Novel mutual prodrug of retinoic and butyric acids with enhanced anticancer activity

Acyloxylalkyl esters of retinoic acid and small carboxylic acids (C3-5) were evaluated for anticancer activity. The derivative of butyric acid (BA) and all-trans-retinoic acid (ATRA) - retinoyloxymethyl butyrate (RN1) - acting as a mutual prodrug was a more potent inducer of cancer cell differentiation and inhibitor of proliferation than the parent acids. ED₅₀ of RN1 for differentiation induction in HL-60 was over 40-fold lower than that of ATRA. The differentiating activity of ATRA compared to that of the acyloxylalkyl esters derived from butyric (RN1), propionic (RN2), isobutyric (RN3), and pivalic (RN4) acids was found to be: RN1 > RN2 > RN3 > ATRA ~ RN4. This observation implies that the activity of the prodrugs depends on the specific acyl fragment attached to the retinoyl moiety, and the butyroyl fragment conferred the highest potency. The IC₅₀ values for inhibition of Lewis lung (3LLD122) and pancreatic (PaCa₂) carcinoma cell line colony formation elicited by RN1 were significantly higher than those of ATRA. In addition to its superiority over ATRA or BA as growth inhibitors of the above cell lines, RN1 was also able to overcome the resistance to ATRA in 3LLD122 cells.