Discovery of 5-naphthylidene-2,4-thiazolidinedione derivatives as selective HDAC8 inhibitors and evaluation of their cytotoxic effects in leukemic cell lines

Tilekar, Kalpana; Upadhyay, Neha; Jänsch, Niklas; Schweipert, Markus; Mrówka, Piotr; Meyer‐Almes, Franz‐Josef; Ramaa, C. S.

doi:10.1016/j.bioorg.2019.103522

Cited by 32 publications

(39 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Selective HDAC8 inhibitors have been found to cause dose-dependent selective apoptosis of CD34 + leukemic stem cells and progenitor cells [7]. Our recently reported selective HDAC8 inhibitor has found to induce apoptosis in CEM, lymphoid leukemia CEM cell line [23]. Also, the up-regulation of HDAC8 have been found to inhibit apoptosis in hepatocellular carcinoma, indicating a role of HDAC8 inhibitors in induction of apoptosis [51].…”

Section: Apoptosis Studies By Flow Cytometry-hdac8mentioning

confidence: 84%

“…Synthesis of final compounds P1-P25 proceeded via four steps. The first step in the synthesis of variously substituted amides was as previously reported [23,[34][35][36][37]. Substituted amines 1a-1y were stirred overnight with chloroacetyl chloride in the presence of potassium carbonate (K 2 CO 3 ) and dichloromethane (DCM) as a solvent to produce 2a-2y.…”

Section: Chemistrymentioning

confidence: 99%

“…In our recent attempt to develop specific HDAC8 inhibitors, we designed naphthylidene TZD derivatives, with naphthalene as the linker, wherein compound 3h (Fig. 2) inhibited HDAC8 potently (IC 50 -6.7 μM), though it was hypothesized that the TZD moiety would act as zinc binding group (ZBG), the docking analysis shown that the carboxylate group interacted with zinc, and TZD occupied the hydrophobic pocket [23]. Thus, based on our previously reported HDAC inhibitors, we designed novel HDAC8selective inhibitors.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Discovery of novel N-substituted thiazolidinediones (TZDs) as HDAC8 inhibitors: in-silico studies, synthesis, and biological evaluation

Upadhyay

Tilekar

Jänsch³

et al. 2020

Bioorganic Chemistry

Self Cite

View full text Add to dashboard Cite

Epigenetics plays a fundamental role in cancer progression, and developing agents that regulate epigenetics is crucial for cancer management. Among Class I and Class II HDACs, HDAC8 is one of the essential epigenetic players in cancer progression. Therefore, we designed, synthesized, purified, and structurally characterized novel compounds containing N-substituted TZD (P1-P25). Cell viability assay of all compounds on leukemic cell lines (CEM, K-562, and KCL22) showed the cytotoxic potential of P8, P9, P10, P12, P19, and P25. In-vitro screening of different HDACs isoforms revealed that P19 was the most potent and selective inhibitor for HDAC8 (IC 50-9.3 μM). Thermal shift analysis (TSA) confirmed the binding of P19 to HDAC8. In-vitro screening of all compounds on the transport activity of GLUT1, GLUT4, and GLUT5 indicated that P19 inhibited GLUT1 (IC 50-28.2 μM). P10 and P19 induced apoptotic cell death in CEM cells (55.19% and 60.97% respectively) and P19 was less cytotoxic on normal WBCs (CC 50-104.2 μM) and human fibroblasts (HS27) (CC 50-105.0 μM). Thus, among this novel series of TZD *

show abstract

Section: Apoptosis Studies By Flow Cytometry-hdac8mentioning

confidence: 84%

Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Discovery of novel N-substituted thiazolidinediones (TZDs) as HDAC8 inhibitors: in-silico studies, synthesis, and biological evaluation

Upadhyay

Tilekar

Jänsch³

et al. 2020

Bioorganic Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…In vitro cytotoxicity of the compounds was determined by MTT assay utilizing three cell lines, myeloid leukemia cell line K562, breast cancer cell line MCF7, and colon cancer cell line HT29, as described previously. [41,42] Each cell line was exposed to test compounds for 48 h. Paclitaxel and pioglitazone were used as standard references and untreated cells were used as negative control. Paclitaxel was selected as one of the standards as it is a clinically used anticancer agent, whereas pioglitazone was chosen as second standard as it is a PPARγ agonist containing the TZD group bio-isostere of pyrrolidine-2,5-dione.…”

