168 



DESCRIPTIONS OF ANTIBIOTICS 



actinomycetes. J. Duclot, Gembloux, 

 France, 1957. 



3. Salton, M. R. J. and Ghuy.sen, J. M. Bio- 



chim. et Biophys. Acta 24: 160-173, 1957. 



4. Malchair, R. Giorn. microbiol. 5: 137-157, 



1958. 



5. Feistinantel, Dr. Centr. Bakteriol Parasi- 



tenk. Abt. 1, Orig. 36: 282-290, 406-415, 

 1904. 



6. Mathieson, D. R. et al. Am. J. Hyg. 21 : 405- 



431, 1935. 



7. Welsch, M. Compt. rend. Soc. Biol. 122: 244- 



246, 1937. 



.\ctinoinyciiis 



Intruduction: Actinomycin A, discovered by 

 Waksman and Woodruff in 1940 (1), was relegated 

 to a decade of oblivion because of its high toxicity 

 (3). Following the fine work on actinomycin C 

 (Brockmann and coworkers) and actinomycin B 

 (by workers in England), and the report that 

 actinomycin C was effective clinically against 

 certain neoplastic diseases (21), interest in the 

 actinomycins was vigorously renewed. 



Altogether, actinomycins A, B, C, D, E, F, I, J, 

 K, M, X, and Z, as well as others, have been re- 

 ported. All are to.xic, red substances that have 

 similar biological properties. They can be ex- 

 tracted and purified in similar ways, V)ut they 

 differ in certain physical and chemical properties. 

 The designations actinomycin A, actinomycin B, 

 etc., do not refer to single substances but to 

 complexes. The components of the actinomycin 

 complexes are very closely related. Two different 

 complexes may contain the same components, but 

 in different proportions. One component may be 

 found in one complex but not in another. 



Brockmann and his coworkers refer to the 

 various components by the letter of the complex, 

 with a subordinate arable number; i.e., Xo , Xi , 

 X2 , etc. As the numbers become larger, the Rt 

 values become larger within a single complex, 

 regardless of the solvent system used. Roussos and 

 Vining (62), on the other hand, introduced another 

 system, using subordinate Roman numerals. These 

 numerals referred to a particular Rf value in a 

 specific system of paper chromatography and ap- 

 plied to a component with that Rf, regardless of its 

 complex. The numeral was used in conjunction 

 with the letter of the complex to indicate the 

 source of the component; e.g., Ai , Bn , Div , etc. 



Waksman et al. (77) proposed to clarify this 

 confusion by terming all actinomycin complexes 

 "mixtures." Each different component of these 



mixtures, when purified and characterized, would 

 be given a roman numeral, with no reference being 

 made to the complex which was the source of the 

 component. 



Ai , Bi , Xfi(j = Actinomycin I 



All , Bii = Actinomycin II 



Am , Bill = Actinomycin III 



Aiv , Biv , Div , Ci , Ii , Xi = Actinomycin IV 



Ay , By , X2 = Actinomycin V 



C> = Actinomycin VI 



C3 = Actinomycin VII 



Thus, what has been called the actinomycin A 

 complex becomes a mi.xture containing actino- 

 mycins I to V. All others, such as the new biosyn- 

 thetic actinomycins {e.g., E, F) would become 

 "mixtures" until their components were more 

 fully characterized. This new system will be used 

 insofar as possible in the following discussion, al- 

 though previously used terminology will be em- 

 ployed parenthetically for historical clarity. 



It is evident from this, as previously mentioned, 

 that the same components can appear in different 

 complexes. Roussos and Vining (62) found by' 

 circular paper chromatography that four "actino- 

 mycin mixtures" (A, B, D, and X) contained 

 actinomycins I, II, III, IV, and V, but in different 

 proportions (Table 38). This was further verified 

 when actinomycins I, IV, and V isolated from the 

 different mixtures \yere shown to have almost 

 completelj' identical physical and chemical 

 properties. 



In general, actinomycins have a m.p. of about 

 215-255 °C. They are soluble in benzene, ethanol, 

 and acetone, slightlj' soluble in water and ether; 

 insoluble in aqueous dilute alkali and petroleum 

 ether. All have peak absorption at about 440 to 450 

 niju and about 240 injj. in ultraviolet light ; many 

 also show a peak at about 415 to 430 m^u. All re- 

 ported thus far are levorotatory. Actinomycins 

 give a transient purple color in ethanolic NaOH, 

 and a dark red color in concentrated HCl. They 

 are most stable at pH 6 to 7, relatively stable at 

 acid pH, and destroyed at alkaline pH. 



Actinomycins are polypeptides linked to a 

 chromophoric ciuinoid moiet}-. This chromophore 

 has been shown to be 3-amino-l ,8-dimethyl- 

 phenoxazone-(2)-dicarboxylic acid (4, 5) for 

 actinomycins I (Xo^), IV(Div , Ci , Ii), V(X2, 

 By), VK'c-), and VII (C.,), and is believed to be the 

 same for all actinomycins (see formula in Chapter 6 

 and references 56, 57, 65, 98). This belief is based 

 on the fact that the main barium hydroxide hy- 

 drolysis degradation product of these components 

 is the same (see references 25, 39, 45, 47, 65). The 



structure of despeptido actinomycin is shown hero: 



