3'-Desamino-3'',4'-anhydro-[2''(S)-methoxy-3''(R)-oxy-4''-morpholinyl]doxorubicin (PNU-159682) is a major metabolite of nemorubicin (methoxymorpholinyl doxorubicin; MMDX) was isolated from an incubate of NADPH and liver microsomes from dexamethasone-induced male rats. PNU-159682 is remarkably more cytotoxic (>3000 fold) than MMDX and doxorubicin in vitro and was effective in the two in vivotumor models tested, i.e., disseminated murine L1210 leukemia and MX-1 human mammary carcinoma xenografts. The clinical application of this anthracycline drug is, however, limited by its toxic side effects. Biotransformation of MMDX to PNU-159682, was achieved by CYP3A4, the major human cytochrome P450s (CYP) in human liver. However this process will provide only small quantities of PNU-159682 for further studies. Selective targeting of receptors over expressed on pathologic cells with ligand-drug conjugates provides an opportunity to reduce toxicity to normal cells. In this poster we present the design and synthesis of PNU-159682 folate conjugates (Fig.1) targeting folate receptor (FR) positive pathologic cells. Furthermore, we report the synthesis of a PNU-159682 esters utilizing regio-selective esterification of primary alcohol in the presence of phenol using pyridne-triazole acylating reagents.

Synthesis and regio-selective esterification of Nemorubicin metabolite (PNU-159682), a highly cytotoxic warhead for targeted therapies, and their folate conjugates

248th National Meeting (2014)

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