C-1027 chromophore

Abstract The structure and the cyloaromatization mechanism of a novel enediyne, C-1027 chromophore, were elucidated. The C-1027 chromophore has a 9-membered 1,5-diyn-3-ene core structure in the 16-membered macrocylic ring.

Structure of an aromatization product of C-1027 chromophore

Abstract The structure of an aromatization product of C-1027 chromophore was determined by means of chemical degradation and detailed 2D-NMR studies.

Synthesis and absolute stereochemistry of the aminosugar moiety of antibiotic C-1027 chromophore

Abstract Stereocontrolled synthesis and absolute stereochemistry of the aminosugar moiety of C-1027 chromophore have been disclosed.

ABSOLUTE CONFIGURATION OF C-1027 CHROMOPHORE

Abstract The absolute configuration of C-1027 chromophore was determined as 8 R , 9 R , 13 R , and 18 S using the modified Moshers, two-dimensional NMR, and molecular modeling methods.

Structure of cypemycin, a new peptide antibiotic

Abstract The structure of cypemycin, a new peptide antibiotic, was determined by means of FAB-MS, NMR, and amino acid analysis. The data have revealed cypemycin as being a structurally unique peptide antibiotic that contains a sulfide bridge at its C-terminus as well as four α,β-unsaturated amino acids.

Remarkable kinetic solvent isotope effect on the cycloaromatization of C-1027 chromophore, a 9-membered enediyne, and the thermochemistry

Abstract Remarkable kinetic solvent isotope effect, experimental activation energy (15.1 kcal/mol) as well as MO calculations present a reaction energy diagram for cycloaromatization reaction of C-1027 chromophore, a highly strained 1,5-diyn-3-ene molecule.

Structure-Activity Relationships between Linkage Style at the C-3 Position and Nuclear Analogues of C(7)-Hydroxyminoaminothiazol Cephalosporins against Methicillin-Resistant Staphylococcus aureus

We have previously shown that hydroxy-imino-aminothiazol at the 7-position was important to the antimethicillin-resistantStaphylococcus aureus (MRSA) activity of isocephems. In this study, in order to optimize the linkage style at the C-3 position and cephem backbones, 9 compounds were prepared by combining 3 cephem backbones with 3 different linkage styles at the C-3 position. The compounds had thiopyridinum-N-carbamoylmethyl fixed as the C-3 side chain and hydroxy-imino-aminothiazol at the C-7 position on the cephem backbones. The cephem backbones tested were cephem, isocephem, and 2-oxaisocephem. The linkage styles at the C-3 position were methylene, vinyl, and propylene linkages. Clinically isolated strains of MRSA were used to determine the MICs of the 9 compounds with different combinations of cephem backbones and linkage styles at the C-3 position. The compounds with vinyl linkage styles were more active against MRSA than the compounds with other linkage styles at the C-3 position, and among the cephem backbones with vinyl linkages, the cephem backbone exhibited the strongest anti-MRSA activity. MIC90s for cephem (1-S-V), isocephem (2-S-V), and 2-oxaisocephem (2-O-V) compounds were 1.56, 6.25, and 12.5 μg/mL, respectively, and the 1-S-V compound had the highest affinity to penicillin-binding protein 2′ among the 3 compounds with the vinyl-style linkage. Thus, the combination of cephem and a vinyl linkage at the C-3 position was shown to be optimal for anti-MRSA activity.

4-oxa-1-azabicyclo [3,2,0] heptan-7-one derivatives as antitumor agents

A series of naturally occurring and synthetic novel oxapenam (4-oxa-1-azabicyclo[3.2.0] heptan-7-one) derivatives with their antitumor activity and the structure-activity relationship among this class of compounds is reported. Among the synthetic 4-oxa-1-azabicyclo[3.2.0]heptan-7-one having an ester, amide, ether derivatives of hydroxy group at C-3 position exhibited either no activity or reduced the antitumor activity in vitro. The 3-amino acid 4-oxa-1-azabicyclo[3.2.0]heptan-7-one derivatives showed better antitumor activity than naturally occurring 4-oxa-1-azabicyclo[3.2.0]heptan-7-one derivative G0069A. The trans isomers exhibited superior stability and activity over the cis isomers at the 3- and 5-position. Some of these compounds showed strong cytotoxicity against P388 and KB cells with IC(50) value ranging from 0.004 to 0.6 micro g/ml and they did not show any cross resistance against ADR, 5-FU and VCR resistant cell lines in vitro. Of these, 3-hydroxy methyl, 3-(2-amino-2-carboxy-1-benzyloxy ethyl) and 3-(2-amino-2-carboxy ethyl) 4-oxa-1-azabicyclo[3.2.0] heptan-7-one inhibited 71-84% in vivo tumor growth of colon 26 and S-180 cells subcutaneously implanted into mice at a varying dose between 0.625-15 mg/kg/day depending upon the compounds and the tumor cell lines.

Preliminary X-ray diffraction study of a new crystal form of C-1027-AG, the apoprotein of the macromolecular antitumor antibiotic C-1027 from Streptomyces globisporus

A new crystal form of C-1027-AG, the apoprotein of the macromolecular antitumor antibiotic C-1027 isolated from Streptomyces globisporus was obtained by the vapor-diffusion procedure using lithium sulfate as a precipitant. In the present crystallization, it is noteworthy that large-sized single crystals successfully grew from very small droplets (less than 1.01 micro l). The present crystals belong to the trigonal system, space group P3(1)21 or P3(2)21 with cell dimensions of a = b = 62.6 and c = 54.2 A. Assuming that the asymmetric unit contains one molecule, the V(m) value is calculated as 2.9 A(3) Da(-1). A total of 3654 independent reflections from two native crystals was obtained up to 2.5 A resolution with synchrotron radiation, the merging R factor being 0.097.

Crystallization and Preliminary X-ray Diffraction Studies of C-1027-AG, the Apoprotein of the Macromolecular Antitumor Antibiotic C-1027 from Streptomyces globisporus

C-1027-AG, the apoprotein of the macromolecular antitumor antibiotic C- 1027, isolated from Streptomyces globisporus, was crystallized by the vapor-diffusion procedure using 2-methyl-2,4-pentanediol as a precipitant. The crystals belong to the orthorhombic system, space group P2(1)2(1)2(1), with unit-cell dimensions a = 55.1, b = 61.3 and c = 79.1 A. Assuming that the asymmetric unit contains two or three molecules, the V(m) value is calculated as 3.2 or 2.1 A(3) Da(-1), respectively. A total of 7630 independent reflections was obtained up to 2.5 A resolution with synchrotron radiation, the merging R factor being 0.077 for 24 713 measurements.