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Dimethyl 2,2′-[2,2′-(ethane-1,1-diyl)bis(1H-indole-3,2-diyl)]-diacetate: a small molecule capable of nano-scale assembly, inhibiting venous thrombosis and inducing no bleeding side effect

Authors Wang Y, Chen H, Zhang X, Gui L, Wu J, Feng Q, Peng S, Zhao M

Received 29 June 2018

Accepted for publication 11 October 2018

Published 22 November 2018 Volume 2018:13 Pages 7835—7844

DOI https://doi.org/10.2147/IJN.S178683

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 2

Editor who approved publication: Dr Mian Wang


Yaonan Wang,1,2 Haiyan Chen,1,2 Xiaoyi Zhang,1,2 Lin Gui,1,2 Jianhui Wu,1,2 Qiqi Feng,1,2 Shiqi Peng,1,2 Ming Zhao1–3

1Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China; 2Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China; 3Beijing Laboratory of Biomedical Materials, School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China

Background:
Due to the discovery that deep venous thrombosis (DVT) inhibitor is of chemotherapeutic importance, the nano-property of dimethyl 2,2'-[2,2'-(ethane-1,1-diyl)bis(1H-indole-3,2-diyl)]-diacetate (DEBIC), a recently reported antitumor agent, is worthy of characterization.
Materials and methods: One-pot reaction was used to prepare DEBIC. Electrospray Ionization (+/-)-Fourier Transform-Ion Cyclotron Resonance-Mass Spectrometer (ESI(+/-)-FT-ICR-MS), quadrupole Collision Induced Dissociation (qCID) and nuclear overhauser effect spectroscopy spectra were used to present the assembly of DEBIC. Transmission electron microscopy, scanning electron microscopy, atomic force microscopy and Faraday–Tyndall effect were used to visualize the nano-property of DEBIC. Rat models were used to evaluate DVT inhibition and the bleeding reaction of DEBIC.
Results: One-pot reaction can provide DEBIC in acceptable yield and high purity. In water, rat plasma and lyophilized powders of DEBIC existed as particles of small nano-size. In vivo DEBIC inhibited DVT in a dose-dependent manner. The minimal effective dose of DEBIC was 1.7 µmol/kg. Even the dose of 36 µmol/kg/day DEBIC did not induce bleeding side effect in DVT rats like in warfarin (0.82 µmol/kg/day).
Conclusion: DEBIC is a small molecule capable of nano-scale assembly, inhibiting venous thrombosis and inducing no bleeding side effect.

Keywords: nano-property, DVT inhibition, bleeding-reaction, tumor, thrombosis

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