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    • These inhibitors possess a cap

    2022-08-09

    These inhibitors possess a cap group build from cyclization of several amino-acid or non-amino-acid residues, four or more, with one residue bearing an alkyl arm terminated by ZBGs of various types: thiols, ketones or epoxides. In the case of romidepsin 30 (Fig. 7), the thiol group is initially in a disulphide prodrug form, cleaved in vivo to have the activated form. The largazole 25 (Fig. 7) is also considered as a prodrug. The replacement of the thiazole by an oxazole in largazole proposed by the Williams’s group [97] gave quetiapine mechanism of action 55 (Fig. 7). This was found especially suitable to increase the activity (Table 5). In cellular assays, prodrugs 54 and 56 were found more active probably due to the degradation of the free compound in the biological environment. MD simulations gave for compound 55 and largazole two docking poses that not interconvert. The thiazole ring in largazole occupies two distinct opposite 180° positions relative to the centre of the tunnel active site while, for compound 55, both poses are oriented almost the same, with a 60° rotation relative to the centre of the tunnel. Kim et al. [98] have replaced the valine of largazole by other amino acids or alternative substituents to evaluate charged groups and they also modified the thioalkyl chain. The phenylalaninyl or tyrosinyl analogues 57 and 58 gave similar activities compared to largazole. The introduction of charged groups reduced the activity. These data indicated that a lipophilic side chain is better suited for higher activity (e.g. Val, Phe, Tyr), in particular to target HDAC1 and HDAC3. Souto et al. [99] modified the largazole dihydrothiazole ring by replacement of the methyl group or oxidation to a thiazole or oxazole ring. All the compounds were highly active for HDAC1 inhibition and about 100–1000-fold less for HDAC4 (Table 5). An exception is compound 59 where the methyl group is replaced by an ethyl group with ten-fold lower HDAC1 inhibition. Intriguingly, the replacement by a benzyl group retains the nanomolar inhibition. Compound 60 illustrates the series. Bhansali et al. [100] reported largazole analogue such as 61 (Fig. 15) with a stable thioether leading to low potency (20–25% HDAC1 and 50–60% HDAC6 inhibitions at 1 μM). The authors [101] replaced the isopropyl of the valine by aromatic groups to modify the surface recognition. The compound 62 and largazole inhibited HDAC1. HDAC6 was only 50% inhibited at the highest dose tested. Compound 62 was also slightly less potent than largazole in H4K9 acetylation assay. Marcaurelle et al. [102] have simplified the macrocyclic structure but retained stereochemical centres to identify the best geometry for HDAC inhibition. Compounds with various ring sizes were produced (8-, 9-, 12-, 13- and 14-membered rings), the rest of the molecules bearing a common scaffold with all the asymmetric centres. The compound 63 was identified as a promising HDAC2 inhibitor, where small substituent on the aromatic ring of the benzoxole group can be tolerated. The compound induced histone acetylation (H3K9 and H4K12 staining) in primary mouse forebrain neurons. From lead compounds belonging to FR235222 obtained by screening and with an hydroxyketone side chain, Terracciano et al. [103] proposed a series of analogues synthesized by supported chemistry. These modifications gave a class II selective compound 64, unprecedented in this group of HDAC inhibitors. With two aromatic residues (Phe or Trp), cis and trans isomers can be observed. A carboxylic acid ZBG version was modelled in HDLP. Cyclic analogues were synthesized by Hoque et al. [104] The activities were measured with and without DTT (dithiothreitol) to force the disulphide bond cleavage in cells to the free thiol. DTT was required in the tests to obtain nanomolar potency. All compounds were almost not active on HDAC6 and have equivalent potency on HDAC1 and HDAC4. An illustrative example is compound 65. Alternative positioning of the disulphide cycle by amino acid shift lowered the activity. The same group designed mono- or bicyclic tetrapeptides where the disulphide bridge, when present, is replaced by a C2 bridge, the necessary thiol being positioned on another alkyl side chain. Compound 66 was found the most promising.