ACS Publications. Most Trusted. Most Cited. Most Read
My Activity
CONTENT TYPES

Synthesis and Biological Evaluation of (Hetero)Arylmethyloxy- and Arylmethylamine-phenyl Derivatives as Potent P-glycoprotein Modulating Agents

View Author Information
Dipartimento Farmacochimico, Universitá degli Studi di Bari, Via Orabona, 4, 70125 Bari, Italy, and Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno, 6, 56126 Pisa, Italy
* To whom correspondence should be addressed. (N.A.C.) Phone: +39-0805442727 . Fax: +39-0805442231. E-mail: [email protected]. (S.R.) Phone: +39-0502219582 . Fax: +39-0502219605. E-mail: [email protected]
†Universitá degli Studi di Bari.
‡Università di Pisa.
Cite this: J. Med. Chem. 2008, 51, 5, 1415–1422
Publication Date (Web):February 8, 2008
https://doi.org/10.1021/jm701267q
Copyright © 2008 American Chemical Society

    Article Views

    624

    Altmetric

    -

    Citations

    LEARN ABOUT THESE METRICS
    Other access options
    Supporting Info (1)»

    Abstract

    Abstract Image

    Starting from lead compounds 12b and 28b, previously characterized as P-glycoprotein (P-gp) modulating agents, two series of new compounds were investigated. Compounds 14a,b and 15a,b displayed high P-gp modulating activity in the submicromolar range (EC50 values from 0.25 to 0.80 µM). Moreover, amino derivatives 2327 showed EC50 values ranging from 0.085 to 0.90 µM. In the pyridyl series, the best result has been obtained for 4-pyridyl derivative 17b (EC50 = 0.85 µM). The best P-gp modulating agents 14a,b, 15a,b, and 2327 also have been studied for determining their breast cancer resistance protein (BCRP) inhibition activity. The results demonstrated that only the amino derivatives 2327 displayed moderate BCRP inhibition activity.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.

    Recommended

    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Supporting Information

    ARTICLE SECTIONS
    Jump To

    Elemental analysis of compounds 11a,b, 13a,b, 14a,b, 15a,b, 16a,b, 17a,b, and 2227 and experimental section for key intermediates 18, 20, and 21. This material is available free of charge via the Internet at http://pubs.acs.org.

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    This article is cited by 16 publications.

