Chemical Synthesis and Drug (or Probe) Development

For selected compounds (by ourselves or in collaboration), we are devising synthetic methods to probe structure–activity relationships (SAR) and to obtain larger quantities of material for biological evaluation, including toxicity, pharmacokinetic and efficacy studies in animal models, which we will carry out in due course. Molecules of interest include largazoles and apratoxins, which we discovered and characterized in our lab.

Largazole, which we isolated from a Floridian cyanobacterium, is the most potent natural HDAC inhibitor to date, and in collaboration with Professor Jiyong Hong (Duke University) we described a concise and convergent synthesis (8 steps, 19% overall yield), which allowed its extension to the preparation of a series of analogues.  SAR studies revealed that the thiol group is the pharmacophore of the natural product and liberated during protein-assisted thioester hydrolysis to largazole thiol.  We determined that largazole inhibits HDACs in vivo, consequently modulates gene expression and thereby shows efficacy in solid tumor xenograft mouse models and bone-forming efficacy in mouse and rabbit models.  The dual action of largazole to stimulate bone formation and inhibit bone resorption indicates largazole’s potential as drug lead for bone-related disorders, in addition to its potential as an anticancer drug. We are also evaluating largazole for other disease indications where cellular reprogramming of transcription may be beneficial.


Apratoxins are cytotoxic marine natural products that prevent cotranslational translocation early in the secretory pathway.  We found that apratoxins downregulate receptor tyrosine kinases and their corresponding ligands, giving a one‒two punch to cancer cells, particularly those that rely on autocrine loops.  Unfortunately, the parent compound apratoxin A displays irreversible toxicity; however, through a 21-step convergent total synthesis (35 steps total) we generated various analogues, one of which (apratoxin S4) has greater potency and selectivity for cancer cells in vitro and in vivo. Apratoxin S4 is a hybrid of natural apratoxins A and E, both of which we isolated from cyanobacteria and which provided the inspiration for this new synthetic molecule.  Apratoxin S4 showed efficacy in a colorectal tumor xenograft mouse model without irreversible toxicity, demonstrating that its mechanism of action has therapeutic potential.


Due to our steady discovery rate of new bioactive metabolites from marine cyanobacteria, additional synthesis projects are constantly emerging.


Sample Publications:

Ying, Y.; Taori, K.; Kim, H.; Hong, J.; Luesch, H. “Total Synthesis and Molecular Target of Largazole, a Histone Deacetylase Inhibitor”J. Am. Chem. Soc. 2008, 130, 8455–8459.

Ying, Y.; Liu, Y.; Byeon, S. R. ; Kim, H.; Luesch, H.; Hong, J. “Synthesis and Activity of Largazole Analogues with Linker and Macrocycle Modification” Org. Lett. 2008, 10, 4021–4024.

Liu, Y.; Salvador, L. A.; Byeon, S.; Ying, Y.; Kwan, J. C.; Law, B. K.; Hong, J.; Luesch, H. “Anticolon Cancer Activity of Largazole, a Marine-Derived Tunable Histone Deacetylase Inhibitor” J. Pharmacol. Exp. Ther. 2010, 335, 351–361.

Lee, S.-U.; Kwak, H. B.; Pi, S.-H.; You, H.-K.; Byeon, S. R.; Ying, Y.; Luesch, H.; Hong, J.; Kim, S. H. “In Vitro and In Vivo Osteogenic Activity of Largazole” ACS Med. Chem. Lett. 2011, 2, 248‒251.

Chen, Q.-Y.; Liu, Y.; Luesch, H. “Systematic Chemical Mutagenesis Identifies a Potent Novel Apratoxin A/E Hybrid with Improved in Vivo Antitumor Activity” ACS Med. Chem. Lett. 20112, 861‒865.

Hong, J.; Luesch, H. “Largazole: From Discovery to Broad-Spectrum Therapy” Nat. Prod. Rep. 2012, 29, 449‒456. 

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