Adriamycin analogs. 3. Synthesis of N-alkylated anthracyclines with enhanced efficacy and reduced cardiotoxicity

Abstract

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.

Synthesis and Cytotoxic Evaluation of Arimetamycin A and Its Daunorubicin and Doxorubicin Hybrids

“…A postglycosidation methylation strategy must account for the susceptibility of the C7–C1′ benzyl ether linkage to hydrogenolysis 20 , 21 and the lability of the C13 α-hydroxy-ketone of the DNR and DOX aglycones to hydride reduction. 22 Conversely, a preglycosylation methylation approach requires the use of a polar glycosyl donor featuring two dimethyl amines. While not unprecedented, 23 − 27 interaction between a Brønsted or Lewis acid promoter and the basic amines complicates the reaction.…”

Adverse Effects of Doxorubicin and Its Metabolic Product on Cardiac RyR2 and SERCA2A

“…First, many anthracyclines are strong alkylating agents that add a methyl group to lysine or arginine residues. However, doxorubicin and doxOL cannot form N-alkyl adducts and are incapable of alkylation (Marchini et al, 1995;Tong et al, 1979). Second, quinone-containing molecules can react via an arylation reaction with nucleophiles, including protein thiol groups, to form Michael adducts (Gant et al, 1988).…”

The ability of new formamidine sugar-modified derivatives of daunorubicin to stimulate free radical formation in three enzymatic systems: NADH dehydrogenase, NADPH cytochrome P450 reductase and xanthine oxidase.

“…Daunorubicin was obtained from Drug Development Branch, National Cancer Institute, Bethesda, MD (U.S.A.). DR19 [16], N,N-diBzl-DR [18] and the formamidine derivatives of DR (A, B, C, D) [17] were prepared according to procedures described in the indicated references.…”