Discovery of ErbB/HDAC inhibitors by combining the core pharmacophores of HDAC inhibitor vorinostat and kinase inhibitors vandetanib,BMS-690514,neratinib,and TAK-285

By combining the core pharmacophores of HDAC inhibitor vorinostat and kinase inhibitors vandetanib,BMS-690514,neratinib,and TAK-285 with 1,2,3-triazole as linker,eight novel 6-substituted-4-aminoquinazolin derivatives were synthesized and characterized by -1H NMR,-（13）C NMR,and high resolution mass spectrometry.Their inhibitory activities against five enzymes（VEGFR2,HER2,EGFR,HDAC1,and HDAC6） and five cancer cell lines（A549,BT-474,A431,SK-BR-3,and NCI-H1975） were evaluated.The bioassay results show that the introduction of triazole linked vorinostat-like segment dramatically changed the selectivity profiles of newly synthetic compounds relative to vandetanib,BMS-690514,neratinib,and TAK-285.Among them,compound 6b exerted outstanding enzymatic and cellular activities through its simultaneous and synergistic inhibitions on multiple pathways,which might have the great potential to confer the better benefits than single-targeted inhibitors in cancer therapy.

Novel synthetic 9-benzyloxyacridine analogue as both tyrosine kinase and topoisomerase I inhibitor

Multi-target agents against tyrosine kinases and topoisomerases are potentially useful for the effective treatment of cancers.Discovery of new multi-target scaffolds are important for developing such agents. A series of five novel acridine analogues,LXL 1-5,were synthesized and their antiproliferative activity against HepC-2 cell lines were evaluated,among which the 9-benzyloxyacridine analogue,LXL-5, showed inhibitory activity against tyrosine kinases,VEGFR-2 and Src.The results of UV-visible absorption spectra and fluorescence emission spectra,as well as DNA topoisomerase I inhibition assay, indicated topoisomerase I inhibitory activity.Our study suggested that acridine scaffold,previously shown to have no multi-target kinase and topoisomerase inhibitory activity,might be potentially developed as a multi-target inhibitor of tyrosine kinases and topoisomerase I.

Discovery of novel dual inhibitors of VEGFR and PI3K kinases containing 2-ureidothiazole scaffold

A series of compounds possessing 2-（3-phenyl）ureidothiazol-4-formamide derivatives with a 2-ureidothiazole scaffold were designed and synthesized. Some compounds demonstrated inhibition of cell proliferation against both MDA-MB-231 and Hep G2 cell lines using Sorafenib as the positive control.Compounds 6i showed a good to moderate inhibition on VEGFR-2 and PI3Ka which was proved by further molecular docking study. This study suggests that compound 6i is a potential dual inhibitor of VEGFR-2 and PI3Ka and is applicable for further investigation.

Novel synthetic acridine-based derivatives as topoisomerase Ⅰ inhibitors

Novel DNA binding agents against topoisomerases are needed for effective treatment of cancers. A series of new acridine-based derivatives 7a-7d were synthesized and their antiproliferative activity against K562 and HepG-2 cell lines were evaluated. Compound 7c with pyridin-2-yl-methanamino group substituted at the C9 position of acridine showed good antitumor activity against both cell lines. The DNA-binding affinity of compound 7c was evaluated by UV-vis absorption spectra and fluorescence emission spectra. DNA topoisomerase I mediated relaxation of plasmid pBR322 DNA was also tested. Our results suggested that compound 7c with good antitumor activity and topoisomerase I inhibition activity can be developed as a prime candidate for further chemical optimization.