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

Acyloxylalkyl esters of retinoic acid and small carboxylic acids (C3-5) wer e evaluated for anticancer activity. The derivative of butyric acid (BA) an d alh-trans-retinoic acid (ATRA) retinoyloxymethyl butyrate (RN1) - acting as a mutual prodrug was a more potent inducer of cancer cell differentiatio n and inhibitor of proliferation than the parent acids. ED50 Of RN1 for dif ferentiation induction in HL-60 was over 40-fold lower than that of ATRA. T he differentiating activity of ATRA compared to that of the acyloxylalkyl e sters derived from butyric (RN1), propionic (RN2), isobutyric (RN3), and pi valic (RN4) acids was found to be: RN1 > RN2 > RN3 > ATRA similar to RN4. T his observation implies that the activity of the prodrugs depends on the sp ecific acyl fragment attached to the retinoyl moiety, and the butyroyl frag ment 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 L ines, RN1 was also able to overcome the resistance to ATRA in 3LLD122 cells .