Next Article in Journal
Metabolic Responses of Poplar to Apripona germari (Hope) as Revealed by Metabolite Profiling
Next Article in Special Issue
Synthesis, Characterization, and Cytotoxicity of the First Oxaliplatin Pt(IV) Derivative Having a TSPO Ligand in the Axial Position
Previous Article in Journal
Antibacterial Activity of Juglone against Staphylococcus aureus: From Apparent to Proteomic
Previous Article in Special Issue
Tetrapyrroles as Endogenous TSPO Ligands in Eukaryotes and Prokaryotes: Comparisons with Synthetic Ligands
Article Menu
Issue 6 (June) cover image

Export Article

Open AccessArticle
Int. J. Mol. Sci. 2016, 17(6), 967;

TSPO Ligand-Methotrexate Prodrug Conjugates: Design, Synthesis, and Biological Evaluation

Department of Pharmacy–Pharmaceutical Sciences, University of Bari “Aldo Moro”, Bari 70125, Italy
Istituto tumori IRCCS “Giovanni Paolo II”, Flacco, St. 65, Bari 70124, Italy
Department of Chemistry, University of Bari “Aldo Moro”, Bari 70125, Italy
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047, USA
Author to whom correspondence should be addressed.
Academic Editor: Genxi Li
Received: 9 May 2016 / Revised: 6 June 2016 / Accepted: 13 June 2016 / Published: 18 June 2016
(This article belongs to the Special Issue Translocator Protein (TSPO))
Full-Text   |   PDF [735 KB, uploaded 18 June 2016]   |  


The 18-kDa translocator protein (TSPO) is a potential mitochondrial target for drug delivery to tumors overexpressing TSPO, including brain cancers, and selective TSPO ligands have been successfully used to selectively deliver drugs into the target. Methotrexate (MTX) is an anticancer drug of choice for the treatment of several cancers, but its permeability through the blood brain barrier (BBB) is poor, making it unsuitable for the treatment of brain tumors. Therefore, in this study, MTX was selected to achieve two TSPO ligand-MTX conjugates (TSPO ligand α-MTX and TSPO ligand γ-MTX), potentially useful for the treatment of TSPO-rich cancers, including brain tumors. In this work, we have presented the synthesis, the physicochemical characterizations, as well as the in vitro stabilities of the new TSPO ligand-MTX conjugates. The binding affinity for TSPO and the selectivity versus central-type benzodiazepine receptor (CBR) was also investigated. The cytotoxicity of prepared conjugates was evaluated on MTX-sensitive human and rat glioma cell lines overexpressing TSPO. The estimated coefficients of lipophilicity and the stability studies of the conjugates confirm that the synthesized molecules are stable enough in buffer solution at pH 7.4, as well in physiological medium, and show an increased lipophilicity compared to the MTX, compatible with a likely ability to cross the blood brain barrier. The latter feature of two TSPO ligand-MTX conjugates was also confirmed by in vitro permeability studies conducted on Madin-Darby canine kidney cells transfected with the human MDR1 gene (MDCK-MDR1) monolayers. TSPO ligand-MTX conjugates have shown to possess a high binding affinity for TSPO, with IC50 values ranging from 7.2 to 40.3 nM, and exhibited marked toxicity against glioma cells overexpressing TSPO, in comparison with the parent drug MTX. View Full-Text
Keywords: translocator protein; methotrexate; TSPO-ligand; bio-conjugate; glioma translocator protein; methotrexate; TSPO-ligand; bio-conjugate; glioma

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
Printed Edition Available!
A printed edition of this Special Issue is available here.

Share & Cite This Article

MDPI and ACS Style

Laquintana, V.; Denora, N.; Cutrignelli, A.; Perrone, M.; Iacobazzi, R.M.; Annese, C.; Lopalco, A.; Lopedota, A.A.; Franco, M. TSPO Ligand-Methotrexate Prodrug Conjugates: Design, Synthesis, and Biological Evaluation. Int. J. Mol. Sci. 2016, 17, 967.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics



[Return to top]
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top