76106-73-5Relevant academic research and scientific papers
Design, Synthesis, and Biological Evaluation of Coupled Bioactive Scaffolds as Potential Anticancer Agents for Dual Targeting of Dihydrofolate Reductase and Thioredoxin Reductase
Ng, Hui-Li,Ma, Xiang,Chew, Eng-Hui,Chui, Wai-Keung
supporting information, p. 1734 - 1745 (2017/03/17)
The dihydrofolate reductase (DHFR) and thioredoxin reductase (TrxR) enzymes are involved in the process of tumor cell growth and survival. The 4,6-diamino-1,2-dihydro-1,3,5-triazine scaffold is well-established as a useful scaffold for DHFR inhibition, while chalcones have been reported to be inhibitors of TrxR. In this study, 15 novel compounds designed by the structural combination of the 4,6-diamino-1,2-dihydro-1,3,5-triazine and chalcone scaffolds via a diether linker were successfully synthesized and characterized. All of the compounds demonstrated dual inhibition against DHFR and TrxR when they were assessed by in vitro enzyme assays. The compounds also exhibited antiproliferative activity against the MCF-7 and HCT116 cells. The more potent analogs 14 and 15 were found to inhibit cellular DHFR and TrxR activities in HCT116 cells. Therefore, this study provided compelling evidence that 14 and 15 could exert their anticancer property via multitarget inhibition at the cellular level.
Structural requirements for activity of propafenone-type modulators in P- glycoprotein-mediated multidrug resistance
Chiba,Ecker,Schmid,Drach,Tell,Goldenberg,Gekeler
, p. 1122 - 1130 (2007/10/03)
The sodium channel blocker propafenone and a series of analogs have been identified as effective modulators of P-glyco-protein-mediated multidrug resistance in human tumor cells. A series of closely related structural homologues showed a highly significant correlation between lipophilicity and pharmacological effect. Reduction of the carbonyl group as well as conversion to a methylether led to a remarkable decrease in activity, whereby lipophilicity lost its predictive character as the main determinant for modulator potency. Similarly, the relative positioning of the acyl- and propanolamine side chains also influences activity, so the distance between carbonyl group and nitrogen atom seems important.
Design, synthesis, and kinetic evaluation of high-affinity FKBP ligands and the X-ray crystal structures of their complexes with FKBP 12
Holt, Dennis A.,Luengo, Juan I.,Yamashita, Dennis S.,Oh, Hye-Ja,Konialian, Arda L.,Yen, Hwa-Kwo,Rozamus, Leonard W.,Brandt, Martin,Bossard, Mary J.,Levy, Mark A.,Eggleston, Drake S.,Liang, Jun,Wayne Schultz,Stout, Thomas J.,Clardy, Jon
, p. 9925 - 9938 (2007/10/02)
The design and synthesis of high-affinity FKBP12 ligands is described. These compounds potently inhibit the cis-trans-peptidylprolyl isomerase (rotamase) activity catalyzed by FKBP12 with inhibition constants (Ki,app) as low as 1 nM, yet they possess remarkable structural simplicity relative to FK506 and rapamycin, from which they are conceptually derived. The atomic structures of three FKBP12-ligand complexes and of one unbound ligand were determined by X-ray crystallography and are compared to the FKBP12-FK506 and FKBP12-rapamycin complexes.
Intramolecular Alkylation of Phenols. Part 4. Base-catalysed Cyclisation of Phenolic Enones. Scope and Limitations
Murphy, William S.,Wattanasin, Sompong
, p. 1555 - 1566 (2007/10/02)
The phenolic enones (4), (5), (8), (9), and (13) cyclise readily under acidic conditions.However, neither these nor the thio-substituted phenols (11a), (13a), (14a), and (15a) closed under basic conditions.Involvement of unfavourable equilibria is disproved.Comparison is made with related successful cyclisations of the saturated ketone (38) and aldehyde (39).Preliminary results suggest that strict stereo-electronic requirements are necessary for enone ring closure and that these conditions are not met in base-catalysed 5-Endo- and 6-Endo-Trigonal ring closures of the phenols of general type (2; n=0 and n=1).
