22504-02-5Relevant academic research and scientific papers
Thiazolidinedione "magic Bullets" Simultaneously Targeting PPARγand HDACs: Design, Synthesis, and Investigations of their in Vitro and in Vivo Antitumor Effects
Tilekar, Kalpana,Hess, Jessica D.,Upadhyay, Neha,Bianco, Alessandra Lo,Schweipert, Markus,Laghezza, Antonio,Loiodice, Fulvio,Meyer-Almes, Franz-Josef,Aguilera, Renato J.,Lavecchia, Antonio,Ramaa
, p. 6949 - 6971 (2021/06/25)
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 PPARγagonists has displayed potential antitumor effects. Based on these observations, this work involves design and synthesis of molecules that can simultaneously target PPARγand 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 PPARγEC50 = 0.245 μM and HDAC4 IC50 = 1.1 μM. Additionally, compounds 7c and 7i were cytotoxic to CCRF-CEM cells (CC50 = 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.
Discovery of novel N-substituted thiazolidinediones (TZDs) as HDAC8 inhibitors: in-silico studies, synthesis, and biological evaluation
Aguilera, Renato J.,Choe, Jun-yong,Henze Macias, Luca,Hess, Jessica D.,Meyer-Almes, Franz-Josef,Mrowka, Piotr,Ramaa, C. S.,Schweipert, Markus,Tilekar, Kalpana,Upadhyay, Neha,J?nsch, Niklas
, (2020/05/22)
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, K562, 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 (IC50 – 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 (IC50 – 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 (CC50 – 104.2 μM) and human fibroblasts (HS27) (CC50 – 105.0 μM). Thus, among this novel series of TZD derivatives, compound P19 was most promising HDAC8 inhibitor and cytotoxic on leukemic cells. Thus, P19 could serve as a lead for further development of optimized molecules with enhanced selectivity and potency.
Inhibition of dengue virus and west Nile virus proteases by click chemistry-derived benz[d]isothiazol-3(2H)-one derivatives
Tiew, Kok-Chuan,Dou, Dengfeng,Teramoto, Tadahisa,Lai, Huiguo,Alliston, Kevin R.,Lushington, Gerald H.,Padmanabhan,Groutas, William C.
experimental part, p. 1213 - 1221 (2012/03/26)
Two click chemistry-derived focused libraries based on the benz[d]isothiazol-3(2H)-one scaffold were synthesized and screened against Dengue virus and West Nile virus NS2B-NS3 proteases. Several compounds (4l, 7j-n) displayed noteworthy inhibitory activity toward Dengue virus NS2B-NS3 protease in the absence and presence of added detergent. These compounds could potentially serve as a launching pad for a hit-to-lead optimization campaign.
Novel aryl ether derivatives as antiinflammatory and analgesics
Rashmi,Rao, Gopal Krishna,Devi, Kshama,Shivananda,Swetha,Ga, Suneetha
, p. 1401 - 1407 (2012/06/29)
The diaryl ether moieties have attracted considerable attention of medicinal chemists as they are endowed with a wide range of diverse biological activities. The present study involves synthesis, characterization of some new aryl ethers and evaluation of their antiinflammatory and analgesic activity. A series of new aryl ether derivatives [4(a-h), 5] were prepared by Ullmann's ether condensation. The structures of new compounds are supported by their IR, 1H NMR and Mass spectra. The new derivatives were evaluated for their antiinflammatory and analgesic activity. Among the tested, compound 3 has shown better antiinflammatory and analgesic activity.
