5-Chloro-6-[2,6-difluoro-4-[3-(methylamino)propoxy]phenyl]-N-((1S)-2,2,2-trifluoro-1-methylethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine

Biological Activity

cevipabulin (tti-237) is a new anti-microtubule agent [1][2][3][4].microtubules are a component of the cytoskeleton that participate in many crucial cellular functions, include maintaining the structure of the cell, forming the cytoskeleton and chromosome separation.cevipabulin (tti-237) is a new anti-microtubule agent with antitumor activity. in colo 205 cells, tti-237 inhibited cell proliferation with ic50 value of 31 nm [1]. at low ratios of tti-237: tubulin heterodimer (about 1:30), tti-237 increased depolymerization kinetics in response to low temperature, but stabilized the aggregates at high ratios (about 1:4). tti-237 inhibited the exchange of [3h]gtp at the exchangeable nucleotide site of the tubulin heterodimer [2]. cevipabulin (tti-237) increased tubulin polymerization. cevipabulin was stable and water-soluble, and could be administered i.v. or p.o. in saline [3]. tti-237 inhibited the binding of [3h]vinblastine to tubulin, but significantly increased turbidity development that more closely resembled the effect of docetaxel. in hela cells, tti-237 (34 nmol/l) induced multiple spindle poles and multi-nuclear cells. at 20-40 nmol/l, tti-237 produced sub-g1 nuclei, while at > 50 nmol/l, tti-237 induced g2-m block.in athymic mice bearing lovo human colon adenocarcinoma, tti-237 exhibited good antitumor activity in a dose-dependent way. in mice bearing u87-mg human glioblastoma, tti-237 (25 mg/kg) given both i.v. and p.o. were equally effective [4].

References

[1]. zhang n, ayral-kaloustian s, nguyen t, et al. 2-cyanoaminopyrimidines as a class of antitumor agents that promote tubulin polymerization. bioorg med chem lett, 2007, 17(11): 3003-3005.
[2]. beyer cf, zhang n, hernandez r, et al. the microtubule-active antitumor compound tti-237 has both paclitaxel-like and vincristine-like properties. cancer chemother pharmacol, 2009, 64(4): 681-689.
[3]. ayral-kaloustian s, zhang n, beyer c. cevipabulin (tti-237): preclinical and clinical results for a novel antimicrotubule agent. methods find exp clin pharmacol, 2009, 31(7): 443-447.
[4]. beyer cf, zhang n, hernandez r, et al. tti-237: a novel microtubule-active compound with in vivo antitumor activity. cancer res, 2008, 68(7): 2292-2300.