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

Ada Rephaeli, Regina Zhuk, Abraham Nudelman

Research output: Contribution to journalReview articlepeer-review

74 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)379-391
Number of pages13
JournalDrug Development Research
Volume50
Issue number3-4
DOIs
StatePublished - 2000

Keywords

  • Alopecia
  • Anticancer drugs
  • Butyric acid
  • Differentiation
  • Prodrugs
  • Retinoic acid
  • β-hemoglobinopathies

Fingerprint

Dive into the research topics of 'Prodrugs of butyric acid from bench to bedside: Synthetic design, mechanisms of action, and clinical applications'. Together they form a unique fingerprint.

Cite this