Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 5, Issue 8, Pages 905-910Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ml500170r
Keywords
Largazole; histone deacetylases; antitumor activity; natural products; prodrugs
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Funding
- National Institutes of Health National Cancer Institute [R01CA138544]
- North Carolina Biotechnology Center (NCBC) [2008-IDG-1010]
- National Science Foundation (NSF) MRI Program [0923097]
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [0923097] Funding Source: National Science Foundation
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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.
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