Synthesis, Antiproliferative Activity, and Effect on Carcinoma A549 Cell Microtubules of New Tubuloclustin Analogs


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Combretastatin analogs of the antitumor agent tubuloclustin {N-[7-(adamant-2-yloxy)-7-oxoheptanoyl]-Ndeacetylcolchicine} were prepared via esterification of combretastatin by monoesters of pimelic or adipic acid with adamantan-2-ol or (adamantan-1-yl)methanol. These conjugates were stable and cytotoxic to human lung carcinoma A549 cells (EC50 ≈ 50 – 70 nM) and caused depolymerization of microtubules and slight clustering of tubulin. Tubuloclustin analogs with shortened linkers were prepared via amidation by N-deacetylcolchicine of monoesters of adipic or succinic acids with adamantan-1-ol or (adamantan-1-yl)methanol. The conjugate N-[6-(adamantyl)-6-oxohexanoyl]-N-deacetylcolchicine was more active (EC50 ≈ 4 nM) than tubuloclustin and promoted strong tubulin clusterization. All compounds induced apoptosis of A549 cells. Tests in vivo of N-[6-(adamantyl)-6-oxoheaxnoyl]-N-deacetylcolchicine on carcinoma A549 experimental models were concluded to be promising.

作者简介

N. Zefirov

M. V. Lomonosov Moscow State University; Institute of Physiologically Active Compounds, Russian Academy of Sciences

Email: olgaz@org.chem.msu.ru
俄罗斯联邦, Moscow, 119991; Chernogolovka, Moscow Oblast, 142432

Yu. Evteeva

M. V. Lomonosov Moscow State University

Email: olgaz@org.chem.msu.ru
俄罗斯联邦, Moscow, 119991

A. Fatkulin

M. V. Lomonosov Moscow State University

Email: olgaz@org.chem.msu.ru
俄罗斯联邦, Moscow, 119991

S. Schulz

Institute of Biological Sciences, University of Rostock

Email: olgaz@org.chem.msu.ru
德国, Rostock

S. Kuznetsov

Institute of Biological Sciences, University of Rostock

Email: olgaz@org.chem.msu.ru
德国, Rostock

O. Zefirova

M. V. Lomonosov Moscow State University; Institute of Physiologically Active Compounds, Russian Academy of Sciences

编辑信件的主要联系方式.
Email: olgaz@org.chem.msu.ru
俄罗斯联邦, Moscow, 119991; Chernogolovka, Moscow Oblast, 142432

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