Development of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates containing piperazine as inhibitors of PI3Kα.

PI3K pathway has been heavily studied and is one of the most potential targets for various cancer treatment. Herein, we designed and synthesized a series of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates contained piperazine based on our previous research. They were evaluated for their PI3Kα wild-type and H1047R mutant inhibitory activities and anticancer effects in vitro. Most of these compounds displayed the potential antiproliferative activities against four cancer cell lines (HCT-116, A549, Huh7 and HL60). Among them, Compound 4p revealed the remarkable antiproliferative activity and was selected for further biological evaluation. Compound 4p displayed the potent activity against both PI3Kα wild-type and H1047R mutant, and a certain degree of selectivity for PI3Kα over PI3Kß, γ and δ, and meanwhile it can remarkable down-regulate the phosphorylation of Akt. In addition, compound 4p was found to induce cell apoptosis via upregulation of Bax and cleaved-caspase 3/9, and downregulation of Bcl-2. The above results suggested that compound 4p could be considered as a promising PI3Kα inhibitor.

Development of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates bearing sulfonylpiperazine as antitumor inhibitors targeting PI3Kα.

PI3K signal pathway plays a vital role in cellular functions and becomes an attractive approach for cancer therapy. Herein, a new series of novel chromeno[4,3-c]pyrazol-4(2H)-one derivatives bearing sulfonylpiperazine based on the PI3K inhibitors and our previous research. They were screened for their PI3K inhibitory activities and anticancer effects in vitro. Biological studies indicated that compound 7m revealed the remarkable antiproliferative activity (IC50 ranging from 0.03 to 0.09 µM) against four cancer cell lines (A549, Huh7, HL60 and HCT-116). Besides, compound 7m displayed a certain selective for PI3Kα (IC50 = 0.009 µM) over PI3Kß, γ and δ, and meanwhile, it can remarkable decreased the expression level of p-Akt (Ser473) and p-S6K. In addition, compound 7m could not only induce HCT-116 cell arrest at G1 phase in a dose-dependent manner, but also induce cell apoptosis via upregulation of Bax and cleaved-caspase 3/9, and downregulation of Bcl-2. Besides, compound 7m can remarkably inhibit the growth of tumor in vivo. The above results suggested that compound 7m could be considered as a promising PI3Kα inhibitor.

Design, synthesis and biological evaluation of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates containing sulfonamido as potential PI3Kα inhibitors.

A series of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates contained sulfonamido were designed and synthesized, and their anticancer effects in vitro was evaluated to develop some new PI3Kα inhibitors. Most of desired compounds exhibited the better antiproliferative activities against four cancer cell lines than that of LY294002. Out of them, compound 4o displayed the potent antiproliferative activity and high selectivity against the PI3Kα protein and it can induce apoptosis of HCT116 in a dose-dependent manner. Western blot assay indicated that compound 4o obviously down-regulated expression of p-Akt (S473). Molecular docking was performed to clarify the possible binding mode between compound 4o and PI3Kα. All these results indicated that compound 4o could be a potential inhibitor of PI3Kα.

Discovery of Chromeno[4,3-c]pyrazol-4(2H)-one Containing Carbonyl or Oxime Derivatives as Potential, Selective Inhibitors PI3Kα.

A series of novel chromeno[4,3-c]pyrazol-4(2H)-one containing carbonyl or oxime derivatives (4a-n, 5a-n) have been synthesized and evaluated their biological activities as phosphatidyl inositol 3-kinase (PI3K) inhibitors. Out of them, compound 5l showed the most potent antiproliferative activities against HCT-116 with IC50 of 0.10 µM in vitro, and exhibited the most potent activity for PI3Kα with the value of 0.012 µM. Docking simulation of 5l into PI3Kα active site were performed to determine the probable binding model, and it indicated that compound 5l could be optimized as a potential inhibitor of PI3Kα in the further study.

Discovery of new 4-alkoxyquinazoline-based derivatives as potent VEGFR2 inhibitors.

VEGFR2 has been proved to play a major role in the regulation of tumor angiogenesis. Twenty-one 4-alkoxyquinazoline-based derivatives have been designed and synthesized as vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors, and their biological activities were evaluated. Among these compounds, compound 3h exhibited the most potent inhibitory activities against VEGFR2 tyrosine kinase and cell proliferation, with the IC50 values of 2.89 nm (for VEGFR2) and 0.25 µm (for MCF-7), which were comparable with the control compound. Docking simulation was performed to position compound 3h into the 4ASE active site, and the result showed that compound 3h could bind well at the 4ASE active site.

6,7-Dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives as selective inhibitors of PI3Kα.

Twenty eight 6,7-dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives were synthesized and evaluated their biological activities as PI3K inhibitors. Biological evaluation against four human tumor cell lines revealed that most target compounds showed impressively better antiproliferative activities than that of LY294002. Among these compounds, compound 25 exhibited the most potent and selective activity for PI3Kα, with the IC50 value of 0.016µM, an approximately 30-fold increase in comparison with LY294002, it also has an increased potency of approximately 11-fold for PI3Kß. It indicated the potential of developing 6,7-dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives as the new PI3Kα selective inhibitors for tumor treatment.

Discovery and synthesis of a novel series of potent, selective inhibitors of the PI3Kα: 2-alkyl-chromeno[4,3-c]pyrazol-4(2H)-one derivatives.

A series of novel 2-alkyl-chromeno[4,3-c]pyrazol-4(2H)-one derivatives were synthesized and evaluated for their biological activities as PI3K inhibitors. In vitro biological evaluation against four human tumor cell lines revealed that most target compounds showed impressively better antiproliferative activities than that of LY294002. Among these compounds, compound 4l exhibited the most potent and selective activity for PI3Kα, with the value of 0.014 µM, an approximately 30-fold increase in comparison with LY294002. Docking simulation was performed to position compound 4l into the PI3Kα active site and the result showed that compound 4l could bind well at the PI3Kα active site and it indicated that compound 4l could be a potential inhibitor of PI3Kα.

Design, synthesis and biological evaluation of (E)-3-(3,4-dihydroxyphenyl)acrylylpiperazine derivatives as a new class of tubulin polymerization inhibitors.

A series of novel (E)-3-(3,4-dihydroxyphenyl)acrylylpiperazine derivatives had been synthesized and evaluated their biological activities as potential tubulin polymerization inhibitors. Among these compounds, compound 3q exhibited potent antiproliferative activities against three cancer cell lines in vitro, and antitubulin polymerization activity with IC50 of 0.92 µM, which was superior to that of colchicine (IC50=1.34 µM). Docking simulation was performed to insert compound 3q into the crystal structure of tubulin at colchicine binding site to determine the probable binding model. These results suggested that compound 3q may be a promising antitubulin agent for the potential treatment of cancer.