New microtubule polymerization inhibitors comprising a nitrooxymethylphenyl group

作者：Kawaratani Yasuyuki; Harada Tomohiko; Hirata Yoshiyuki; Nagaoka Yasuo; Tanimura Susumu; Shibano Makio; Taniguchi Masahiko; Yasuda Masahide; Baba Kimiye; Uesato Shinichi^*

来源：Bioorganic & Medicinal Chemistry, 2011, 19(13): 3995-4003.

DOI：10.1016/j.bmc.2011.05.031

• Tubulin polymerization inhibitor
• Nitrooxymethylphenyl group
• M phase regulator
• Phospho-histone H3
• HCT116 xenograft

We have designed cancer antiproliferative compounds, starting from aniline or phenol derivative, which comprise one or two nitrooxymethylphenyl groups as do the hybrid drugs NCX4040 and NCX530. Compound 2a with p-nitrooxymethylbenzoyl-oxy and -amino groups as well as 8a with a p-nitrooxymethylbenzoylamino group showed more promising effects than NCX4040 against human colon and breast cancer cells. Since 2a and 8a, but not NCX4040, arrested human colon carcinoma HCT116 cells in the M phase, the former two compounds may inhibit cell growth differently from NCX4040. Merged images of immunofluorescence-stained a-tubulin and Hoechst-stained nuclei in human fibrosarcoma HT1080 cells showed that 2a and 8a disrupted microtubule formation just as did vincristine, the tubulin polymerization inhibitor. In experiments in vivo, the intraperitoneal administration of 8a at 80 mg/kg/day reduced the growth of HCT116 xenografts in nude mice to T/C 55%.

• 出版日期2011-7-1