Hitoshi Hotoda

Synthesis and antimycobacterial activity of capuramycin analogues. Part 1: substitution of the azepan-2-one moiety of capuramycin

Capuramycin analogues with a variety of substituents in place of the azepan-2-one moiety were synthesized from A-500359E and were tested for their translocase I inhibitory activity and in vitro antimycobacterial activity. Phenyl-type moieties were found to be effective substituents for capuramycin analogues.

Synthesis and antimycobacterial activity of capuramycin analogues. Part 2: acylated derivatives of capuramycin-related compounds.

Acylated derivatives of capuramycin and A-500359A were synthesized and tested for antimycobacterial activity. Compound 20 having a decanoyl group showed very potent activity.

IP3 receptor-ligand. 1: Synthesis of adenophostin A

Abstract Adenophostin A, a potent IP 3 receptor-agonist, was synthesized. The basic skeleton with 3′-O-(α-D-glucosyl)adenosine was constructed by AgClO 4 -γ-collidine-promoted glycosylation employing 2-O-benzyl-3,4,6-tri-O-acetyl-α-D-glucopyranosyl bromide as a glycosyl donor.

A new class of condensing reagents for rapid internucleotide bond formation in the phosphotriester approach and preparation of n3-benzoylthymidine as a key intermediate in oligodeoxyribonucleotide synthesis

Abstract Rapid internucleotide bond formation in the phosphotriester approach has been achieved in high yield by use of bis(2,4,6-trihalophenyl) phosphorochloridates (TCP and TBP) as new condensing reagents and the benzoyl group as the N 3 -imide protecting group of thymidine.

Biologically Active Oligodeoxyribonucleotides - II1: Structure Activity Relationships of Anti-HIV-1 Pentadecadeoxyribonucleotides Bearing 5′-End-Modifications

Abstract 5′-End-modified pentadecadeoxyribonucleotides (15mers) with a sequence complementary to the tat 2nd splicing acceptor region of human immunodeficiency virus type 1 (HIV-1) were prepared and evaluated for anti-HIV-1 activity. The structures of modified 15mers were confirmed by negative ion LSI mass spectroscopy, and the anti-HIV-1 activities were evaluated in vitro by MTT assay using MT-4 cells. While the unmodified 15mer had no activity in our assay system, the 15mers bearing modifications with trityl-type substituents at the 5′-end showed potent anti-HIV-1 activities.

2-cyanoethyl nucleoside 3′-phosphonates as a novel starting materials for oligonucleotide synthesis

Abstract Various disubstituted phosphonates including alkylnucleoside 3′-phosphonates were converted rapidly into the corresponding phosphorochloridites by use of tris(2, 4, 6-tribromophenoxy) dichlorophosphorane (BDCP) as a chlorinating reagent. The reaction was found to be applicable to the rapid and practical synthesis of oligonucleotides.

Tris(2,4,6-tribromophenoxy) dichlorophosphorane: A novel condensing agent for rapid internucleotidic bond formation in the phosphotriester approach

Abstract A new class of condensing agent, tris (2,4,6-tribromophenoxy) - dichlorophosphorane (BDCP), was applied to the oligodeoxyribonucleotide synthesis. This reagent enabled us to perform a rapid internucleotidic bond formation in the phosphotriester approach only in 1 minute via an active phosphorylnitrotriazole intermediate.

Protection of hu-PBL-SCID/beige mice from HIV-1 infection by a 6-mer modified oligonucleotide, R-95288

We analyzed the anti-HIV-1 activity of an oligonucleotide derivative, R-95288, in severe combined immunodeficient (SCID/beige) mice transplanted with normal human peripheral blood leukocytes (PBLs), designated hu-PBL-SCID/beige mice. The human chimeric mice were inoculated with HIV-1(CC1) 3 weeks after the transplantation and sacrificed 2 weeks later. Virus infection was determined by coculture of splenocytes with fresh human PBLs and also by detection of HIV- specific DNA sequences using the polymerase chain reaction. No evidence of infection was observed in mice treated with R-95288 (100 mg/kg/day) using intraperitoneal delivery by osmotic minipumps starting 1 day before virus challenge. In contrast, virus infection was observed in over 80% of the saline-treated control mice. In addition, partial inhibition of HIV-1 infection was obtained in mice treated subcutaneously with R-95288 (100 mg/kg/day). Toxicity towards the engrafted human cells was not observed by flow cytometric analysis. Moreover, R-95288 failed to inhibit lymphocyte proliferation (CC50 > 400 microg/ml), while 90% inhibition of HIV-1 replication was achieved at 3.1 microg/ml in vitro. These results suggest the ability of R-95288 to protect the human chimeric mice against HIV-1 infection.

Biologically Active Oligodeoxyribonucleotides - IV 1 : Anti-HIV-1 Activity of Tgggag Having Hydrophobic Substituent at Its 5′-End via Phosphodiester Linkage §

Abstract Hexadeoxyribonucleotides (6-mers) having a 5′-TGGGAG-3′ sequence bearing hydrophobic substituents at their 5′-ends via phosphodiester linkages were prepared and evaluated for anti-HIV-1 activity in vitro. Some of these modified 6-mers showed weak anti-HIV-1 activities and they were less potent than the 6-mer having a DMTr group directly attached at its 5′-terminus. 1. Part 111: Hotoda, H.; Koizumi, M.; Koga, R.; Momota, K.; Ohmine, T.; Furukawa, H.; Nishigaki, T.; Kinoshita, T.; Kaneko, M.; Kimura, S.; and Shimada, K. (1994) Proceedings of First International Antisense Conjierence of Japan p62 (Pl-24): In print in Antisense Research and Development. §This paper is dedicated to Dr. Yoshihisa Mizuno, Emeritus Professor of Hokkaido University, on the occasion of his 75th birthday.

Self-complementary tetradeoxyribonucleoside triphosphates: convenient chemical preparation and spectroscopic studies in solution

Abstract Eight kinds of self-complementary tetradeoxyribonucleoside triphosphates were prepared by a simplified method which enabled us to omit purification of synthetic intermediates and provided the tetramers very rapidly and conveniently. The tetramers were characterized by enzyme assay and their conformations were studied by the use of UV and CD spectroscopic methods under various conditions. The detailed analysis of the CD spectra suggested that conformation of the tetramer duplexes was dependent on the sequence.