74631-59-7Relevant articles and documents
Design, synthesis, cytotoxicity screening and molecular docking of new 3-cyanopyridines as survivin inhibitors and apoptosis inducers
Sabour, Rehab,Harras, Marwa F.,Mehany, Ahmed B.M.
, (2020)
Recently, targeting survivin proved to be an attractive strategy for developing anticancer agents. Survivin overexpression is highly correlated with cancer aggressiveness, recurrence and resistance to chemotherapeutic treatment and radiotherapy. Additionally, survivin is overexpressed selectively in most cancer types with a very little expression in completely differentiated cells, which encouraged us to design and synthesize a novel series of 3-cyanopyridine derivatives targeting survivin. The newly synthesized compounds were evaluated for their cytotoxic activities against three cancer cell lines; PC-3, HepG2 and MDA-MB-231. Compounds 4a, 4b, 5c and 6c showed significant cytotoxic activities that were more potent than the reference drug, 5-FU. Hence, these compounds were selected to be further studied regarding their apoptotic potential in PC-3 cells. Interestingly, they decreased the level of Bcl-2 by 1.9–3.8 folds and increased the level of Bax by 6.1–8.8 folds compared to the control. Moreover, they elevated the level of active caspase-3 by 7.1–8.5 folds in comparison to the control. In order to estimate the cytotoxicity level of these compounds in non-tumorigenic cells, WI38 cells were treated with these compounds. They showed high IC50 values (148.57–193.64 μM), indicating selective cytotoxicity to the tumor cells, and much less toxic effect to the normal ones. Additional studies on the mechanism of 4a, the most active compound, revealed that it induced cell cycle arrest at the G2/M phase in addition to an increase in the percentage of pre-G1 apoptotic cells. Furthermore, western blotting was carried out using different concentrations of 4a. Results showed that 4a markedly suppressed survivin expression in PC-3 cells and caused a decrease in the caspase-7/cleaved caspase-7 ratio and in Bcl-2/Bax ratio, in addition to an increase in the level of the cleaved PARP. Finally, docking study of the most active compound in the active site (dimerization site) of survivin was in agreement with the in vitro survivin inhibitory activity.
Natural and Semisynthetic Chalcones as Dual FLT3 and Microtubule Polymerization Inhibitors
Malik, Haleema Sadia,Bilal, Aishah,Ullah, Rahim,Iqbal, Maheen,Khan, Sardraz,Ahmed, Ishtiaq,Krohn, Karsten,Saleem, Rahman Shah Zaib,Hussain, Hidayat,Faisal, Amir
, p. 3111 - 3121 (2020/11/02)
Activating mutations in FLT3 receptor tyrosine kinase are found in a third of acute myeloid leukemia (AML) patients and are associated with disease relapse and a poor prognosis. The majority of these mutations are internal tandem duplications (ITDs) in the juxtamembrane domain of FLT3, which have been validated as a therapeutic target. The clinical success of selective inhibitors targeting oncogenic FLT3, however, has been limited due to the acquisition of drug resistance. Herein the identification of a dual FLT3/microtubule polymerization inhibitor, chalcone 4 (2′-allyloxy-4,4′-dimethoxychalcone), is reported through screening of 15 related chalcones for differential antiproliferative activity in leukemia cell lines dependent on FLT3-ITD (MV-4-11) or BCR-ABL (K562) oncogenes and by subsequent screening for mitotic inducers in the HCT116 cell line. Three natural chalcones (1-3) were found to be differentially more potent toward the MV-4-11 (FLT3-ITD) cell line compared to the K562 (BCR-ABL) cell line. Notably, the new semisynthetic chalcone 4, which is a 2′-O-allyl analogue of the natural chalcone 3, was found to be more potent toward the FLT3-ITD+ cell line and inhibited FLT3 signaling in FLT3-dependent cells. An in vitro kinase assay confirmed that chalcone 4 directly inhibited FLT3. Moreover, chalcone 4 induced mitotic arrest in these cells and inhibited tubulin polymerization in both cellular and biochemical assays. Treatment of MV-4-11 cells with this inhibitor for 24 and 48 h resulted in apoptotic cell death. Finally, chalcone 4 was able to overcome TKD mutation-mediated acquired resistance to FLT3 inhibitors in a MOLM-13 cell line expressing FLT3-ITD with the D835Y mutation. Chalcone 4 is, therefore, a promising lead for the discovery of dual-target FLT3 inhibitors.
Inhibitors of Yellow Fever Virus replication based on 1,3,5-triphenyl-4,5-dihydropyrazole scaffold: Design, synthesis and antiviral evaluation
Fioravanti, Rossella,Desideri, Nicoletta,Carta, Antonio,Atzori, Elena Maria,Delogu, Ilenia,Collu, Gabriella,Loddo, Roberta
, p. 15 - 25 (2017/10/16)
By the antiviral screening of an in house library of pyrazoline compounds, 4-(3-(4-phenoxyphenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamide (5a) was identified as a promising hit compound for the development of anti- Yellow Fever Virus (YFV)
Studies in Potential Antifertility Agents: Part XXIV - Synthesis of 2,3-Disubstituted 4'-(&β-dialkylaminoethoxy)propiophenones
Rao, K. V. B.,Iyer, R. N.
, p. 54 - 58 (2007/10/02)
A number of 2,3-disubstituted 4'-(β-dialkylaminoethoxy)propiophenones (32-41) have been synthesized as the structural analogs of a potent antifertility agent erythro-2,3-diphenyl-4'-(β-pyrrolidinoethoxy)valerophenone (1).Compounds 34, 35, 38 and 40 show cent per cent activity at dose levels of 2.5, 10, 10, 10 and 1 mg/kg, respectively.The structure activity relationship has also been discussed.
