387850-60-4Relevant academic research and scientific papers
Discovery of tertiary amide derivatives incorporating benzothiazole moiety as anti-gastric cancer agents in vitro via inhibiting tubulin polymerization and activating the Hippo signaling pathway
Song, Jian,Gao, Qiu-Lei,Wu, Bo-Wen,Zhu, Ting,Cui, Xin-Xin,Jin, Cheng-Jun,Wang, Shu-Yu,Wang, Sheng-Hui,Fu, Dong-Jun,Liu, Hong-Min,Zhang, Sai-Yang,Zhang, Yan-Bing,Li, Yong-Chun
, (2020)
On the basis and continuation of our previous studies on anti-tubulin and anti-gastric cancer agents, novel tertiary amide derivatives incorporating benzothiazole moiety were synthesized and the antiproliferative activity was studied in vitro. Preliminary structure activity relationships (SARs) were explored according to the in vitro antiproliferative activity results. Some of compounds could significantly inhibit the proliferation of three cancer cells (HCT-116, MGC-803 and PC-3 cells) and compound F10 exhibited excellent antiproliferative activity against HCT-116 cells (IC50 = 0.182 μM), MGC-803 cells (IC50 = 0.035 μM), PC-3 cells(IC50 = 2.11 μM) and SGC-7901 cells (IC50 = 0.049 μM). Compound F10 effectively inhibited tubulin polymerization (IC50 = 1.9 μM) and bound to colchicine binding site of tubulin. Molecular docking results suggested compound F10 could bind tightly into the colchicine binding site of β-tubulin. Moreover, compound F10 could regulate the Hippo/YAP signaling pathway. Compound F10 activated Hippo signaling pathway from its very beginning MST1/2, as the result of Hippo cascade activation YAP were inhibited. And then it led to a decrease of c-Myc and Bcl-2 expression. Further molecular experiments showed that compound F10 arrested at G2/M phase, inhibited cell colony formatting and induced extrinsic and intrinsic apoptosis in MGC-803 and SGC-7901 cells. Collectively, compound F10 was the first to be reported as a new anticancer agent in vitro via inhibiting tubulin polymerization and activating the Hippo signaling pathway.
Synthesis and Biochemical Evaluation of 3-Phenoxy-1,4-diarylazetidin-2-ones as Tubulin-Targeting Antitumor Agents
Greene, Thomas F.,Wang, Shu,Greene, Lisa M.,Nathwani, Seema M.,Pollock, Jade K.,Malebari, Azizah M.,McCabe, Thomas,Twamley, Brendan,OBoyle, Niamh M.,Zisterer, Daniela M.,Meegan, Mary J.
, p. 90 - 113 (2016/01/29)
Structure-activity relationships for a series of 3-phenoxy-1,4-diarylazetidin-2-ones were investigated, leading to the discovery of a number of potent antiproliferative compounds, including trans-4-(3-hydroxy-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (78b) and trans-4-(3-amino-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (90b). X-ray crystallography studies indicate the potential importance of the torsional angle between the 1-phenyl A ring and 4-phenyl B ring for potent antiproliferative activity and that a trans configuration between the 3-phenoxy and 4-phenyl rings is generally optimal. These compounds displayed IC50 values of 38 and 19 nM, respectively, in MCF-7 breast cancer cells, inhibited the polymerization of isolated tubulin in vitro, disrupted the microtubular structure in MCF-7 cells as visualized by confocal microscopy, and caused G2/M arrest and apoptosis. Compound 90b possessed a mean GI50 value of 22 nM in the NCI60 cell line screen, displayed minimal cytotoxicity, and was shown to interact at the colchicine-binding site on β-tubulin. Phosphate and amino acid prodrugs of both 78b and 90b were synthesized, of which the alanine amide 102b retained potency and is a promising candidate for further clinical development.
Synthesis, biochemical and molecular modelling studies of antiproliferative azetidinones causing microtubule disruption and mitotic catastrophe
O'Boyle, Niamh M.,Carr, Miriam,Greene, Lisa M.,Keely, Niall O.,Knox, Andrew J.S.,McCabe, Thomas,Lloyd, David G.,Zisterer, Daniela M.,Meegan, Mary J.
experimental part, p. 4595 - 4607 (2011/11/04)
The structure-activity relationships of antiproliferative β-lactams, focusing on modifications at the 4-position of the β-lactam ring, is described. Synthesis of this series of compounds was achieved utilizing the Staudinger and Reformatsky reactions. The
Lead identification of conformationally restricted β-lactam type combretastatin analogues: Synthesis, antiproliferative activity and tubulin targeting effects
Carr, Miriam,Greene, Lisa M.,Knox, Andrew J.S.,Lloyd, David G.,Zisterer, Daniela M.,Meegan, Mary J.
experimental part, p. 5752 - 5766 (2011/02/23)
The synthesis and study of the structure-activity relationships of a series of rigid analogues of combretastatin A-4 are described which contain the 1,4-diaryl-2-azetidinone (β-lactam) ring system in place of the usual ethylene bridge present in the natur
