Prodrugs of butyric acid. Novel derivatives possessing increased aqueous solubility and potential for treating cancer and blood diseases

The synthesis and biological activities of acidic, basic and neutral types of butyric acid (BA) prodrugs possessing increased aqueous solubility are d escribed. The compounds are butyroyloxyalkyl derivatives of carboxylic acid s, which possess functionalities suitable for aqueous solubilization. The a nticancer activity of the prodrugs in vitro was evaluated by examining thei r effect on the growth of human colon, breast and pancreatic carcinoma cell lines, and their solubility in aqueous media was determined. The most prom ising compounds, with respect to activity and solubility, were found to be the butyroyloxymethyl esters of glutaric 2a and nicotinic acids 4a and phos phoric acid as its diethyl ester 10a, which displayed IC50 values of 100 mu M or lower. These prodrugs are expected to release formaldehyde upon metabo lic hydrolysis. The corresponding butyroyloxyethyl esters (2b, 4b and 10b) that release acetaldehyde upon metabolism were significantly less potent. A similar correlation was observed for growth inhibition of the human prosta te carcinoma cell lines PC-3 and LnCap and for induction of differentiation and apoptosis in the human myeloid leukemia cell line HL-60. The higher bi ological activity of the formaldehyde-releasing prodrugs 2a and 10a was fur ther confirmed when induction of hemoglobin (Hb) synthesis in the human ery throleukemic cell line K562 was measured. Moreover, a therapeutic index (IC 50/ED50) of ca. 5 was observed. The acute i.p. toxicity LD50 in mice for 2a , 2b, 10a and 10b was similar and in the range of 400-600 mg kg(-1). The re sults obtained support the potential use of the butyric acid prodrugs for t he treatment of neoplastic diseases and beta -globin disorders. (C) 2001 Ed itions scientifiques et medicales Elsevier SAS.