European Journal of Medicinal Chemistry, volume 227, pages 113936
PSMA-targeted small-molecule docetaxel conjugate: Synthesis and preclinical evaluation
Zyk Nikolay Y
1
,
Nimenko Ekaterina A.
1
,
Ber Anton P
1
,
Shafikov Radik R
1, 2
,
Pokrovsky Vadim S.
3, 4
,
Khudyakov Alexander D
1
,
Kovalev Sergey
1
,
Khazanova Elena S
,
Erofeev Alexander S.
5
,
Skvortsov Dmitry A.
1, 6
,
Kolmogorov Vasilii S
5
,
Gorelkin Petr V.
5
,
Zyk Nikolay V.
1
,
Smirnova Galina B.
3
,
Ivanenkov Yan A
1, 5, 7, 8, 9
Publication type: Journal Article
Publication date: 2022-01-01
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 6.7
ISSN: 02235234, 17683254
Organic Chemistry
Drug Discovery
General Medicine
Pharmacology
Abstract
Prostate cancer is one of the most commonly diagnosed men's cancers and remains one of the leading causes of cancer death. The development of approaches to the treatment of this oncological disease is an ongoing process. In this work, we have carried out the selection of ligands for the creation of conjugates based on the drug docetaxel and synthesized a series of three docetaxel conjugates. In vitro cytotoxicity of these molecules was evaluated using the MTT assay. Based on the assay results, we selected the conjugate which showed cytotoxic potential close to unmodified docetaxel. At the same time, the molar solubility of the resulting compound increased up to 20 times in comparison with the drug itself. In vivo evaluation on 22Rv1 (PSMA+) xenograft model demonstrated a good potency of the synthesized conjugate to inhibit tumor growth: the inhibition turned out to be more than 80% at a dose of 30 mg/kg. Pharmacokinetic parameters of conjugate distribution were analyzed. Also, it was found that PSMA-targeted docetaxel conjugate is less toxic than docetaxel itself, the decrease of molar acute toxicity in comparison with free docetaxel was up to 20%. Obtained conjugate PSMA-DOC is a good candidate for further expanded preclinical trials because of high antitumor activity, fewer side toxic effects and better solubility.
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Citations by publishers
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7 publications, 53.85%
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2 publications, 15.38%
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1 publication, 7.69%
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Frontiers Media S.A.
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1 publication, 7.69%
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Russian Society of Cardiology
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1 publication, 7.69%
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- We do not take into account publications that without a DOI.
- Statistics recalculated only for publications connected to researchers, organizations and labs registered on the platform.
- Statistics recalculated weekly.
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Machulkin A. E. et al. PSMA-targeted small-molecule docetaxel conjugate: Synthesis and preclinical evaluation // European Journal of Medicinal Chemistry. 2022. Vol. 227. p. 113936.
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Zyk N. Y., Erofeev A. S., Zyk N. V., Gorelkin P. V., Vaneev A. N., Kolmogorov V. S., Smirnova G. B., Skvortsov D. A., Uspenskaya A. A., Majouga A. G., Khazanova E. S., Beloglazkina E. K., Kovalev S., Khudyakov A. D., Ivanenkov Y., Pokrovsky V. S., Borisova Y. A., Shafikov R. R., Petrov S. B., Ber A. P., Nimenko E. A., Machulkin A. E., Ivanenkov Y. A. PSMA-targeted small-molecule docetaxel conjugate: Synthesis and preclinical evaluation // European Journal of Medicinal Chemistry. 2022. Vol. 227. p. 113936.
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TY - JOUR
DO - 10.1016/j.ejmech.2021.113936
UR - https://doi.org/10.1016%2Fj.ejmech.2021.113936
TI - PSMA-targeted small-molecule docetaxel conjugate: Synthesis and preclinical evaluation
T2 - European Journal of Medicinal Chemistry
AU - Machulkin, Aleksei E.
AU - Zyk, Nikolay Y
AU - Nimenko, Ekaterina A.
AU - Ber, Anton P
AU - Petrov, Stanislav B.
AU - Shafikov, Radik R
AU - Borisova, Yulia A.
AU - Pokrovsky, Vadim S.
AU - Ivanenkov, Yan
AU - Khudyakov, Alexander D
AU - Kovalev, Sergey
AU - Beloglazkina, Elena K
AU - Khazanova, Elena S
AU - Majouga, Alexander G.
AU - Uspenskaya, Anastasia A
AU - Skvortsov, Dmitry A.
AU - Smirnova, Galina B.
AU - Kolmogorov, Vasilii S
AU - Vaneev, Alexander N
AU - Gorelkin, Petr V.
AU - Zyk, Nikolay V.
AU - Erofeev, Alexander S.
AU - Ivanenkov, Yan A
PY - 2022
DA - 2022/01/01 00:00:00
PB - Elsevier
SP - 113936
VL - 227
SN - 0223-5234
SN - 1768-3254
ER -
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@article{2022_Machulkin,
author = {Aleksei E. Machulkin and Nikolay Y Zyk and Ekaterina A. Nimenko and Anton P Ber and Stanislav B. Petrov and Radik R Shafikov and Yulia A. Borisova and Vadim S. Pokrovsky and Yan Ivanenkov and Alexander D Khudyakov and Sergey Kovalev and Elena K Beloglazkina and Elena S Khazanova and Alexander G. Majouga and Anastasia A Uspenskaya and Dmitry A. Skvortsov and Galina B. Smirnova and Vasilii S Kolmogorov and Alexander N Vaneev and Petr V. Gorelkin and Nikolay V. Zyk and Alexander S. Erofeev and Yan A Ivanenkov},
title = {PSMA-targeted small-molecule docetaxel conjugate: Synthesis and preclinical evaluation},
journal = {European Journal of Medicinal Chemistry},
year = {2022},
volume = {227},
publisher = {Elsevier},
month = {jan},
url = {https://doi.org/10.1016%2Fj.ejmech.2021.113936},
pages = {113936},
doi = {10.1016/j.ejmech.2021.113936}
}