Gentamicin,1 a New Antibiotic Complex from Micromonospora

Journal of Medicinal Chemistry
1963.0

Abstract

Compounds I (ClPy@), I1 (ClPyH), IV (HOPy@), and V (HOPyH) were assayed for alkylating activity with y(4 nitrobenzyl)-pyridine (SBP). Only the reduced chloropyridine I1 showed alkylating activity directly related to concentration; the other three compounds had insignificant activity. Cytotoxicity against the KB cell line: oxidized compounds I and IV had no cytotoxicity (ED50 > 100 μg/ml); reduced dihydropyridine V had borderline activity (ED50 120 μg/ml); reduced chloride I1 had significant cytotoxicity (ED50 26 μg/ml). I1 was 4-5 times more cytotoxic than V, probably due to its alkylating capacity. Pyridinium compound I was inactive as an alkylating agent and biologically inert, while the corresponding dihydro compound I1 was both chemically reactive and significantly cytotoxic. Such compounds may be selectively active via reductive activation or oxidative detoxification in vivo and represent a new class of agents with potential for cancer chemotherapy. A new wide-spectrum, basic, water-soluble antibiotic complex Gentamicin was isolated from two new species of Micromonospora. It consists of two closely related isomeric pseudo-oligosaccharides C1 and C2. Isolation involved cation-exchange resin from fermentation broth, selective precipitation of dodecylbenzenesulfonate salts, and recovery with a strong basic anion-exchange resin. Structure analysis: acetylation gave triacetyl C1 and C2; hydrolysis yielded 2-deoxystreptamine. Both C1 and C2 have three primary amino groups, one N-methyl, one C-methyl, positive Elson-Morgan and ninhydrin tests, and negative maltol, furfural, and Sakaguchi reactions. In vitro, Gentamicin was highly active against Gram-positive and Gram-negative bacteria. Acute toxicity in mice: LD50 72 mg/kg intravenously, 484 mg/kg subcutaneously, 433 mg/kg intraperitoneally, and >9050 mg/kg orally. Pharmacological studies showed excretion via glomerular filtration (some biliary excretion); intramuscular administration in dogs and humans had predictable blood levels and excretion patterns. Therapeutic activity was demonstrated in mice infected with Salmonella schottmuelleri, Klebsiella pneumoniae, etc. Clinical studies for Gram-negative infections are ongoing. Thalidomide-induced malformations have been reported in mice, rats, and rabbits; effects of d,l-3-Phthalimidoglutarimide and N-Phthalyl-d,l-aspartimide on rat pregnancy were being studied.

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