Synthesis of Tetrahydroisoquinoline Derivatives as Perspective Inhibitors of P-glycoprotein 1
     
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Synthesis of Tetrahydroisoquinoline Derivatives as Perspective Inhibitors of P-glycoprotein 1

Tetrahydroisoquinoline Derivatives as Perspective Inhibitors of P-glycoprotein 1P-glycoprotein 1 (P-gp, Pgp, multidrug resistance protein 1, MDR1, ATP-binding cassette sub-family B member 1, ABCB1, cluster of differentiation 243 or CD243) is an important protein of the cell membrane that pumps many foreign substances out of cells. It is an ATP-dependent efflux pump with broad substrate specificity wich evolved as a defense mechanism against harmful substances. But at the same time it pumps many drugs, including anticancer chemotherapeutics, from the cell thereby weakening their action. Consequently, P-gp overexpression is one of the main mechanisms behind decreased intracellular drug accumulation and development of multidrug resistance.

We offer the chemical optimization service - synthesis of target-specific sets of novel tetrahydroisoquinoline derivatives for your biological projects. These novel compounds will be selected from a set of 2,000+ unique virtual tetrahydroisoquinoline derivatives using our company’s proprietary molecular modeling platform.

These target-specific sets of novel analogs will be synthesized exclusively upon your request.

This is referred to a paper from Journal of Medicinal Chemistry* which showed that authors synthesized series of tetrahydroisoquinolines through structure modulation of [4 ′-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-biphenyl-4-ol] (MC70, lead compound from their previous study, EC50 = 0.69 μM), modifying the phenolic group of it. Among them, compound 5b showed activity against P-glycoprotein (EC50 = 15 nM) and was capable of restoring doxorubicin antiproliferative activity at nontoxic concentration:

Tetrahydroisoquinoline Derivatives as Perspective Inhibitors of P-glycoprotein 1

Compound 5b
 
Targeting the Cancer Stem Cells (CSCs) in tumors, in particular overcoming their multidrug-resistant phenotype, is a still unsolved problem, but it may represent a sure advantage in cancer treatment. The identification of compound 5b is a step forward in this direction.
 

* Chiara Riganti, Marialessandra Contino, Stefano Guglielmo, Maria G. Perrone, Iris C. Salaroglio, Vladan Milosevic, Roberta Giampietro, Francesco Leonetti, Barbara Rolando, Loretta Lazzarato, Nicola A. Colabufo, Roberta Fruttero. Design, Biological Evaluation, and Molecular Modeling of Tetrahydroisoquinoline Derivatives: Discovery of A Potent P ‑ Glycoprotein Ligand Overcoming Multidrug Resistance in Cancer Stem Cells. J. Med. Chem. 2019, Vol. 62, pp. 974−986, DOI: 10.1021/acs.jmedchem.8b01655.

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