Skip to main content
Journal cover image

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

Publication ,  Journal Article
Salvador, LA; Park, H; Al-Awadhi, FH; Liu, Y; Kim, B; Zeller, SL; Chen, Q-Y; Hong, J; Luesch, H
Published in: ACS medicinal chemistry letters
August 2014

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

ACS medicinal chemistry letters

DOI

EISSN

1948-5875

ISSN

1948-5875

Publication Date

August 2014

Volume

5

Issue

8

Start / End Page

905 / 910

Related Subject Headings

  • 3405 Organic chemistry
  • 3404 Medicinal and biomolecular chemistry
  • 1115 Pharmacology and Pharmaceutical Sciences
  • 0305 Organic Chemistry
  • 0304 Medicinal and Biomolecular Chemistry
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Salvador, L. A., Park, H., Al-Awadhi, F. H., Liu, Y., Kim, B., Zeller, S. L., … Luesch, H. (2014). Modulation of Activity Profiles for Largazole-Based HDAC Inhibitors through Alteration of Prodrug Properties. ACS Medicinal Chemistry Letters, 5(8), 905–910. https://doi.org/10.1021/ml500170r
Salvador, Lilibeth A., Heekwang Park, Fatma H. Al-Awadhi, Yanxia Liu, Bumki Kim, Sabrina L. Zeller, Qi-Yin Chen, Jiyong Hong, and Hendrik Luesch. “Modulation of Activity Profiles for Largazole-Based HDAC Inhibitors through Alteration of Prodrug Properties.ACS Medicinal Chemistry Letters 5, no. 8 (August 2014): 905–10. https://doi.org/10.1021/ml500170r.
Salvador LA, Park H, Al-Awadhi FH, Liu Y, Kim B, Zeller SL, et al. Modulation of Activity Profiles for Largazole-Based HDAC Inhibitors through Alteration of Prodrug Properties. ACS medicinal chemistry letters. 2014 Aug;5(8):905–10.
Salvador, Lilibeth A., et al. “Modulation of Activity Profiles for Largazole-Based HDAC Inhibitors through Alteration of Prodrug Properties.ACS Medicinal Chemistry Letters, vol. 5, no. 8, Aug. 2014, pp. 905–10. Epmc, doi:10.1021/ml500170r.
Salvador LA, Park H, Al-Awadhi FH, Liu Y, Kim B, Zeller SL, Chen Q-Y, Hong J, Luesch H. Modulation of Activity Profiles for Largazole-Based HDAC Inhibitors through Alteration of Prodrug Properties. ACS medicinal chemistry letters. 2014 Aug;5(8):905–910.
Journal cover image

Published In

ACS medicinal chemistry letters

DOI

EISSN

1948-5875

ISSN

1948-5875

Publication Date

August 2014

Volume

5

Issue

8

Start / End Page

905 / 910

Related Subject Headings

  • 3405 Organic chemistry
  • 3404 Medicinal and biomolecular chemistry
  • 1115 Pharmacology and Pharmaceutical Sciences
  • 0305 Organic Chemistry
  • 0304 Medicinal and Biomolecular Chemistry