Section: In Vitro Antiproliferative Effects Determined By Mtt Assaymentioning

confidence: 99%

“…The assay was conducted as described earlier. [41] Quickly, the cells were seeded at a density of around 5 × 10 3 cells/well in a flat 96-well plate and kept overnight at 37°C in 95 % humidity and supplied with 5 % CO 2 . Increasing concentrations of compounds were made in DMSO and added to the cells.…”

mentioning

confidence: 99%

Synthesis and Biological Evaluation of Pyrazoline and Pyrrolidine‐2,5‐dione Hybrids as Potential Antitumor Agents

et al. 2020

Self Cite

View full text Add to dashboard Cite

In search of novel and effective antitumor agents, pyrazolinesubstituted pyrrolidine-2,5-dione hybrids were designed, synthesized and evaluated in silico, in vitro and in vivo for anticancer efficacy. All the compounds exhibited remarkable cytotoxic effects in MCF7 and HT29 cells. The excellent antiproliferative activity toward MCF7 (IC 50 = 0.78 � 0.01 μM), HT29 (IC 50 = 0.92 � 0.15 μM) and K562 (IC 50 = 47.25 � 1.24 μM) cell lines, prompted us to further investigate the antitumor effects of the best compound S2 (1-(2-(3-(4-fluorophenyl)-5-(ptolyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxoethyl)pyrrolidine-2,5-dione). In cell-cycle analysis, S2 was found to disrupt the growth phases with increased cell population in G 1 /G 0 phase and decreased cell population in G 2 /M phase. The excellent in vitro effects were also supported by inhibition of anti-apoptotic protein Bcl-2. In vivo tumor regression studies of S2 in HT29 xenograft nude mice, exhibited equivalent and promising tumor regression with maximum TGI, 66 % (i. p. route) and 60 % (oral route) at 50 mg kg À 1 dose by both the routes, indicating oral bioavailability and antitumor efficacy. These findings advocate that hybridization of pyrazoline and pyrrolidine-2,5dioes holds promise for the development of more potent and less toxic anticancer agents.

show abstract

Design, synthesis, and molecular docking studies of thiazolidinediones as PPAR‐γ agonists and thymidylate synthase inhibitors

Nazreen

2021

Archiv der Pharmazie

View full text Add to dashboard Cite

New thiazolidine‐2,4‐dione hybrids were designed and synthesized as potential peroxisome proliferator‐activated receptor (PPAR)‐γ agonists and thymidylate synthase inhibitors. All the synthesized compounds follow Lipinski's and Veber's rules and possess the desired pharmacokinetics properties. The PPAR‐γ transactivation results displayed that compounds 12 (78.9%) and 11 (73.4%) were the most active compounds and they increased PPAR‐γ gene expression by 2.2‐ and 2.4‐fold, respectively. Compounds 12, 11, and 8 showed promising cytotoxicity, with IC50 values ranging from 1.4 to 4.5 μM against MCF‐7 cells and from 1.8 to 8.4 μM against HCT‐116 cells. Compounds 11 and 12 also inhibited thymidylate synthase with IC50 values of 5.1 and 3.2 μM, respectively, confirming their mode of action as thymidylate synthase inhibitors. Finally, molecular docking studies supported the in vitro biological activity results.

show abstract

Discovery of 5-naphthylidene-2,4-thiazolidinedione derivatives as selective HDAC8 inhibitors and evaluation of their cytotoxic effects in leukemic cell lines

Cited by 32 publications

References 52 publications

Discovery of novel N-substituted thiazolidinediones (TZDs) as HDAC8 inhibitors: in-silico studies, synthesis, and biological evaluation

Discovery of novel N-substituted thiazolidinediones (TZDs) as HDAC8 inhibitors: in-silico studies, synthesis, and biological evaluation

Synthesis and Biological Evaluation of Pyrazoline and Pyrrolidine‐2,5‐dione Hybrids as Potential Antitumor Agents

Design, synthesis, and molecular docking studies of thiazolidinediones as PPAR‐γ agonists and thymidylate synthase inhibitors

Contact Info

Product

Resources

About