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Structural characteristics of Adriamycin and daunorubicin analogs are discussed in terms of three antitumor activity classifications: compounds with potency and efficacy equivalent to or superior to the parent antibiotics, compounds displaying high efficacy but with decreased potency, and compounds in which a key structural change has destroyed all in vivo antitumor activity. It is first concluded that analogs possessing efficacy and potency comparable to the parent antibiotics are quite similar to the parents in structural terms, ie, their hydrophilic character, functional groups, and stereochemistry. Within this group there is suggestive evidence that altered electronic character of the aglycones may be associated with improved cardiotoxicity characteristics. The second general conclusion is that high efficacy accompanied by decreased potency is compatible with a much wider array of structural variants than is high efficacy accompanied by high potency. Thus, analogs with substantially higher or lower lipophilicity than the parent antibiotics, as well as those with an array of ionic characteristics differing from the parents, retained significant efficacy. These characteristics are compatible with the concept of multiple mechanisms of action for the anthracycline antibiotics. In general, structural changes in the sugar side chain are appreciably more compatible with retention of in vivo antitumor efficacy than are changes in the aglycone, both in terms of functional groups and stereochemistry.

Reaction of daunorubicin (1) and adriamycin (2) with aldehydes and ketones in the presence of NaCNBH3 afforded N-alkyl- and N,N-dialkylanthracyclines along with their 13-dihydro derivatives. Product ratios depended upon the nature of the carbonyl reagent and the starting drug. The majority of these analogues retained in vivo antitumor activity comparable to 1 and 2. However, unlike the parent compounds, which inhibit DNA and RNA synthesis at comparable concentrations, several of these analogues inhibit RNA synthesis at markedly lower concentrations than required to inhibit DNA synthesis. In addition, in some cases the ability to bind to DNA in vitro was reduced while antitumor activity was retained. N,N-Dibenzyldaunorubicin was especially notable for increased efficacy (T/C 259, qd 1--9) against P388 leukemia in mice, despite reduction of DNA binding in vitro. It showed almost complete loss of mutagenicity vs S. typhimurium (Ames test) and it was tenfold less cardiotoxic by electrocardiographic measurements (Zbinden test) in the rat.

The syntheses of several 13-deoxyanthracyclines are described. Koenigs-Knorr condensation of epsilon-rhodomycinone (12) with the protected daunosaminyl chloride 15 afforded 14 after deprotection. Efforts to decarbomethoxylate 12, as well as attempts to selectively deoxygenate the 13 position of daunomycinone and adriamycinone, were unsuccessful as approaches to 13-deoxyanthracyclines. However, reaction of the readily available tosylhydrazones 4 and 5, of daunorubicin and adriamycin with NaCNBH3 in acidic MeOH, afforded the 13-deoxy analogues 6 and 7 in satisfactory yield. These compounds retained antitumor activity, being comparable to the parent compounds in both efficacy and potency in the P-388 mouse leukemia screen. The epsilon-rhodomycinone glycoside 14 was less active than 6 and 7.

Adriamycin is selectively cleaved in high yield at the C13-C14 bond by 1 equiv of sodium metaperiodate to yield carboxylic acid 3. The corresponding methyl ester 4 is obtained by Fischer esterification. Spectral studies indicate that 3 and 4 bind to calf thymus DNA in a manner similar to adriamycin and daunomycin but Tm measurements suggest that less stable complexes are formed. Ester 4 inhibits DNA and RNA synthesis in cultured L1210 cells at levels comparable to adriamycin but acid 3 is much less effective. Both new compounds are moderately effective as antitumor agents against P388 lymphocytic leukemia in the mouse.