Synthesis and biological evaluation of largazole analogues with modified surface recognition cap groups

Abstract

Several largazole analogues with modified surface recognition cap groups were synthesized and their HDAC inhibitory activities were determined. The C7-epimer 12 caused negligible inhibition of HDAC activity, failed to induce global histone 3 (H3) acetylation in the HCT116 colorectal cancer cell line and demonstrated minimal effect on growth. Although previous studies have shown some degree of tolerance of structural changes at C7 position of largazole, these data show the negative effect of conformational change accompanying change of configuration at this position. Similarly, analogue 16a with D-1-naphthylmethyl side chain at C2 too had negligible inhibition of HDAC activity, failed to induce global histone 3 (H3) acetylation in the HCT116 colorectal cancer cell line and demonstrated minimal effect on growth. In contrast, the L-allyl analogue 16b and the L-1-naphthylmethyl analogue 16c were potent HDAC inhibitors, showing robust induction of global H3 acetylation and significant effect on cell growth. The data suggest that even bulky substituents are tolerated at this position, provided the stereochemistry at C2 is retained. With bulky substituents, inversion of configuration at C2 results in loss of inhibitory activity. The activity profiles of 16b and 16c on Class I HDAC1 vs Class II HDAC6 are similar to those of largazole and, taken together with x-ray crystallography information of HDAC8-largazole complex, may suggest that the C2 position of largazole is not a suitable target for structural optimization to achieve isoform selectivity. The results of these studies may guide the synthesis of more potent and selective HDAC inhibitors.

Largazole Analogues as Histone Deacetylase Inhibitors and Anticancer Agents: An Overview of Structure–Activity Relationships

“…A few analogues of largazole containing non‐standard amino acid units, including 1‐naphtylmethyl and 1‐allylglycine (Figure ), has been recently reported and tested for enzymatic activities on HDACs 1 and 6, and for growth inhibition of HCT116 colon carcinoma cells . The results obtained further confirmed that heterogeneous aromatic substituents at C2 position of the macrocycle were well tolerated, provided that the proper stereochemistry was maintained.…”

Natural and Synthetic Macrocyclic Inhibitors of the Histone Deacetylase Enzymes

“…The stereochemical configuration of largazole proved to be crucial for activity, with the C2‐epimer 239 a , the C7‐epimer 239 d , the C17‐epimer 239 c , and the enantiomer 239 b of largazole/largazole thiol showing weaker HDAC inhibitory activity than the parent compounds (Scheme ) . The ability of 239 c and 239 d to inhibit HCT‐116 cell growth has also been evaluated, and a substantially reduced activity relative to largazole was measured …”

“… In vitro and in vivo activity of largazole analogues. [a] Data reported by Tillekeratne and co‐workers . [b] Percent inhibition at 1 μ m inhibitor concentration.…”

“…Analogues in which valine is replaced with aromatic amino acids such as phenylalanine (compound 260 h ), tyrosine (compound 260 i ), and histidine (compounds 260 j and 260 k , Scheme ) are tolerated well . Incorporation of the noncanonical amino acid 1‐naphthylalanine, also resulted in HDAC inhibitory activity, as long as the l ‐amino acid was used (compound 260 g ) . Analogues containing charged amino acids exhibited loss of activity, with the greatest loss occurring when valine was replaced by aspartic acid (compound 260 l ), whereas the loss in activity was less pronounced when a positively charged amino acid was incorporated (compounds 260 a , 260 c ).…”

Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue

“…27,30–32 In contrast, potent analogues have been generated by structural modification of the depsipeptide ring (surface recognition cap group). 28,30,31,33–35 The lower sequence homology between different HDAC isoforms at the surface near the opening to the binding pocket may be exploited to design more potent HDAC inhibitors by targeting the depsipeptide ring. 17 …”