Katsuhisa Kojiri

An endothelin receptor (ETA) antagonist isolated from Streptomyces misakiensis.

A competitive endothelin (ET) antagonist, BE-18257B, was isolated from the fermentation products of Streptomyces misakiensis. It is a novel cyclic pentapeptide, cyclo(-D-Glu-L-Ala-allo-D-Ile-L-Leu-D-Trp-), and binds to ETA receptors (ET-1 selective) in cardiovascular tissues, but not to ETB receptors (equally sensitive to isopeptides of ET family) in kidney, adrenal gland and cerebellum tissues. BE-18257B also antagonizes ET-1-induced vasoconstriction in rabbit iliac artery and pressor action in rats. Thus it is a selective ETA antagonist and should provide a valuable tool for elucidation of the pharmacological and pathophysiological roles of ET-1.

BE-31405, a new antifungal antibiotic produced by Penicillium minioluteum. I. Description of producing organism, fermentation, isolation, physico-chemical and biological properties.

A new antifungal antibiotic, BE-31405, was isolated from the culture broth of a fungal strain, Penicillium minioluteum F31405. BE-31405 was isolated by adsorption on high porous polymer resin (Diaion HP-20), followed by solvent extraction, precipitation and crystallization. BE-31405 showed potent growth inhibitory activity against pathogenic fungal strains such as Candida albicans, Candida glabrata and Cryptococcus neoformans, but did not show cytotoxic activity against mammalian cells such as P388 mouse leukemia. The mechanism studies indicated that BE-31405 inhibited the protein synthesis of C. albicans but not of mammalian cells.

Synthesis and biological activities of topoisomerase I inhibitors, 6-N-amino analogues of NB-506

6-N-Amino analogues of NB-506 [6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(beta-D-glucopyranosyl) -5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione] (3b) were synthesized and tested with respect to topoisomerase inhibition, cytotoxicity and anticancer effects. Among them, a 1,3-dihydroxypropane analogue (J-109,404, 5t) showed more than ten times more potent anticancer activity in MKN-45 human stomach cancer cells implanted in mice than NB-506.

ED-110, a Novel Indolocarbazole, Prevents the Growth of Experimental Tumors in Mice

A new indolocarbazole compound, ED‐110, which was obtained by glucosylating a microbial product (BE‐13793C) and is a potent topoisomerase I inhibitor, showed characteristic inhibitory effects on the growth of 12 human tumor cell lines tested. The IC50 values of ED‐110 against 9 of the 12 lines ranged from 11.5 μg/ml to 0.07 μg/ml, while the remaining 3 lines were quite resistant (IC50, >100μg/ml). In in vivo experiments, i.p. treatment with ED‐110 increased the survival period by more than two‐fold in mice implanted i.p. with P388, L1210, L5178Y or EL4 murine leukemic cells. The minimum effective dose increasing the life‐span of mice bearing P388 leukemia by 25% was <2.5 mg/kg/day × 10 and the maximum tolerated dose was > 160 mg/kg/day × 10. ED‐110 was also effective against the spontaneous metastasis of mouse Meth A fibrosarcoma cells and the growth of xenografted MKN‐ 45 human stomach cancer cells as well as s.c. implanted mouse colon 26 and IMC carcinoma cells. These results indicated that ED‐110 may have potential as a new antineoplastic agent with a large chemotherapeutic index and a wide range of effective doses.

New cytotoxic agents, BE-52440A and B, produced by a streptomycete

New cytotoxic substances, designated BE-52440A and B, were isolated from the mycelium of Streptomyces sp. A52440. The active principles were extracted from the mycelium by methanol and purified by silica gel column chromatography. BE-52440A and B exhibited cytotoxic activity against murine and human tumor cell lines.