Adriamycin analogs. Preparation and biological evaluation of some novel 14-thiaadriamycins

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Abstract
Condensation of 14-bromodaunorubicin with thiols in methanol, in the presence of potassium carbonate, resulted in the formation of 14-thia analogs of the antitumor antibiotic adriamycin. However, similar condensation of N-(trifluoroacetyl)-14-iododaunorubicin with thiols invariably led to a redox reaction, with the formation of N-(trifluoroacetyl)daunorubicin and disulfides. Accordingly, N-(trifluoroacetyl)- 14-bromodaunorubicin was used for reaction with thiols to yield thia analogs of the clinically active but non-DNA-binding adriamycin analog N-(trifluoroacetyl)adriamycin 14-valerate (AD 32). Reaction of 14-bromodaunorubicin with .alpha.,.omega.-alkanedithiols gave bis(thiaadriamycin) analogs as potential difunctional intercalating agents. The aforementioned products, plus 2 related phenylselena derivatives, were examined for in vitro growth inhibition [CCRF-CEM human lymphoblastic leukemia], in vivo antitumor activity [murine leukemia L1210], and, where appropriate, DNA binding. A number of agents, most notably 14-(carbethoxymethyl)-14-thiaadriamycin and N-(trifluoroacetyl)14-phenyl-14-selenaadriamycin, were active against L1210 leukemia in vivo. Several of the amino glycoside unsubstituted 14-thiaadriamycin analogs exhibited DNA-binding properties equivalent to those of adriamycin.