Development of new estradiol-cationic lipid hybrids: Ten-carbon twin chain cationic lipid is a more suitable partner for estradiol to elicit better anticancer activity

• Estradiol and C-10 chain length conjugate is the most potent anticancer agent.
• ES-C10 is broadly anticancer against breast, skin and pancreatic cancer cells.
• ES-C10 induces selective sub-G0 arrest and apoptosis in cancer cells.
• ES-C10-induced tumor growth regression is estrogen receptor-mediated.

The present study illustrates the synthesis and anticancer evaluation of six, ten, twelve and fourteen carbon chain containing cationic lipidated-estradiol hybrids. Previously, we have established the lipidation strategy to introduce anticancer activities in various pharmacophores including estradiol (ES). In this structure activity study the length of the carbon chain is narrowed down between C6–C14 to screen out the most potent anticancer molecule among the class. Among the newly developed ES-cationic lipid conjugates, ten-carbon chain containing derivative, ES-C10 (5c) exhibited 4–12 folds better anticancer activity than the previously established derivative, ES-C8 (5b) in various cancer cells of different origin. Moreover cytotoxicity of this molecule was not observed in non-cancer cells. Notably, in spite of bearing estrogenic moiety, ES-C10 exhibited anticancer activity irrespective of estrogen receptor (ER) expression status. ES-C10 exhibited prominent sub-G0 arrest of cancer cells with concomitant induction of apoptosis and demonstrated significant inhibition of tumor growth in mouse melanoma model. Collectively, ES-C10 exemplifies the development of an anticancer agent with broader activity against cancer cells of different origins.

The present report describes the synthesis and in vitro & in vivo anticancer evaluation of the new cationic lipid-modified estradiol derivatives by varying the carbon chain length between C6 to C14. Our findings disclose that the C10 analogue is a more suitable partner than the existing potent C8 analogue towards imparting selective anticancer activity. IC50 as represented are obtained in B16F10 melanoma cells.Figure optionsDownload as PowerPoint slide