    1. Fabio Broccatelli, Emanuele Carosati, Annalisa Neri, Maria Frosini, Laura Goracci, Tudor I. Oprea, and Gabriele Cruciani . A Novel Approach for Predicting P-Glycoprotein (ABCB1) Inhibition Using Molecular Interaction Fields. Journal of Medicinal Chemistry 2011, 54 (6) , 1740-1751. https://doi.org/10.1021/jm101421d
    2. Nicola Antonio Colabufo, Francesco Berardi, Roberto Perrone, Simona Rapposelli, Maria Digiacomo, Michael Vanni and Aldo Balsamo . 2-[(3-Methoxyphenylethyl)phenoxy]-Based ABCB1 Inhibitors: Effect of Different Basic Side-Chains on Their Biological Properties. Journal of Medicinal Chemistry 2008, 51 (23) , 7602-7613. https://doi.org/10.1021/jm800928j
    3. Serhii Holovach, Kostiantyn P. Melnykov, Illia Poroshyn, Rustam T. Iminov, Dmytro Dudenko, Ivan Kondratov, Mark Levin, Oleksandr O. Grygorenko. C−C Coupling through Nitrogen Deletion: Application to Library Synthesis. Chemistry – A European Journal 2023, 29 (4) https://doi.org/10.1002/chem.202203470
    4. Joana Costa, Vanessa Almonti, Ludovica Cacopardo, Daniele Poli, Simona Rapposelli, Arti Ahluwalia. Investigating Curcumin/Intestinal Epithelium Interaction in a Millifluidic Bioreactor. Bioengineering 2020, 7 (3) , 100. https://doi.org/10.3390/bioengineering7030100
    5. Clarissa Willers, Hanna Svitina, Michael J. Rossouw, Roan A. Swanepoel, Josias H. Hamman, Chrisna Gouws. Models used to screen for the treatment of multidrug resistant cancer facilitated by transporter-based efflux. Journal of Cancer Research and Clinical Oncology 2019, 145 (8) , 1949-1976. https://doi.org/10.1007/s00432-019-02973-5
    6. Debora Petroni, Antonietta Bartoli, Simona Rapposelli, Maria Digiacomo, Silvia Burchielli, Giulia Nesi, Annalina Lapucci, Silvia Pardini, Sabrina Fucci, Marco Macchia, Piero A. Salvadori, Luca Menichetti. Synthesis and In Vivo Imaging of N-(3-[11C]Methoxybenzyl)-2-(3-Methoxyphenyl)ethylaniline as a Potential Targeting Agent for P-glycoprotein. Molecular Imaging and Biology 2016, 18 (6) , 916-923. https://doi.org/10.1007/s11307-016-0965-6
    7. Theresa Schwarz, Floriane Montanari, Anna Cseke, Katrin Wlcek, Lene Visvader, Sarah Palme, Peter Chiba, Karl Kuchler, Ernst Urban, Gerhard F. Ecker. Subtle Structural Differences Trigger Inhibitory Activity of Propafenone Analogues at the Two Polyspecific ABC Transporters: P‐Glycoprotein (P‐gp) and Breast Cancer Resistance Protein (BCRP). ChemMedChem 2016, 11 (12) , 1380-1394. https://doi.org/10.1002/cmdc.201500592
    8. K.-M. Thai, N.-T. Huynh, T.-D. Ngo, T.-T. Mai, T.-H. Nguyen, T.-D. Tran. Three- and four-class classification models for P-glycoprotein inhibitors using counter-propagation neural networks. SAR and QSAR in Environmental Research 2015, 26 (2) , 139-163. https://doi.org/10.1080/1062936X.2014.995701
    9. Floriane Montanari, Gerhard F. Ecker. BCRP Inhibition: from Data Collection to Ligand‐Based Modeling. Molecular Informatics 2014, 33 (5) , 322-331. https://doi.org/10.1002/minf.201400012
    10. Giulia Nesi, Nicola Antonio Colabufo, Marialessandra Contino, Maria Grazia Perrone, Maria Digiacomo, Roberto Perrone, Annalina Lapucci, Marco Macchia, Simona Rapposelli. SAR study on arylmethyloxyphenyl scaffold: Looking for a P-gp nanomolar affinity. European Journal of Medicinal Chemistry 2014, 76 , 558-566. https://doi.org/10.1016/j.ejmech.2014.02.051
    11. Thirumurthy Madhavan, Changdev G. Gadhe, Gugan Kothandan, Seung Joo Cho. Enhancement of P-gylcoprotein modulators of arylmethylamine-phenyl derivatives: an integrative modeling approach. Medicinal Chemistry Research 2013, 22 (5) , 2511-2523. https://doi.org/10.1007/s00044-012-0246-0
    12. Simona Rapposelli, Alessio Coi, Marcello Imbriani, Anna Maria Bianucci. Development of Classification Models for Identifying “True” P-glycoprotein (P-gp) Inhibitors Through Inhibition, ATPase Activation and Monolayer Efflux Assays. International Journal of Molecular Sciences 2012, 13 (6) , 6924-6943. https://doi.org/10.3390/ijms13066924
    13. Nicola Antonio Colabufo, Marialessandra Contino, Francesco Berardi, Roberto Perrone, Maria Antonietta Panaro, Antonia Cianciulli, Vincenzo Mitolo, Amalia Azzariti, Annelisa Quatrale, Angelo Paradiso. A new generation of MDR modulating agents with dual activity: P-gp inhibitor and iNOS inducer agents. Toxicology in Vitro 2011, 25 (1) , 222-230. https://doi.org/10.1016/j.tiv.2010.11.004
    14. Yan Xia, Kyeong Lee. Targeting Multidrug Resistance with Small Molecules for Cancer Therapy. Biomolecules and Therapeutics 2010, 18 (4) , 375-385. https://doi.org/10.4062/biomolther.2010.18.4.375
    15. . Discovery of Highly Potent Multidrug Resistance (MDR) Reversal Agents: Aminosulfonylaryl Isoxazole Derivatives. Bulletin of the Korean Chemical Society 2009, 779-780. https://doi.org/10.5012/bkcs.2009.30.4.779
    16. Nicola A. Colabufo, Francesco Berardi, Maria Grazia Perrone, Mariangela Cantore, Marialessandra Contino, Carmela Inglese, Mauro Niso, Roberto Perrone. Multi‐Drug‐Resistance‐Reverting Agents: 2‐Aryloxazole and 2‐Arylthiazole Derivatives as Potent BCRP or MRP1 Inhibitors. ChemMedChem 2009, 4 (2) , 188-195. https://doi.org/10.1002/cmdc.200800329

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    MENDELEY PAIRING EXPIRED
    Your Mendeley pairing has expired. Please reconnect