Design, synthesis, and preliminary bioactivity studies of substituted purine hydroxamic acid derivatives as novel histone deacetylase (HDAC) inhibitors

Abstract

Histone deacetylase (HDAC) is a clinically validated target for anti-tumor therapy. In order to increase HDAC inhibition and efficiency, we developed a series of novel substituted purine hydroxamic acids as potent HDAC inhibitors.

Discovery of Thieno[2,3-d]pyrimidine-Based Hydroxamic Acid Derivatives as Bromodomain-Containing Protein 4/Histone Deacetylase Dual Inhibitors Induce Autophagic Cell Death in Colorectal Carcinoma Cells

“…In the process of histone acetylation, two types of protein families are considered as potential drugable targets: bromodomain-containing protein 4 (BRD4) plays a role as a histone acetylated lysine “reader” and histone deacetylases (HDAC) act as an acetylated lysine “eraser” . BRD4 is a member of the bromodomain and extra-terminal (BET) protein family, and it acts as a central element in the recognition of histone or nonhistone substrates, which may regulate many molecular and cellular processes in epigenetic modification and gene transcription. − HDACs are actuators of deacetylation reactions of lysine residues, which have been recently deemed as potential therapeutic targets in human malignancies. − There are four main subgroups containing 11 isoforms of HDAC that have been recently categorized: HDACs 1, 2, 3, and 8 are class I; HDACs 4, 5, 7, and 9 are class IIa; HDACs 6 and 10 are class IIb; and HDAC11 is class IV. , In the past investigations on BRD4 and HDAC inhibition, a number of structurally diverse inhibitors have been reported, and some HDAC inhibitors were approved by the U.S. food and drug administration (FDA) or discovered in various clinical evaluation or preclinical stages for cancer therapy, for example, vorinostat, panobinostat, mocetinostat, trichostatin A, romidepsin, 9Z8, and so forth. In addition, some BRD4 inhibitors were evaluated in preclinical or clinical evaluation stages, such as JQ-1, I-BET151, I-BET726, I-BET762, XD14, RVX-208, PFI-1, ZL0420, Mivebresib (ABBV-075), Alobresib (GS-5829), PLX51107, BIC1, − and so forth (Figure ).…”

Oxazole-Bridged Combretastatin A-4 Derivatives with Tethered Hydroxamic Acids: Structure–Activity Relations of New Inhibitors of HDAC and/or Tubulin Function

“…The ZBGs should be connected to the cap by a hydrophobic linker, which is slim enough to fit in the tunnel between the active site and the capping groups. The latter are used for surface recognition and can induce sub-class selectivity [8,9]. Several HDACi such as vorinostat (SAHA, Figure 1), belinostat (PXD101, Figure 1) and panobinostat (LBH589) which were modelled on this pharmacophore template are already approved for the therapy of lymphoma and myeloma [10,11,12,13].…”

Design, synthesis and preliminary bioactivity evaluations of substituted quinoline hydroxamic acid derivatives as novel histone deacetylase (HDAC) inhibitors

“…The cap group enhances the affinity with the surface of HDACs and linker connects the ZBG and the cap group. Previously, we have used different heterocycles as the surface recognition cap group in the design of novel HDAC inhibitors, such as tetrahydroisoquinoline [7,8] , 1,3,4-thiadiazole [9,10] , 2-dihydrobenzo[d]isothiazol-3-one-1,1-dioxide [11] , indole [12,13] and purine [14] . In particular, the tetrahydroisoquinoline-bearing hydroxamic acid analogues showed potent HDAC inhibitory activity in in-vitro biological evaluations and intriguing growth inhibition in multiple tumor cell lines.…”