Antitumor antibacterial agents
AssigneeBristol-Myers Company
InventorsHideo Koshiyama, Fumihide Sakai, Hiroaki Ohkuma
Life of this patent
Estimating the term…
Abstract
An antitumor antibacterial complex referred to as BBM-928 is described which is produced by microbiological fermentation under controlled conditions using a species of actinomycetes. The bioactive components of the complex have pronounced antitumor activity and are moderately to weakly active against gram-positive and acid fast bacteria but practically inactive against gram-negative bacteria and fungi. Based on median survival time, the component designated BBM-928A is substantially more active than mitomycin C by a factor of 10 to 300 fold against intraperitoneally implanted mouse tumors.
Claims6
The antitumor antibiotic compound BBM-928A which in its substantially pure form has these characteristics:
- (a) soluble in chloroform and methylene chloride, slightly soluble in benzene, ethanol, methanol and n-butanol, and substantially insoluble in water and n-hexane;
- (b) gives a positive reaction with ferric chloride and Ehrlich reagents and a negative reaction with Tollens, Sakaguchi and ninhydrin reagents;
- (c) is an effective antitumor agent against P388 leukemia, L1210 leukemia, B16 melanoma, Lewis Lung carcinoma, and sarcoma 180 ascites tumors intraperitoneally implanted in the mouse;
- (d) has a melting point of 246.degree.-248.degree. C.;
- (e) has a specific rotation of [.alpha]sub.D.sup.25 =-27.degree. (c 1, CHCl.sub.3);
- (f) has a molecular weight of 1427;
- (g) has an approximate elemental composition of 52.47% carbon, 5.48% hydrogen, 13.81% nitrogen, and 28.24% oxygen;
- (h) exhibits in silica gel thin layer chromatography a R.sub.f value of 0.71 with the solvent system n-butanol-methanol-water (63:27:10), and a R.sub.f value of 0.48 with the solvent system xylene-methylethylketone-methanol (5:5:1);
- (i) affords on acid hydrolysis water-soluble ninhydrin positive substances including beta-hydroxy-N-methylvaline, glycine, serine, and sarcosine;
- (j) affords on base hydrolysis Fragment VI ##STR8## wherein Ser is serine, Gly is glycine, Sar is sarcosine, HM-Val is beta-hydroxy-N-methulvaline and the symbol X represents an amino acid moiety;
- (k) has an infrared absorption spectrum in potassium bromide substantially as shown in FIG. 1;
- and
- (l) when dissolved in deuterated chloroform gives a proton NMR spectrum substantially as shown in FIG. 5.
The antitumor antibiotic compound BBM-928A having a quinoline chromophore and affording, on acid hydrolysis, water soluble components including serine, glycine, sarcosine, and beta-hydroxy-N-methyl-valine which in its substantially pure form has these characteristics:
- (a) soluble in chloroform and methylene chloride, slightly soluble in benzene, ethanol, methanol, and n-butanol, and substantially insoluble in water and n-hexane;
- (b) gives a positive reaction with ferric chloride and Ehrlich reagents and a negative reaction with Tollens, Sakaguchi, and ninhydrin reagents;
- (c) is an effective antitumor agent against P388 leukemia intraperitoneally implanted in the mouse;
- (d) has a melting point of 214.degree.-217.degree. C.;
- (e) has a specific rotation of [.alpha]sub.D.sup.25 =-74.degree. (c 1, CHCl.sub.3);
- (f) has an approximate elemental composition of 50.14% carbon, 5.29% hydrogen, 12.34% nitrogen, and 32.23% oxygen;
- (g) exhibits in silica gel thin layer chromatography a R.sub.f value of 0.53 with the solvent system n-butanol-methanol-water (63:27:10), and a R.sub.f value of 0.26 with the solvent system xylene-methylethylketonemethanol (5:5:1);
- (h) has an infrared absorption spectrum in potassium bromide substantially as shown in FIG. 2;
- (i) when dissolved in dueterated chloroform gives a proton NMR spectrum substantially as shown in FIG. 6;
- and
- (j) a molecular weight of 1385.
The antitumor antibiotic compound BBM-928C having a quinoline chromophore and affording, on acid hydrolysis, water soluble components including serine glycine, sarcosine, and beta-hydroxy-N-methylvaline, which in its substantially pure form has these characteristics:
- (a) soluble in chloroform and methylene chloride, slightly soluble in benzene, ethanol, methanol and n-butanol, and substantially insoluble in water and n-hexane;
- (b) gives a positive reaction with ferric chloride and Ehrlich reagents and a negative reaction with Tollens, Sakaguchi and ninhydrin reagents;
- (c) is an effective antitumor agent against P388 leukemia, L1210 leukemia, B16 melanoma, Lewis Lung carcinoma, and sarcoma 180 ascites tumors intraperitoneally implanted in the mouse;
- (d) has a melting point of 244.degree.-248.degree. C.;
- (e) has a specific rotation of [.alpha]sub.D.sup.25 =-91.degree. (c 1, CHCl.sub.3);
- (f) has a molecular weight of 1343;
- (g) has an approximate elemental composition of 51.77% carbon, 5.29% hydrogen, 13.55% nitrogen, and 29.39% oxygen;
- (h) exhibits in silica gel thin layer chromatography a R.sub.f value of 0.27 with a solvent system n-butanol-methanol-water (63:27:10), and a R.sub.f value of 0.07 with the solvent system xylene-methylethylketone-methanol (5:5:1);
- (i) has an infrared absorption spectrum in potassium bromide substantially as shown in FIG. 3;
- and
- (j) when dissolved in deuterated chloroform gives a proton NMR spectrum substantially as shown in FIG. 7.
The antitumor antibiotic BBM-928D having these characteristics:
- (a) soluble in chloroform and methylene chloride, slightly soluble in benzene, ethanol, methanol and n-butanol, and substantially insoluble in water and n-hexane;
- (b) gives a positive reaction with ferric chloride and Ehrlich reagents and a negative reaction with Tollens, Sakaguchi and ninhydrin reagents;
- (c) is an effective antitumor agent against intraperitoneally implanted P388 leukemia in the mouse;
- (d) has a melting point of 224.degree.-227.degree. C.;
- (e) has a specific rotation of [.alpha]sub.D.sup.25 =-13.degree. (c 1, CHCl.sub.3);
- (f) has an approximate elemental composition of 50.75% carbon, 5.25% hydrogen, 12.58% nitrogen, and 31.42% oxygen;
- (g) exhibits in silica gel thin layer chromatography a R.sub.f value of 0.73 with the solvent system n-butanol-methanol-water (63:27:10), and a R.sub.f value of 0.53 with the solvent system xylene-methylethylketone-methanol (5:5:1);
- (h) has an infrared spectrum in potassium bromide substantially as shown in FIG. 4;
- and
- (i) when dissolved in dueterated chloroform gives a proton NMR spectrum substantially as sown in FIG. 8.
Dependencies are inferred from the claim text.