2. Academic Validation
  3. Modulation of Activity Profiles for Largazole-Based HDAC Inhibitors through Alteration of Prodrug Properties

Modulation of Activity Profiles for Largazole-Based HDAC Inhibitors through Alteration of Prodrug Properties

  • ACS Med Chem Lett. 2014 Jul 7;5(8):905-10. doi: 10.1021/ml500170r.
Lilibeth A Salvador 1,  Heekwang Park 2,  Fatma H Al-Awadhi 3,  Yanxia Liu 4,  Bumki Kim 2,  Sabrina L Zeller 2,  Qi-Yin Chen 4,  Jiyong Hong 5,  Hendrik Luesch 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry and Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida , Gainesville, Florida 32610, United States ; Marine Science Institute, College of Science, University of the Philippines , Diliman, Quezon City 1101, Philippines.
  • 2 Department of Chemistry, Duke University , Durham, North Carolina 27708, United States.
  • 3 Department of Medicinal Chemistry and Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida , Gainesville, Florida 32610, United States.
  • 4 Department of Medicinal Chemistry and Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida , Gainesville, Florida 32610, United States ; Department of Medicinal Chemistry and Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida , Gainesville, Florida 32610, United States.
  • 5 Department of Chemistry, Duke University , Durham, North Carolina 27708, United States ; Department of Pharmacology and Cancer Biology, Duke University Medical Center , Durham, North Carolina 27710, United States.
PMID: 25147612 DOI: 10.1021/ml500170r
Abstract

Largazole is a potent and class I-selective histone deacetylase (HDAC) inhibitor purified from marine cyanobacteria and was demonstrated to possess antitumor activity. Largazole employs a unique prodrug strategy, via a thioester moiety, to liberate the bioactive species largazole thiol. Here we report alternate prodrug strategies to modulate the pharmacokinetic and pharmacodynamics profiles of new largazole-based compounds. The in vitro effects of largazole analogues on Cancer cell proliferation and enzymatic activities of purified HDACs were comparable to the natural product. However, in vitro and in vivo histone hyperacetylation in HCT116 cells and implanted tumors, respectively, showed differences, particularly in the onset of action and oral bioavailability. These results indicate that, by employing a different approach to disguise the "warhead" moiety, the functional consequence of these prodrugs can be significantly modulated. Our data corroborate the role of the pharmacokinetic properties of this class of compounds to elicit the desired and timely functional response.

Keywords

Largazole; antitumor activity; histone deacetylases; natural products; prodrugs.

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