English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Tools annual

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Presents the access of premium content as premium feature

Premium Content

Global: Zendy Plus annual

Global: Zendy Free Plan

A novel series of 3,6-diaryl-7 H -[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines were designed, synthesized and biologically evaluated as vinylogous CA-4 analogues, which involved a rigid [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine scaffold to fix the configuration of ( Z , E )-butadiene linker of A-ring and B-ring. Among these rigidly vinylogous CA-4 analogues, compounds  4d ,  5b ,  5i ,  6c ,  6e ,  6g ,  6i  and  6k  showed excellent antiproliferative activities against SGC-7901, A549 and HT-1080 cell lines with IC 50  values at the nanomolar level. Compound  6i  showed the most highly active antiproliferative activity against the three human cancer cell lines with an IC 50  values of 0.011–0.015 µM, which are comparable to those of CA-4 (IC 50  = 0.009–0.013 µM). Interestingly, SAR studies revealed that 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3-methoxyphenyl and 4-methoxyphenyl could replace the classic 3,4,5-trimethoxyphenyl in CA-4 structure and keep antiproliferative activity in this series of designed compounds. Tubulin polymerization experiments showed that  6i  could effectively inhibit tubulin polymerization, which was corresponded with CA-4, and immunostaining experiments suggested that  6i  significantly disrupted microtubule/tubulin dynamics. Furthermore,  6i  potently induced cell cycle arrest at G 2 /M phase in SGC-7901 cells. Competitive binding assays and docking studies suggested that compound  6i  binds to the tubulin perfectly at the colchicine binding site. Taken together, these results revealed that  6i  may become a promising lead compound for new anticancer drugs discovery.

Design, synthesis and structure-activity relationship of 3,6-diaryl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines as novel tubulin inhibitors