TY - JOUR
T1 - Prodrugs of butyric acid from bench to bedside
T2 - Synthetic design, mechanisms of action, and clinical applications
AU - Rephaeli, Ada
AU - Zhuk, Regina
AU - Nudelman, Abraham
PY - 2000
Y1 - 2000
N2 - We describe the synthesis, biological activities, and clinical applications of a novel family of butyric acid (BA) prodrugs having the general formula Me(CH2)2COOCH(R)OR1, where R = H, Me, Pr, tert-Bu; R1 = 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 anticancer activity, induction of hemoglobin (Hb) expression and protection of hair follicles from damage caused by cytotoxic agents. Structure activity relationship studies (SAR) for the different activities were conducted. The anticancer activity of the compounds was demonstrated in vitro and in animal models. The best-studied member of the family is AN-9, Pivanex®, currently in phase II clinical trial with non-small cell lung carcinoma patients. The mutual prodrug of two potent differentiation inducers, BA and all-trans-retinoic acid (ATRA) - retinoyloxymethyl butyrate (RN1) was also synthesized. It displayed enhanced differentiation activity in leukemic cells with ED50, 40-fold lower than that of ATRA and about 4 orders of magnitude lower than that of BA. Butylidene dibutyrate (AN-10), predicted to release 3 equivalents of BA in the cells, is characterized by low toxicity. It induces Hb expression in erythroleukemic cell lines and fetal hemoglobin (FHb) expression in sickle cell anemia (SCA) and β-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. (C) 2000 Wiley-Liss, Inc.
AB - We describe the synthesis, biological activities, and clinical applications of a novel family of butyric acid (BA) prodrugs having the general formula Me(CH2)2COOCH(R)OR1, where R = H, Me, Pr, tert-Bu; R1 = 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 anticancer activity, induction of hemoglobin (Hb) expression and protection of hair follicles from damage caused by cytotoxic agents. Structure activity relationship studies (SAR) for the different activities were conducted. The anticancer activity of the compounds was demonstrated in vitro and in animal models. The best-studied member of the family is AN-9, Pivanex®, currently in phase II clinical trial with non-small cell lung carcinoma patients. The mutual prodrug of two potent differentiation inducers, BA and all-trans-retinoic acid (ATRA) - retinoyloxymethyl butyrate (RN1) was also synthesized. It displayed enhanced differentiation activity in leukemic cells with ED50, 40-fold lower than that of ATRA and about 4 orders of magnitude lower than that of BA. Butylidene dibutyrate (AN-10), predicted to release 3 equivalents of BA in the cells, is characterized by low toxicity. It induces Hb expression in erythroleukemic cell lines and fetal hemoglobin (FHb) expression in sickle cell anemia (SCA) and β-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. (C) 2000 Wiley-Liss, Inc.
KW - Alopecia
KW - Anticancer drugs
KW - Butyric acid
KW - Differentiation
KW - Prodrugs
KW - Retinoic acid
KW - β-hemoglobinopathies
UR - http://www.scopus.com/inward/record.url?scp=0033819869&partnerID=8YFLogxK
U2 - 10.1002/1098-2299(200007/08)50:3/4<379::AID-DDR20>3.0.CO;2-8
DO - 10.1002/1098-2299(200007/08)50:3/4<379::AID-DDR20>3.0.CO;2-8
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AN - SCOPUS:0033819869
SN - 0272-4391
VL - 50
SP - 379
EP - 391
JO - Drug Development Research
JF - Drug Development Research
IS - 3-4
ER -