Glycopeptide antibiotics Bu-2231 A and B and process for producing same
AssigneeBristol-Myers Company
InventorsHiroshi Kawaguchi, Koji Tomita, Hiroshi Tsukiura, Masataka Konishi
Life of this patent
Estimating the term…
Abstract
A novel water-soluble basic glycopeptide antibiotic complex designated herein as Bu-2231 is produced by fermentation of a Bu-2231-producing strain of Streptoalloteichus hindustanus. Complex Bu-2231 and two of its major components designated herein as Bu-2231 A and B are found to inhibit the growth of various Gram-positive and Gram-negative and acid-fast bacteria as well as certain plant pathogens. The complex and components Bu-2231 A and B are also useful in inhibiting the growth of various tumors in rodents, for example, Walker 256 carcinosarcoma and Lewis Lung carcinoma.
Claims15
The glycopeptide antitiotic Bu-2231 A or a pharmaceutically acceptable acid addition salt thereof;
- which antibiotic substance is a base capable of existing in both a copper complex form and a copper-free form;
- which when subjected to acid hydrolysis gives the amino acids L-threonine, .beta.-amino-.beta.-(4-amino-6-carboxy-5-methylpyrimidine-2-yl)propionic acid, .beta.-hydroxyhistidine, L-.beta.-aminoalanine, 4-amino-3-hyroxy-n-valeric acid, .beta.-lysine and an amino acid exhibiting an ultraviolet absorption maximum at 283 m.mu.(E.sub.1cm.sup.1% 280), the terminal amine spermidine and the carbohydrates mannose and gulose;
- which in the copper complex form (1) is a bluish amorphous solid soluble in water and methanol, slightly soluble in ethanol and practically insoluble in other organic solvents, (2) gives a positive reaction with ninhydrin, (3) has the following elemental analysis (percent):
- C, 42.66;
- H, 6.16;
- N, 15.31;
- and S, 3.14, (4) shows ultraviolet absorption .lambda..sub.MAX.sup.H.sbsp.2.sup.0 243 and 291 m.mu. (E.sub.1cm.sup.1% 125 and 98), (5) has a specific rotation of [.alpha]sub.D.sup.23 = +50.degree. (c, 0.5, H.sub.2 O), and (6) exhibits an Rf of 0.22 in thin layer chromatography using silica gel and methanol--10% ammonium acetate (1:1) and an Rf of 0.05 using silica gel and methanol-10% ammonium acetate-10% ammonium hydroxide (10:9:1), which in the copper-free form (1) is a white amorphous solid, (2) has a specific rotation of [.alpha]sub.D.sup.23 =-21.degree. (c, 0.5, H.sub.2 O), (3) has the following elemental analysis (percent):
- C, 45.10;
- H, 6.51;
- N, 16.05;
- and S, 3.55, (4) shows ultraviolet absorption .lambda..sub.MAX.sup.H.sbsp.2.sup.0 235 and 290 m.mu. (E.sub.1cm.sup.1% sh and 67), and (5) exhibits an Rf of 0.16 in thin layer chromatography using silica gel and methanol -- 10% ammonium formate (1:1) and an Rf of 0.04 using silica gel and methanol-- 10% ammonium acetate -- 10% ammonium hydroxide (10:9:1);
- which as the copper-free hydrochloride salt when pelleted in potassium bromide has an infrared spectrum substantially as shown in FIG. 1 and when dissolved in deuterium oxide at a concentration of 10% gives an NMR spectrum substantially as shown in FIG. 2;
- and which in both the copper-free and copper complex forms is effective in inhibiting the growth of bacteria and fungi.
The glycopeptide antibiotic Bu-2231 B or a pharmaceutically acceptable acid addition salt thereof;
- which antibiotic substance is a base capable of existing in both a copper complex form and a copper-free form;
- which when subjected to acid hydrolysis gives the amino acids L-threonine, .beta.-amino-.beta.-(4-amino-6-carboxy-5-methylpyrimidine-2-yl)propionic acid, .beta.-hydroxyhistidine, L-.beta.-aminoalanine, 4-amino-3-hydroxy-n-valeric acid and an amino acid exhibiting an ultraviolet absorption maximum at 283 m.mu. (E.sub.1cm.sup.1% 280), the terminal amine spermidine and the carbohydrates mannose and gulose;
- which in the copper complex form (1) is a bluish amorphous solid soluble in water and methanol, slightly soluble in ethanol and practically insoluble in other organic solvents, (2) gives a positive reaction with ninhydrin, (3) has the following elemental analysis (percent):
- C, 40.96 H, 5.61;
- N, 14.78;
- and S, 3.39, (4) shows ultraviolet absortpion .lambda..sub.Max.sup.H.sbsp.2.sup.0 243 and 291 mu (E.sub.1cm.sup.1% 134 and 109), (5) has a specific rotation of [.alpha]sub.D.sup.23 = +76.degree. (c, 0.5, H.sub.2 O) and (6) exhibits an Rf of 0.41 in thin layer chromatography using silica gel and methanol -- 10% ammonium acetate (1:1) and an Rf of 0.11 using silica gel and methanol -- 10% ammonium acetate -- 10% ammonium hydroxide (10:9:1), which in the copper-free form (1) is a white amorphous solid;
- (2) has a specific rotation of [.alpha]sub.D.sup.23 =-19.degree. (c, 0.5, H.sub.2 O), (3) has the following elemental analysis (percent):
- C, 43.01;
- H, 6.22;
- N, 14.81 and s, 3.61, (4) shows ultraviolet absorption .lambda..sub.MAX.sup.H.sbsp.2.sup.0 235 and 289.5 m.mu. (E.sub.1cm.sup.1% sh and 77) and (5) exhibits an Rf of 0.31 in thin layer chromatography using silica gel and methanol -- 10% ammonium formate (1:1) and an Rf of 0.09 using silica gel and methanol -- 10% ammonium acetate -- 10% ammonium hydroxide (10:9:1);
- which as the copper-free formate salt when pelleted in potassium bromide has an infrared spectrum substantially as shown in FIG. 3 and when dissolved in deuterium oxide at a concentration of 10% gives an NMR spectrum substantially as shown in FIG. 4;
- and which in both the copper-free and copper complex forms is effective in inhibiting the growth of bacteria and fungi.
A process for producing the antibiotic complex Bu-2231 which comprises cultivating Streptoalloteichus hindustanus A.T.C.C. 31158 in an aqueous nutrient medium containing assimilable sources of nitrogen and carbon under submerged aerobic conditions until a substantial amount of Bu-2231 complex is produced by said organism in said culture medium.
Dependencies are inferred from the claim text.