Thiazolidinedione “Magic Bullets” Simultaneously Targeting PPARγ and HDACs: Design, Synthesis, and Investigations of their In Vitro and In Vivo Antitumor Effects

Abstract

Monotargeting anticancer agents suffer from resistance and target nonspecificity concerns, which can be tackled with a multitargeting approach. The combined treatment with HDAC inhibitors and PPARγ agonists has displayed potential antitumor effects. Based on these observations, this work involves design and synthesis of molecules that can simultaneously target PPARγ and HDAC. Several out of 25 compounds inhibited HDAC4, and six compounds acted as dual-targeting agents. Compound 7i was the most potent, with activity toward PPARγ EC 50 = 0.245 μM and HDAC4 IC 50 = 1.1 μM. Additionally, compounds 7c and 7i were cytotoxic to CCRF-CEM cells (CC 50 = 2.8 and 9.6 μM, respectively), induced apoptosis, and caused DNA fragmentation. Furthermore, compound 7c modulated the expression of c-Myc, cleaved caspase-3, and caused in vivo tumor regression in CCRF-CEM tumor xenografts. Thus, this study provides a basis for the rational design of dual/multitargeting agents that could be developed further as anticancer therapeutics.

Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases

“…Most recently, Tilekar et al [97] and Upadhyaya et al [99] designed compounds 32-34 (Figure 7) with the intention of using the TZD group as ZBG. Further investigations by Tilekar et al [160] with the objective of designing dual HDAC4, HDAC8, and PPARγ inhibitors led to exemplary compound 85 and 86, which differ in the substitution pattern of the naphthyl linker compared to 32-34, forming a more extended shape. In silico analysis supported a complexation via the TZD group in HDAC4.…”

“…Evaluation of 86 showed an IC 50 of 1.1 µM toward HDAC4, yielded cell apoptosis in several cancer cell lines, and caused DNA fragmentation in CEM cells with an IC 50 value of 9.6 µM. Additional evaluation of 85 in CCRF-CEM tumor xenografts led to significant tumor regression [160]. Follow-up studies by Tilekar et al [161] identified TZD derivatives with a pyridine linker, replacing the naphthyl group.…”

Mechanistic Insights into Binding of Ligands with Thiazolidinedione Warhead to Human Histone Deacetylase 4

“…TZD ligands act via activation of the gamma type of peroxisome proliferator-activated receptors (PPARγ) in the nucleus [16,17]. Furthermore, some TZD ligands are capable to inhibit aldose reductase (ALR2), protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase [18]. Very recently, we reported on TZD-containing ligands, which are capable to inhibit HDAC4 [18,19].…”

“…Furthermore, some TZD ligands are capable to inhibit aldose reductase (ALR2), protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase [18]. Very recently, we reported on TZD-containing ligands, which are capable to inhibit HDAC4 [18,19]. Enzyme activity assays of the HDAC family demonstrated activity of TZD ligands against HDAC4 or HDAC8 depending on the substitution pattern.…”

“…Furthermore, some TZD containing compounds exhibited also activity towards other protein families such as the glucose transporters GLUT1, GLUT4 and GLUT5 [20,21]. Importantly, some of the dual targeting TZD ligands show in vivo effects by drastically lowering the viability of K562 chronic myeloid leukaemia cell lines resulting in rapid cell death as well as anti-tumor effects in tumor xenograft models [18]. Although the activity of TZD ligands towards HDAC4 has been described very recently, their mode of action is still uncharted [18].…”