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The discovery of small molecule inhibitors of cytotoxicity induced by amyloid-beta (Abeta) oligomers, either applied extracellularly or accumulated intraneuronally, is an important goal of drug development for Alzheimer's disease (AD), but has been limited by the lack of efficient screening methods. Here we describe our approach using two cell-based(More)
Stereoisomeric cis and trans substrate analogues for Pin1 were designed and synthesized. The central phosphoSer-Pro core of the Pin1 substrate was replaced by cis and trans amide isosteres in Ac-Phe-Phe-pSer-Psi[(Z and E)CH=C]-Pro-Arg-NH(2), 1 and 2, peptidomimetics. They were synthesized on solid phase in 17% yield for the cis analogue 1, and 16% yield for(More)
Pin1 is a modular enzyme that accelerates the cis-trans isomerization of phosphorylated-Ser/Thr-Pro (pS/T-P) motifs found in numerous signaling proteins regulating cell growth and neuronal survival. We have used NMR to investigate the interaction of Pin1 with three related ligands that include a pS-P substrate peptide, and two pS-P substrate analogue(More)
A series of novel 2,4-disubstituted quinazoline derivatives were prepared and their inhibitory activities on hPin1 were evaluated. Of all the synthesized compounds, eight compounds displayed inhibitory activities with IC(50) value at the level of 10(-6)mol/L. Preliminary structure-activity relationships were analyzed in details and the binding mode of the(More)
A series of novel N(4)-(hetero)arylsulfonylquinoxalinone derivatives were prepared in a straight and efficient way. Of all the synthesized compounds, five compounds exhibited potent anti-HIV-1 replication activities with IC(50) value at the level of 10(-7) mol/L. Preliminary structure-activity relationships were studied in details and that will shed light(More)
Novel 1H-benzo[d]immidazole-4-carboxamide derivatives bearing five-membered or six-membered N-heterocyclic moieties at the 2-position were designed and synthesized as PARP-1 inhibitors. Structure-activity relationships were conducted and led to a number of potent PARP-1 inhibitors having IC50 values in the single or double digit nanomolar level. Some potent(More)
A series of novel indole derivatives was synthesized as inhibitors of fructose-1,6-bisphosphatase (FBPase). Extensive structure-activity relationships were conducted and led to a potent FBPase inhibitor 3.9 with an IC₅₀ of 0.99 μM. The binding mode of this series of indoles was predicted using CDOCKER algorithm. The results of this research will shed light(More)
A series of novel benzophenone derivatives were prepared and their inhibitory activities were evaluated on hPin1. Of all the synthesized compounds, the most active compound displayed inhibitory activities with an IC(50) value of 5.99 μmol/L. Preliminary structure-activity relationships were analyzed in details and the binding mode of the titled compounds(More)
The PARP-2 selective inhibitor is important for clarifying specific roles of PARP-2 in the pathophysiological process and developing desired drugs with reduced off-target side effects. In this work, a series of novel quinazoline-2,4(1H,3H)-dione derivatives was designed and synthesized to explore isoform selective PARP inhibitors. As a result, compound 11a(More)
Poly (ADP-ribose) polymerases (PARPs) facilitate repairing of cancer cell DNA damage as a mean to promote cancer proliferation and metastasis. Inhibitors of PARPs which interfering DNA repair, in context of defects in other DNA repair mechanisms, can thus be potentially exploited to inhibit or even kill cancer cells. However, nondiscriminatory inhibition of(More)