Antibiotics streptozotocin

Treatment with sodium hydroxide caused evolution of diazomethane from the antibiotic streptozotocin (98) and formation of the 3a,5,6,6a-tetrahydro-6-hydroxy-5-[(2i )-l,2-dihydroxy-ethyl]-cw-furo[2,3-d]oxazol-2-one 136 (79JOC9) (Scheme 41). 

In a saline solution at pH 4.6, the antibiotic streptozotocin 98 decomposed to a mixture of several products. Acetylation of this mixture and separation of the products gave the acetylated 5,10-di-(D-eryf/iTO-trititol-l-yl)-bisoxazolo[3,4-a 3, 4 -J]pyrazine-3,8-dione 710 (79JOC9) (Scheme 182)... 

Whish WJD, Davies MI, Shall S (1975) Stimulation of poly(ADP-ribose) polymerase activity by the antitumour antibiotic, streptozotocin. Biochem Biophys Res Commun 65 722-730... 

Another line of evidences comes from studies on experimental diabetes. Liver mitochondria from rats made diabetic with the cytotoxic antibiotic streptozotocin show after four weeks (when the blood glucose is over 300 mg/100 ml) only a small fraction (20-30%) of the HBD activity, the magnitude of this decrease seems to be related with the severity of the diabetic condition (Boveris et al., 1969 Roldan et al., 1971). This decrease in activity is not modified by addition of insulin to mitochondria but can be prevented or reversed by insulin administration to diabetic animals. 

Some antibiotics are alkylating agents. A prominent example is streptozotocin, an antibiotic produced by the soil bacterium Streptomyces achromogenes. This compound is a 2-deoxy-D-glucose derivative of the potent alkylating agent methylnitrosourea (MNU). 

Streptozotocin is unique both in origin and pharmacology. It is an antibiotic obtained from Streptomyces achromogenes and contains a glucosamine component in its structure, which may contribute to its tendency to be taken up into the P-cells of the islets of Langerhans of the pancreas. Where it was initially used to induce diabetes in experimental animals, it is now used to treat pancreatic islet cell carcinoma, resulting in about a 50% response rate, but few survivors past 1 year. 

The nitrosoureas, which include compounds such as 1,3-fcii-(2-chloroethyl)-/-nitrosourea (carmustine BCNU), l-(2-chloroelhyl)-3-cyclohexyl-l-nitrosourea (lomustine CCNU), and its methyl derivative (semustine methyl-CCNU), as well as the antibiotic streptozocin (streptozotocin), exert their cytotoxicity through the spontaneous breakdown to an alkylating intermediate, the 2-chloroethyl diazonium ion. 

Some nitrosoamines have other biological effects than carcinogenic action. A/-(2-Chloroethyl)-A -cyclohexyl-A/-nitrosourea (4.15) has a cytostatic effect (Ferguson, 1975) and another A/-nitrosourea derivative, streptozotocin (4.16), is an antibiotic (Herr et al., 1967). 

Methods for synthesizing anisomycin and pentenomycin, ° and the chemistry and biological transformations of bleomycin and phleomycin have been reviewed.D-Ribo-furanosyl and -pyranosyl derivatives of iV-methyl-iV-nitroso-urea have been prepared as analogues of streptozotocin [2-deoxy-2-(JV-methyl-A -nitrosoureido)-D-glucose] they were reported to be more active against LI 210 leukaemia in mice and less toxic than the parent antibiotic. Likewise N- 2-chloroethyl)-iV-nitrosoureido derivatives of cyclopentane tetrols (35) and cyclohexane tetrols (36) have been synthesized for comparison with streptozotocin. ... 

Streptozotocin, a broad spectrum antibiotic with anitumour activity produced by Streptomyces achromogenes [163], has been shown to be the A -methyl-A -nitrosourea derivative of glucosamine (XLa) by chemical degradation and spectroscopic studies [164], Two syntheses have confirmed the structure, one of which is suitable for the commercial preparation of the drug [165]. Treatment of glucosamine with 7V-methylisocyanate has afforded the A -methylurea derivative (XLb), which gave streptozotocin on treatment with nitrogen trioxide. 

A few antitumor antibiotics whose use is strictly limited to a single indication deserve a brief mention. Streptozotocin, produced by Streptomyces achromogenes, is selectively active against P-cells of pancreatic islets. It was approved by FDA in 1982. Pentostatin (deoxycoformycin), a product of Streptomyces antibioticus, although rather toxic, is used to treat some forms of leukemia. The FDA granted approval for pentostatin in 1993. 

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