DC 107, a novel antitumor antibiotic produced by a Streptomyces sp.

The Journal of Antibiotics
1989.0

Abstract

We have screened microorganisms isolated from soil and plants for their ability to produce antitumor antibiotics, and now have isolated a novel antitumor antibiotic DC107 which has the molecular formula C22H26N2O6S3 from a culture broth of a streptomycete. We report the production, isolation and characterization of DC107. The producing organism was isolated from a soil collected in Natori-shi, Miyagi, Japan and was taxonomically classified as Streptomyces sp. Seed medium (glucose, soluble starch, Bacto-tryptone, yeast extract, beef extract, CaCO3, pH 7.2) was incubated for 48 hours at 28°C; vegetative seed culture (0.9 liter) inoculated into 30-liter jar fermentor with medium (soluble starch, soybean meal, CaCO3, KH2PO4, MgSO4·7H2O, antiform agents, pH 7.0), stirred at 300rpm, aeration 18 liters/minute at 28°C. Antibacterial activity (paper-disc method, Bacillus subtilis) reached maximum after 2 days. Isolation: culture liquor filtered, filtrate (pH 4.0 with AcOH) applied to Diaion HP-20 column (washed with deionized water-MeOH-AcOH 5:5:0.02, eluted with MeOH-AcOH 10:0.02); active fractions diluted with deionized water, applied to Diaion HP20ss column (washed with same, eluted with deionized water-MeOH-AcOH 2:8:0.02); active eluate concentrated, extracted with EtOAc (pH 4.0), concentrated to dryness. Purification via two silica gel chromatographies (hexane-EtOAc-AcOH 5:5:0.1, CHCl3-MeOH 50:1) to get crude precipitate, recrystallized from CHCl3 to yield 50 mg white-needled crystals of DC107. DC107's physico-chemical properties: MP 155°C (dec); soluble in MeOH, EtOAc, CHCl3, DMSO, insoluble in H2O and n-hexane; UV λMeOH nm (ε) 211 (14,000), 322 (12,000); [α]D5 -140° (c 0.1, MeOH); elemental analysis (calcd for C22H26N2O6S3·EtOAc: C 52.06, H 5.59, N 4.86, S 16.68; found: C 51.93, H 5.39, N 4.75, S 16.96); HRFAB-MS m/z 511.1004 (M++l, calcd for C22H27N2O6S3: 511.1031). It is novel compared with known sulfur-containing antitumor antibiotics (esperamicins, calichemicins) due to differences in UV, optical rotation, IR and NMR spectra; structure determination by X-ray analysis is in progress. DC107 showed broad antimicrobial activity against Gram-positive and Gram-negative bacteria but not against fungi (MIC data provided). It was effective against murine leukemia P388 (ip), with significant increase in life span (ILS 57%) at a dose of 0.38 mg/kg (ip), and also showed antitumor activity against mouse sarcoma 18.0 (sc).

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