Hiromitsu Saito

Covalent alkylation of DNA with duocarmycin A. Identification of abasic site structure

Alkylation of d(CGTATACG) by antitumor antibiotic duocarmycin A was investigated. It was found that N3 of adenine6 (A6) attacks the cyclopropane subunit of duocarmycin A to produce covalently alkylated adduct 5. Upon heating (90 degrees C, 5 min) the adduct 5 decomposed to modified oligomer 1 with concomitant release of adenine adduct 2.

A novel guanine N3 alkylation by antitumor antibiotic duocarmycin A

Antitumor antibiotic duocarmycin A was found to undergo a novel N3 alkylation of the guanine residue (G7) of d(GCAATTGC)2. Guanine base was shown to be a second major target of duocarmycin A in DNA.

Synthetic approach to quinocarcin

Abstract A basic synthetic route to quinocarcin is elaborated. The optically active basic skeleton of quinocarcin, iminoazepinoisoquinoline 1 was efficiently synthesized starting from phenylalanine and glutamic acid derivative.

Thiol-independent DNA cleavage by a leinamycin degradation product.

To understand the mechanism of action of a novel antitumor antibiotic leinamycin (1) which induces single-strand scission of DNA in the presence of thiol, the reaction of 1 with thiol in aqueous conditions was investigated. Two major degradation products were obtained from 1 in the presence of thiol. 2 was an inactive product, while 3 caused DNA cleavage in the absence of thiol. The DNA-cleaving activity of their synthetic derivatives indicates that the DNA alkylation and subsequent strand scission by leinamycin require the conversion of leinamycin to an electrophilic episulfonium species.

Synthetic studies on leinamycin. A synthesis of the 1-oxo-1,2-dithiolan-3-one moiety

A synthesis of the 1-oxo-1,2-dithiolan-3-one moiety of antitumor antibiotic leinamycin (1) is described. An intramolecular delivery of a sulfur atom (7 to 8) and a facile Beckmann fragmentation (10 to 12) constitute the backbone of our synthesis.

Studies on duocarmycin SA and its derivatives.

New duocarmycin SA derivatives have been synthesized and evaluated for in vitro anticellular activity against HeLa S3 cells, and in vivo antitumor activity against murine sarcoma 180 in mice. The results suggested that the N,N-dialkylcarbamoyl derivatives bearing the p-methoxy cinnamoyl group, which was prepared from duocarmycin SA, showed good in vivo antitumor activities superior to native duocarmycin SA.

The synthesis of [3H]KW‐2189, a novel active antitumor antibiotic

The synthesis of [3H]KW-2189, 2, a novel active antitumor antibiotic, is described. The key intermediate, 6, in the synthesis, was synthesized in four steps from duocarmycin B2 (1). Treatment of 6 with [3H]methyl iodide in the presence of NaHCO3 in MeOH-Me2CO (1:1) afforded the [3H]KW-2189 with highly specific activity of 86.4 Ci/mmol.