1.Application of an ultra-performance liquid chromatography method with tandem mass spectrometry to pharmacokinetics, tissue distribution and excretion in the study of DAT-230, a novel tubulin-binding agent candidate, in rats.
Tang J1, Zhang C1, Sun J2, Zhao L1, Zhang W2, Liu Z1, Sun L3, Chen X4. J Pharm Biomed Anal. 2015 Jun 10;110:49-57. doi: 10.1016/j.jpba.2014.09.025. Epub 2014 Sep 28.
A rapid, sensitive and high-throughput ultra-performance liquid chromatography method with tandem mass spectrometry (UPLC-MS/MS) has been developed for the determination of DAT-230 in rat plasma, urine, feces and tissues (heart, liver, spleen, lung, kidney, stomach, intestine and brain). The biological samples were prepared by protein precipitation, and separation was achieved on an ACQUITY™ UPLC BEH C18 column (50 mm × 2.1mm, 1.7 μm) with a mobile phase that consisted of methanol - 0.2% formic acid water (80:20, v/v) at a flow rate of 0.2 mL/min. The MS/MS ion transitions were monitored at m/z 372.17 → 357.17 for DAT-230 and m/z 406.08 → 345.16 for COH-203 (internal standard, IS). The calibration curve was linear in the range of 0.1-5200 ng/mL for all biological matrices (r(2) ≥ 0.996), and it had the same value for the lower limit of quantification. The validated method was successfully applied to the pharmacokinetics, tissue distribution and excretion study after intravenous administration of a 5mg/kg dose of DAT-230 to healthy Sprague-Dawley rats.
2.DAT-230, a Novel Microtubule Inhibitor, Induced Aberrant Mitosis and Apoptosis in SGC-7901 Cells.
Qiao F1, Zuo D, Wang H, Li Z, Qi H, Zhang W, Wu Y. Biol Pharm Bull. 2013;36(2):193-201.
2-Methoxy-5-(2-(3,4,5-trimethoxyphenyl)thiophen-3-yl) aniline (DAT-230) is a novel synthesized compound of combretastatin-A-4 derivative with more stability. The present study is to investigate its anti-tumor activity and molecular mechanisms in human gastric adenocarcinoma SGC-7901 cells. DAT-230 inhibited SGC-7901 cells growth. The treatment of DAT-230 resulted in microtubule de-polymerization and G2/M phase arrest. Besides the accumulation and translocation of Cyclin B1, reduction of p-14/15-cdc2 and mitosis delay denoted the Cyclin B1-cdc2 complex active and M phase arrest in SGC-7901 cells treated with DAT-230. Mitochondria pathway participated in apoptosis after G2/M arrest in SGC-7901 cells treated with DAT-230, which was characterized by DNA fragmentation, cleavage of poly(ADP-ribose) polymerase (PARP), activation of caspase-3 and caspase-9, changes of Bcl-2 and Bax expression, decrease of mitochondrial membrane potential and release of cytochrome c from mitochondria.
3.DAT-230, a novel microtubule inhibitor, exhibits potent anti-tumor activity by inducing G2/M phase arrest, apoptosis in vitro and perfusion decrease in vivo to HT-1080.
Qiao F1, Zuo D, Shen X, Qi H, Wang H, Zhang W, Wu Y. Cancer Chemother Pharmacol. 2012 Aug;70(2):259-70. doi: 10.1007/s00280-012-1907-x. Epub 2012 Jun 30.
PURPOSE: The anti-mitotic agent, combretastatin A-4 (CA-4), is the lead compound of a new class of anti-cancer drugs that target tumor vasculature. 2-Methoxy-5-(2-(3, 4, 5-trimethoxyphenyl) thiophen-3-yl) aniline (DAT-230) is a structurally novel CA-4 analog with more stability. We investigated its anti-tumor activity and mechanisms in vitro and in vivo for the first time.