Synthesis, Antiproliferative Activity, and Effect on Carcinoma A549 Cell Microtubules of New Tubuloclustin Analogs
- Authors: Zefirov N.A.1,2, Evteeva Y.A.1, Fatkulin A.R.1, Schulz S.3, Kuznetsov S.A.3, Zefirova O.N.1,2
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Affiliations:
- M. V. Lomonosov Moscow State University
- Institute of Physiologically Active Compounds, Russian Academy of Sciences
- Institute of Biological Sciences, University of Rostock
- Issue: Vol 53, No 5 (2019)
- Pages: 423-428
- Section: Article
- URL: https://journals.rcsi.science/0091-150X/article/view/245794
- DOI: https://doi.org/10.1007/s11094-019-02014-y
- ID: 245794
Cite item
Abstract
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.
Keywords
About the authors
N. A. Zefirov
M. V. Lomonosov Moscow State University; Institute of Physiologically Active Compounds, Russian Academy of Sciences
Email: olgaz@org.chem.msu.ru
Russian Federation, Moscow, 119991; Chernogolovka, Moscow Oblast, 142432
Yu. A. Evteeva
M. V. Lomonosov Moscow State University
Email: olgaz@org.chem.msu.ru
Russian Federation, Moscow, 119991
A. R. Fatkulin
M. V. Lomonosov Moscow State University
Email: olgaz@org.chem.msu.ru
Russian Federation, Moscow, 119991
S. Schulz
Institute of Biological Sciences, University of Rostock
Email: olgaz@org.chem.msu.ru
Germany, Rostock
S. A. Kuznetsov
Institute of Biological Sciences, University of Rostock
Email: olgaz@org.chem.msu.ru
Germany, Rostock
O. N. Zefirova
M. V. Lomonosov Moscow State University; Institute of Physiologically Active Compounds, Russian Academy of Sciences
Author for correspondence.
Email: olgaz@org.chem.msu.ru
Russian Federation, Moscow, 119991; Chernogolovka, Moscow Oblast, 142432