Discovery of DEBIC to correlate P-selectin inhibition and DNA intercalation in cancer therapy and complicated thrombosis.

Abstract

Arterial thrombosis is one of the major complications of cancer and can seriously worsen the prognosis of the patients. These clinical findings encouraged this paper to correlate P-selectin inhibition and DNA intercalation in cancer therapy and complicated thrombosis. By designing and docking 12 derivatives of bisindole- 2-carboxylic acids into the active sites of P-selectin and d(CGATCG)2 9 derivatives were assigned to receive in vivo anti-tumor assay, and finally provided dimethyl 2,2'-[(2,2'-(ethane-1,1-diyl)bis(1H-indole-3,2-diyl)]diacetate (DEBIC) to receive assays. DEBIC intercalated DNA and inhibited proliferation of tumor cells but not non-tumor cells. It slowed tumor growth of S180 mice at a dose of 0.36 μmol/kg, and slowed tumor growth of A549 bearing BABL/C mice at a dose of 8.9 μmol/kg. DEBIC was also found to inhibit arterial thrombosis by down regulating P-selectin effectively at a dose of 0.36 μmol/kg.

• Authors: Haiyan Chen, Wenjing Wang, Xiaoyi Zhang, Shan Liu, Yaonan Wang, Haimei Zhu, Jianhui Wu, Yuji Wang, Ming Zhao, Shiqi Peng
• Journal: Oncotarget (Oncotarget) Vol. 9 Issue 63 Pg. 32119-32133 (Aug 14 2018) ISSN: 1949-2553 [Electronic] United States
• PMID: 30181803 (Publication Type: Journal Article)