Chymostatin, a chymotrypsin inhibitor, was shown to be a mixture of components A, B and C. The structure of component A as determined to be N-[((S)-1-carboxy-2-phenylethyl)-carbamoyl]-α-[2-iminohexahydro-4(S)-pyrimidyl]-L-glycyl-L-leucyl-phenylalaninal. Components B and C differed only in that the L-leucyl residue was replaced by L-valine and L-isoleucine, respectively.
The lankacidin-group (T-2636) antibiotics, neutral seventeen-membered macrocyclic antibiotics, are mainly active against Gram-positive bacteria. Chemical modifications of certain functions of lankacidin C has provided a group of lankacidin C analogs and derivatives. These new antibiotics were examined for their in vitro antimicrobial activities, their therapeutic effects against experimental infections in mice, and for their acute toxicities in mice and subacute toxicities in rats. Some of the lankacidin C mono-esters were found to be superior in their biological properties to the parent antibiotic.
The metabolic fate of lankacidin C 14-propionate-14C was studied in rats and mice. In these animals, the antibiotic administered orally was absorbed slowly, distributed widely in tissues and metabolized to be excreted mainly in bile. The metabolites in bile were then excreted into feces together with the unabsorbed radioactivity. The elimination of the antibiotic from the body was completed within 72 hours in both species. In rats, 77 and 6.5% of the radioactivity was excreted in feces and urine, respectively. In mice, 88 and 5.5% was eliminated into feces and urine, respectively. No significant amount of radioactivity was excreted in the expiratory air of either animal. After oral administration, the blood level of radioactivity reached a peak after 2 hours in rats and after 15 minutes in mice. Of the tissues tested, relatively higher concentrations were noted in liver, kidney, lung and spleen in rats and mice. At any time after the administration to mice, the levels of antibiotic activity in the infected region of liver, kidney and abdominal ascites were much higher than the blood levels. The antimicrobial activities in these tissues were mainly derived from the metabolites, lankacidin C and lankacidinol. The biliary metabolites identified were lankacidin C, lankacidinol, lankacyclinol, lankacidinol 14-P and T-2636 H in rats, and lankacidin C, lankacidinol and lankacyclinol in mice. The results obtained are discussed in relation to therapeutic activities of these antibiotics.
Acetyl-kidamycin administered intravenously to mice disappears rapidly from blood and is distributed widely in various organs, where much of it is adsorbed and/or inactivated. A large quantity of the antibiotic is found in the intestinal content indicating the possibility of excretion into the bile. Inactivation of acetyl-kidamycin with homogenates of mouse organs such as liver, intestine, kidney, etc. was observed in vitro. Tumor tissue shows low concentrations of acetyl-kidamycin but also low rates of inactivation. The inhibitory effects of acetyl-kidamycin on incorporation of 3H-thymidine were correlated with organ levels of the drug, but in the case of S-180 tumor, a marked inhibitory effect was observed even with a low concentration of the antibiotic.
A new antibiotic with hypolipidemic activity, ascofuranone, C23H29C1O5, and related substance, ascofuranol, C23H31C1O5, were isolated from the filter cake of the fermented broth of Ascochyta viciae LIBERT, an ascochlorin-producing fungus, and their structures were elucidated. They possess 3-substituted-5-chloro-orcylaldehyde moiety with novel sesquiterpenyl side chains.
Ascofuranone significantly reduced serum lipid levels of rats fed with normal diet 6 hours after a single oral administration of 108 mg/kg. When the antibiotic was orally given for consecutive 10 days to normolipidemic rats, the treatment resulted in marked reduction of serum cholesterol, triglycerides, phospholipids and free fatty acids without affecting organ weight gain, serum total protein, albumin/globulin ratio and serum transaminases. Reduction was also noted with cardiac cholesterol content but liver total sterol and fecal sterol excretion were unchanged. Acute toxicity of ascofuranone is weak to mice and rats and the antibiotic did not induce hepatomegaly which is the main side effect of a positive control agent, ethyl-p-chlorophenoxyisobutyrate.
Tritiated antibiotic tylosin was prepared by aqueous exchange, purified, then stabilized under phosphate form. After oral administration to rats, the balance study showed the following distribution: urine 10%, feces 46%. Urinary and fecal metabolites were identified as tylosin and desmycosin; 65% of the urinary radioactivity was tritiated water. The elimination is biphasic. 3H-Tissue accumulation and depletion have been studied; 80-90% of the recovered radioactivity was associated to tritiated water. In six tissues including blood, muscle and liver, tissue residue levels were established within 20 days at 0.1-0.3 ppm; depletion is slow.
A new crystalline antibiotic, dactylarin, C16H16O6, was isolated from the culture broth of the hyphomycete Dactylaria lutea ROUTIEN. Isolation, purification, properties and structure of the new antibiotic are described. Dactylarin exhibits antiprotozoal activity against Leishmania braziliensis and Entamoeba invadens and is slightly active against Gram-positive bacteria.
Benzyl 6α-acetoxypenicillanate was transformed into benzyl 6α-hydroxypenicillanate by enzymatic cleavage of the acetyl group. The preparation of several side chain oxygen analogues of the penicillins is described.