Prodrugs of butyric acid from bench to bedside: Synthetic design, mechanisms of action, and clinical applications

We describe the synthesis, biological activities, and clinical applications of a novel family of butyric acid (BA) prod rugs having the general formul a Me(CH2)(2)COOCH(R) OR1, where R = H, Me, Pr, tert-Bu; R-1 = OC-alkyl, OC- Ar, OC-heterocycles, and P(O)(OEt)(2). These acyloxyalkyl prodrugs serve as molecular devices for efficient transport of BA into the cells, leading to a significant increase in its potency. The prodrugs were studied for antic ancer activity induction of hemoglobin (Hb) expression and protection of ha ir follicles from damage caused by cytotoxic agents. Structure activity rel ationship studies (SAR) for the different activities were conducted. The an ticancer activity of the compounds was demonstrated in vitro and in animal models. The best-studied member of the family is AN-9, Pivanex(R), currentl y in phase II clinical trial with non-small cell lung carcinoma patients. T he mutual prodrug of two potent differentiation inducers, BA and all-trans- retinoic acid (ATRA) - retinoyloxymethyl butyrate (RN1) was also synthesize d, It displayed enhanced differentiation activity in leukemic cells with ED 50, 40-fold lower than that of ATRA and about 4 orders of magnitude lower t han that of BA. Butylidene dibutyrate (AN-10), predicted to release 3 equiv alents of BA in the cells, is characterized by low toxicity. It induces Hb expression in erythroleukemic cell lines and fetal hemoglobin (FHb) express ion in sickle cell anemia (SCA) and beta-thalassemia progenitor blood cells . AN-10 was also shown to protect hair follicles and may have potential use for treatment of radio- and chemo-therapy induced alopecia. Drug Dev. Res. 50:370-391, 2000. (C) 2000 Wiley-Liss, Inc.