Bailing Xu

Synthesis and biological evaluation of novel quinazoline-derived human Pin1 inhibitors.

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 titled compounds was predicted using FlexX algorithm. The design and optimization of novel small molecule Pin1 inhibitors will be guided by the results of this report.

Synthesis and antiproliferative evaluation of novel benzoimidazole-contained oxazole-bridged analogs of combretastatin A-4

A series of novel oxazole-bridged analogs of combretastatin A-4 bearing a benzo[d]-imidazole as B ring were synthesized and evaluated for antiproliferative activities against five human cancer cell lines. Among all the synthesized compounds, the N-unsubstituted benzoimidazole analog 5 and the analogs 6b, 7a and 7b with a small hydrophobic group on nitrogen atom of benzoimidazole ring were identified as the most potent inhibitors of tumor cell growth with IC50 values at nanomolar levels (5, IC50=8.4 nM, HT29; 6b, 7a, 7b, IC50=9.6 nM, 3.8 nM, 3.0 nM, A549). In a murine H22 tumor xenograft model, compound 5 exhibited significant antitumor activity. The binding mode of compound 5 in the colchicine binding site of tubulin was probed.

Synthesis and biological evaluation of N4-(hetero)arylsulfonylquinoxalinones as HIV-1 reverse transcriptase inhibitors.

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 on the discovery of more potent non-nucleoside reverse-transcriptase inhibitors.

Discovery of 1-substituted benzyl-quinazoline-2,4(1H,3H)-dione derivatives as novel poly(ADP-ribose)polymerase-1 inhibitors

Poly(ADP-ribose)polymerase-1 (PARP-1) has emerged as a promising anticancer drug target due to its key role in the DNA repair process. In this work, a novel series of 1-benzyl-quinazoline-2,4(1H,3H)-dione derivatives were designed and synthesized as human PARP-1 inhibitors, structure-activity relationships were conducted and led to a number of potent PARP-1 inhibitors having IC50 values of single or double digit nanomolar level. Compound 7j was a potent PARP-1 and PARP-2 inhibitor and it could selectively kill the breast cancer cells MX-1 and MDA-MB-468 with mutated BRCA1/2 and PTEN, respectively, in comparison with homologous recombination proficient cell types such as breast cancer cells MDA-MB-231. In addition, compound 7j displayed the strongest potentiation effect on temozolomide in MX-1 cells (PF50=3.77) in this series of PARP-1 inhibitors.

Synthesis and biological evaluation of novel human Pin1 inhibitors with benzophenone skeleton.

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 was predicted using FlexX algorithm. The results of this research will shed light on further design and optimization of novel small molecule Pin1 inhibitors.

Design, synthesis and biological evaluation of 7-nitro-1H-indole-2-carboxylic acid derivatives as allosteric inhibitors of fructose-1,6-bisphosphatase

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 on the further design and optimization of novel small molecules as FBPase inhibitors.

Synthesis and Pin1 inhibitory activity of thiazole derivatives

Pin1 (Protein interacting with NIMA1) is a peptidyl prolyl cis-trans isomerase (PPIase) which specifically catalyze the conformational conversion of the amide bond of pSer/Thr-Pro motifs in its substrate proteins and is a novel promising anticancer target. A series of new thiazole derivatives were designed and synthesized, and their inhibitory activities were measured against human Pin1 using a protease-coupled enzyme assay. Of all the tested compounds, a number of thiazole derivatives bearing an oxalic acid group at 4-position were found to be potent Pin1 inhibitors with IC50 values at low micromolar level. The detailed structure-activity relationships were analyzed and the binding features of compound 10b (IC50 5.38μM) was predicted using CDOCKER program. The results of this research would provide informative guidance for further optimizing thiazole derivatives as potent Pin1 inhibitors.

A novel derivative of quinazoline, WYK431 induces G2/M phase arrest and apoptosis in human gastric cancer BGC823 cells through the PI3K/Akt pathway

WYK431, a novel synthetic quinazoline derivative, showing potent inhibition of proliferation activity against a broad spectrum of human cancer cell lines. We investigated the anticancer effects of WYK431 on BGC823 cells both in vitro and in vivo. The results showed that WYK431 inhibited proliferation, arrested the cell cycle at the G(2)/M phase, which was related to CDK1 and CDC25C, and induced apoptosis associated with activation of caspase-3 and caspase-9 rather than caspase-8 in BGC823 cells. Treatment of BGC823 cells with WYK431 resulted in upregulation of Bax, release of cytochrome c from the mitochondria to the cytosol and disruption of mitochondrial membrane potential. Western blot analysis showed that WYK431 downregulated the levels of the PI3K/Akt signaling pathway. Moreover, WYK431 effectively suppressed tumor growth in xenograft models in BALB/c athymic nude mice without major side action. TUNEL analysis showed that WYK431 induced BGC823 cell apoptosis in vivo. Collectively, WYK431 is a novel small molecule agent which inhibits BGC823 cell proliferation inducing G(2)/M phase arrest and apoptosis via the mitochondrial apoptotic pathway. To assess its potential as a promising anticancer agent requires further investigation.

Discovery of novel indole derivatives as allosteric inhibitors of fructose-1,6-bisphosphatase

A series of novel indole derivatives was designed and synthesized as inhibitors of fructose-1,6-bisphosphatase (FBPase). The most potent compound 14c was identified with an IC50 value of 0.10 μM by testing the inhibitory activity against recombinant human FBPase. The structure-activity relationships were investigated on the substitution at 4- and 5-position of the indole scaffold. The binding interactions of the title compounds at AMP binding site of FBPase were predicted using CDOCKER algorithm.

Poly (ADP-ribose) polymerases inhibitor, Zj6413, as a potential therapeutic agent against breast cancer

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 PARPs, such as PARP2, may lead to undesired consequences. Here, we demonstrated the design and development of the Zj6413 as a potent and selective PARP1 catalytic inhibitor. It trapped PARP1/2 at damaged sites of DNA. As expected, the Zj6413 showed notable anti-tumor activity against breast cancer gene (BRCA) deficient triple negative breast cancers (TNBCs). Zj6413 treated breast cancers (BCs) showed an elevated level of DNA damage evidenced by the accumulation of γ-H2AX foci and DNA damaged related proteins. Zj6413 also induced G2/M arrest and cell death in the MX-1, MDA-MB-453 BC cells, exerted chemo-sensitizing effect on BRCA proficient cancer cells and potentiated Temozolomide (TMZ)s cytotoxicity in MX-1 xenograft tumors mice. In conclusion, our study provided evidence that a new PARP inhibitor strongly inhibited the catalytic activity of PARPs, trapped them on nicked DNA and damaged the cancer cells, eventually inhibiting the growth of breast tumor cells in vitro and in vivo.