Largazole Analogues as Histone Deacetylase Inhibitors: Synthesis and Biological Evaluation

A. Al-Hamashi, J. Almaliti, R. Farrell, V. L. Tillekeratne University of Toledo Purpose Histone deacetylase (HDAC) enzymes, which are overexpressed in many cancer tissues, present a potential target for cancer chemotherapy.HDAC inhibitors (HDACis) are currently being investigated as potential anticancer agents. Most of the current HDACis are not selective and have high potential toxicity. Selective inhibition of specific HDAC isoforms to preferentially su the proliferation of specific cancer cells is a goal yet to be achieved. Largazole is a macrocyclic depsipeptide anticancer agent form a marine cyanobacterium. It is a class I selective HDAC inhibitor. The depsipeptide cap group of largazole interacts with conserved area of the HDACs surface and can be targeted to develop isoform selective HDACi. Methods We have used molecular modeling approaches to design several new largazole analogues with modified cap groups to modula binding interaction with the enzyme surface. We used a novel protection/deprotection protocol to synthesize these analogues. evaluated their antiproliferative activity and HDAC isoform selectivity. Results We investigated the binding modes of free thiols of largazole, AA1 and AA2 in the X-ray structure of HDAC1, 2, 4 and 8 enz using Glide (Fig 2). The interactions between AA1 and AA2 with HDACs1, 2, 4, and 8 were consistent with those expected b design. The method of synthesis was improved using a novel protection/ deprotection protocol. We tested largazole analogues in the NCI 60 human tumor cell line screen. In the growth inhibition assay at a single dose of 1 they showed relatively higher cytotoxicity on several melanoma, colon and renal cancer cell lines (Fig 3). Conclusion Structure based drug design was carried out to design new largazole analogues. The designed analogues (JA4-JA6, AA1 and AA2) with modified surface recognition cap groups were synthesized and their biological activity evaluated. The method of synthesis was improved using a novel protection/ deprotection protocol. ppress isolated a less