256 



DESCRIPTIONS OF ANTIBIOTICS 



C, 0.8 to l.U. Infrared absorption .spectra given in 

 reference 1. Elementary analysis: A, C = 44.34%; 

 H = 5.08%; N = 17.22%. B, C = 43.15%; H = 

 5.59%; N = 19.22%. C, C = 46.03%,; H = 5.93%; 

 N = 23.82%. 



Biological activity: Active against certain yeasts 

 and bacteria. B. subtilis used as the assay organ- 

 ism. Diazomycin B is the most active biologically, 

 then A, then C. Active in animals against sarcoma 

 180, adenocarcinoma 755, and to a lesser extent 

 against leukemia 1210. 



Reference: 1. Rao, K. V. et al. Antiljiotics 

 Ann. 943-949, 1959-1960. 



I ) i li > < I ros I re p I c> 111 N f i 1 1 



Produced by: Catalytic hydrogenation of strep- 

 tomycin (1), Streptomijces humidus (23) (organism 

 also produces humidin), and Streptomyces sp. (32). 



Synonym: Antibiotic 23572 (23). 



Method of extraction: I. See references 1, 14, 

 and 23 for chemical details on hydrogenation. II. 

 Extracted from culture-filtrate with n-butanol (or 

 isoamyl alcohol) containing 3 per cent lauric acid, 

 at pH 7.5. Organic layer shaken with acpieous acid 

 at pH 2.0. Aqueous extract shaken with ether 

 (23). III. Crystalline sulfate is precipitated 

 from an acjueous solution (pH 5.5) on addition of 

 glycerol (or formamide). Heating to 50-60°C, addi- 

 tion of methanol to turbidity, temperature nuiin- 

 tained at 60°C, stirring (21). 



Chemical and physical properties: In (Hhydro- 

 streptomycin, the aldehyde of streptomycin is re- 

 duced to the corresponding carbinol (see formula 

 in Chapter 6). Trihydrochloride: White powder or 

 fine needles containing methanol (lost on heating) ; 

 ni.]). 185-190°C (decomposition). Powder soluble 

 in methanol to 1 gm per ml; needles to 45 mg per 

 ml (1, 11). No characteristic absorption in ultra- 

 violet light. Infrared spectrum given in reference 

 23. [a]:? = -89.5° (c = 0.98 per cent in water) (1). 

 Crystallographic data given in references 11 and 

 14. Differs from streptomycin in these reactions: 



(a) not inactivated by hydroxylamine or cysteine; 



(b) not degraded to maltol in alkali; (c) more 

 stable in alkali; and (d) forms many complex 

 mixed acid salts but not the double CaClj salt 

 that streptomycin forms (1-3, 15). Positive Saka- 

 guchi test. Negative Fehling (boiling), phenol- 

 H2SO4 , and silver mirror tests. Slightly positive 

 Tollen test. CoiHjiNtOis^HCI: C = 36.5%; H = 

 0.21%,; N = 3.91%. Equivalent weight, 690. pKa' 

 = 7.7. Yields streptidine and dihydrostreptobiosa- 

 mine on alkaline hydrolysis (1, 3, 23). Sulfate: 

 Trapezoidal plates or small noidiygroscopic plate- 

 lets. Anhydrous salt: m.j). 25()°C or 255-265°C 

 (decomposition). Soluble in water, and moderately 



soluble in aqueous nietlianol. [aYu = —88° (c = 1 

 per cent in water) (10, 11, 23). Crystallographic 

 data given in reference 11. Trihelianthate: Plates 

 (23); m.p. 215-225°C (decomposition) (1), 222- 

 225°C (23), or 224-330°C (decomposition) (3). 

 Reineckate: Needles. Sinter at 194°C; m.p. 204- 

 206°C (decomposition) (3). Forms metal chelates: 

 Dihydrostreptomycin-copper : Dark blue sub- 

 stance. Decomposes at 178-183°C (19). 



Biological activity: In vitro and in vivo activity 

 is of the same order as streptomycin (2, 9) except 

 that against Salmonella it is one third to one 

 fourth as active in vitro, and in vivo it is even less 

 active (6). Dihydrostreptomycin has some rickett- 

 siostatic activity, but less than streptomycin (5). 

 In vivo: A dihydrostreptomycin-dependent strain 

 derived from a pathogenic strain of Sal. typhosa 

 was nonpathogenic for mice, but capable of stim- 

 ulating immunity (16). Inhibits the killer action 

 of Paramecium aurelia (13). Active on crown-gall 

 {Agrobacterium tumefaciens) of geranium (17). 



Toxicity: Sulfate: LD50 (mice) 262.5 mg per kg 

 intravenously (4) , 1700 mg per kg intraperitoneally 

 (23), 1600 ± 108 mg per kg (6), 910 mg per kg (30), 

 or 1200 mg per kg (22), or 1800 mg per kg (23) 

 subcutaneously. LD50 (1 -week-old chicks) 743 mg 

 per kg intramuscularly; (4-week-old chicks) 1868 

 mg per kg, same route (20). LDso (10-day -old 

 chick embryos, allantoic cavity) 80.6 mg (29). As 

 in the case of streptomycin, the reduced toxicity 

 of the jjantothenate salt of dihydrostreptomycin 

 was reported. Pantothenate: LD50 (mice) 1550 mg 

 per kg (expressed as base) subcutaneously (22). 

 This was confirmed by some (24, 26) ; others dis- 

 agreed (25). Dihydrostreptomycin was reported 

 to have less severe vestibular toxicity than that of 

 streptomycin in cats (7) and in human beings (8, 

 27). However, it produces a delayed deafness 

 which is more serious than that produced by strep- 

 tomycin (12, 31). Nephrotoxic (8). Plants: Pro- 

 duces aiiochlorosis antl growth inhibition in l)arley 

 (18). 



Utilization: Clinically effective in tuberculosis 

 and in numerous other infectious diseases due to 

 gram+ and gram— l)acteria (27, 28). 



References: 



1. Peck, R. L. et al. J. Am. Chem. Soc. 68: 



1390-1391, 1946. 



2. Bartz, Q. R. et al. .J. Am. Chem. Soc. 68: 



2163-2166, 1946. 



3. Fried, J. and Wintersteiner, O. J. Am. 



Chem. Soc. 69: 79-86, 1947. 



4. Donovick, R. and Rake, (i. J. Bacteriol. 



53: 205-211, 1947. 



5. Smadel, J. E. et al. J. Immunol. 57: 273- 



284, 1947. 



