Toshiaki Miyake

Caprazamycins, Novel Lipo-nucleoside Antibiotics, from Streptomyces sp : II. Structure Elucidation of Caprazamycins

Novel antibiotics, active against acid-fast bacteria, caprazamycins, were isolated from the culture broth of Streptomyces sp. MK730-62F2. The planar structures of the compounds were determined by 2D NMR spectroscopic study. Furthermore, the absolute structure of caprazamycin B (2) was established by NMR spectroscopy and X-ray crystallography of its degradation products and by total synthesis of the 5-amino-5-deoxy-D-ribose moiety. In the course of degradation studies of 2 under alkaline and acidic conditions, we obtained the two core components, caprazene (11) and caprazol (14), respectively, in high yield.Structurally, caprazamycins belong to a family of lipo-uridyl antibiotics, which have been discovered as specific inhibitors of a bacterial translocase.

Novel semisynthetic antibiotics from caprazamycins A-G: caprazene derivatives and their antibacterial activity.

Acidic treatment of a mixture of caprazamycins (CPZs) A–G isolated from a screen of novel antimycobacterial agents gave caprazene, a core structure of CPZs, in high yield. Chemical modification of the resulting caprazene was performed to give its various derivatives. The structure–activity relationships of the caprazene derivatives against several mycobacterial species and pathogenic Gram-positive and Gram-negative bacteria were studied. Although caprazene showed no antibacterial activity, the antibacterial activity was restored for its 1′′′-alkylamide, 1′′′-anilide and 1′′′-ester derivatives. Compounds 4b (CPZEN-45), 4d (CPZEN-48), 4f and 4g (CPZEN-51) exhibited more potent activities against Mycobacterium tuberculosis and M. avium complex strains than CPZ-B. These results suggest that caprazene would be a good precursor from which novel semisynthetic antibacterial antibiotics can be designed for the treatment of mycobacterial diseases such as tuberculosis and M. avium complex infection.

Facile and practical synthesis of optically pure 1d-chiro-inositol from myo-inositol

Abstract Optically pure 1 d - chiro -inositol (DCI) has been synthesized from optically inactive myo -inositol practically in four steps. The crystalline nature of most intermediates and the utilization of inexpensive reagents facilitate the economical mass production of DCI, which is expected to be used in the future for treatment of Type 2 diabetes and polycystic ovary syndrome (PCOS).

Total synthesis of the disaccharide of bleomycin, 2-0-(α-D-mannopyranosyl)-L-gulopyranose

Abstract 2-0-(α- D -Mannopyranosyl)- L -gulopyranose, the sugar portion of bleomycin has been synthesized.

Reaction of methyl 2-deoxy-3-o-sulfonyl-2-p-toluenesulfonamido-α- and β-d-glucopyranoside derivatives with halide ions

Abstract Methyl 2-deoxy-3- O -sulfonyl-2- p -toluenesulfonamido-α- d -glucopyranoside derivatives were treated with halides in N , N -dimethylformamide. The corresponding 3-halo-α- d -glucopyranosides were formed by a double S N 2 process in high yields via the 3-halo-α- d -allopyranosides, despite the presence of an axial methoxyl group at C-1. The reactions proceeded more readily than the reaction for methyl 4,6- O -cyclohexylidene-2-deoxy-3- O - p -tolylsulfonyl-2- p -toluenesulfonamido-β- d -glucopyranoside. The mechanism for the ready displacement at C-3 in the α- d anomers is discussed. Deoxy compounds were prepared from the corresponding 3-halides by action of tributylstannane, or of sodium in liquid ammonia. Treatment of methyl 4,6- O -cyclohexylidene-2-deoxy-3- O - p -tolylsulfonyl-2- p -toluenesulfonamido-α- d -glucopyranoside with nucleophiles other than halide ions gave the corresponding 2.3-epimino derivative.

A novel cyclic lipoundecapeptide, pholipeptin, isolated from Pseudomonas sp.

An inhibitor of phosphatidylinositol-specific phospholipase C, pholipeptin, was purified from the culture broth of Pseudomonas sp. Structural determination by 2D NMR spectroscopy with addition of a small amount of trifluoroacetic acid revealed that it was a novel cyclic lipodepsipeptide (1) consisting of 11 amino acids and a 3-hydroxydecanoic acid moiety.

Synthesis and antibacterial activity of tripropeptin C derivatives modified at the carboxyl groups

Synthesis and antibacterial activity of tripropeptin C derivatives modified at the carboxyl groups

Synthesis and antibacterial activity of 4″ or 6″-alkanoylamino derivatives of arbekacin.

Arbekacin, an aminoglycoside antibiotic, is an important drug because it shows a potent efficacy against methicillin-resistant Staphylococcus aureus. However, resistance to arbekacin, which is caused mainly by the bifunctional aminoglycoside-modifying enzyme, has been observed, becoming a serious problem in medical practice. To create new arbekacin derivatives active against resistant bacteria, we modified the C-4″ and 6″ positions of its 3-aminosugar portion. Regioselective amination of the 6″-position gave 6″-amino-6″-deoxyarbekacin (1), and it was converted to a variety of 6″-N-alkanoyl derivatives (6a−z). Furthermore, regioselective modifications of the 4″-hydroxyl group were performed to give 4″-deoxy-4″-epiaminoarbekacin (2) and its 4″-N-alkanoyl derivatives (12 and 13). Their antibacterial activity against S. aureus, including arbekacin-resistant bacteria, was evaluated. It was observed that 6″-amino-6″-N-[(S)-4-amino-2-hydroxybutyryl]-6″-deoxyarbekacin (6o) showed excellent antibacterial activity, even better than arbekacin.

Synthesis of 17-membered azalides from a 16-membered macrolide utilizing amide-selective silane reduction

The synthesis of 17-membered azalides was achieved using the following key steps: (i) Beckmann rearrangement of 16-membered oxime derivatives obtained from 3,4′-dideoxymycaminosyltylonolide (DDMT), (ii) amide-selective silane reduction of the corresponding ring-enlarged lactams catalyzed by RhCl3 in the presence of Et3N, and (iii) N-methylation of the resulting secondary amines.

Discovery of 2-hydroxyarbekacin, a new aminoglycoside antibiotic with reduced nephrotoxicity

The emergence and spread of bacteria with resistance to antibacterial drugs in recent years is now considered a significant threat to global public health and the world economy.1, 2 In particular, the severe bacterial infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa have become serious clinical problems because of increased antimicrobial resistance, as observed for vancomycin-resistant S. aureus and multi-drug resistant P. aeruginosa.3 Arbekacin4 (ABK), an aminoglycoside antibiotic, is efficacious against MRSA, and is commonly used to treat infected patients in the clinical setting. This semi-synthetic antibiotic is stable toward AAC(6′)-APH(2″), a bifunctional enzyme present in MRSA, and is also effective against almost all antibiotic-resistant bacteria that produce aminoglycoside-modifying enzymes.5 However, despite its superior antibacterial activity and stability toward aminoglycoside-modifying enzymes, treatment with ABK is limited because of its adverse effect on the kidneys.6, 7 Therefore, we have conducted synthetic studies on a number of ABK derivatives in an effort to decrease the associated toxicity.8, 9