Largazole and Analogues with Modified Metal-Binding Motifs Targeting Histone Deacetylases: Synthesis and Biological Evaluation

Abstract

The histone deacetylase inhibitor, largazole 1 was synthesized by a convergent approach which involved several efficient and high yielding single pot multistep protocols. Initial attempts using t-butyl as thiol protecting group proved problematic and synthesis was accomplished by switching to trityl protecting group. This synthetic protocol provides a convenient approach to many new largazole analogues. Three side chain analogues with multiple heteroatoms for chelation with Zn2+ were synthesized and their biological activities were evaluated. They were less potent than largazole 1 in growth inhibition of HCT116 colon carcinoma cell line and in inducing increases in global H3 acetylation. Largazole 1 and the three side chain analogues had no effect on HDAC6 as indicated by the lack of increased acetylation of α-tubulin.

Evaluation of class I HDAC isoform selectivity of largazole analogues

“…1) with other Zn 2+ chelating groups have resulted in significant decreases in inhibitor potency. 2,10,13,21,25 While the active site of HDACs is highly conserved, sequence variety in the cap region is relatively high. 28 It is believed that the interactions between this hydrophobic cap region and the macrocycle of largazole ( 1 ) influence its class selectivity.…”

Predicting the unpredictable: Recent structure–activity studies on peptide-based macrocycles

“…Another approach that was taken by Tillekeratne and co-workers involved using the thiol to chelate the metal ions [96]. Three analogues of L1 were synthesized bearing a pyridine, a thiazole, and a substituted phenol (L14-16, Table 9).…”

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

“…The synthetic strategy we previously employed in the assembly of largazole [39] was conveniently adopted in the synthesis of these analogues. Using ( S )-α-methylcysteine HCl ( 6 ), instead of ( R )-α-methylcysteine HCl used in largazole synthesis, gave the C7-epimer 12 (Scheme 1).…”

“…As HDACs proteins are associated with many basic cellular processes and aberrant HDAC activity is also linked to human disorders other than cancer, the effect of largazole on other disease states such as inflammation and rheumatoid arthritis too are being explored [17–19]. A number of largazole analogues have been synthesized and their HDAC inhibitory activities determined revealing some of the structure-activity relationship (SAR) requirements of the molecule [20–38],[39]. Changes in all three sectors of the molecule have been effected.…”

“…We recently reported the synthesis and biological activity of several largazole analogues incorporating multiple heteroatoms in the metal binding domain [39]. In continuation of our efforts in the search for selective and potent anticancer agents [39–43], we report here the synthesis and biological activity of several largazole analogues with modifications in the depsipeptide ring, which serves as the cap group that interacts with the hydrophobic rim of the active site. These modifications include inversion of stereochemistry at C7 of largazole to generate the C7-epimer 12 as well as structural and stereochemical changes in the valine side chain at C2 to generate analogues 16a – c .…”