A Potent and Selective P-gp Modulator for Altering Multidrug Resistance Due to Pump Overexpression

ChemMedChem
Stefano GuglielmoNicola Antonio Colabufo

Abstract

P-glycoprotein (P-gp) is a membrane protein responsible for the active transport of several endogenous and exogenous substances. It constitutes a defense mechanism and, at the same time, it severely compromises the success rate of antitumor chemotherapy. In this study a small library of alkyl/oxyalkyl derivatives of MC70 [4'-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-4-ol], a well-known P-gp inhibitor, was synthesized through straightforward functionalization of the phenolic group present in the structure of MC70. All compounds were characterized for their effect on P-gp, proving capable of blocking P-gp-mediated calcein-AM efflux with micromolar potency, following their ability to act as high-affinity substrates of this transporter. Excitingly, compound 4 [6,7-dimethoxy-2-((4'-butoxybiphen-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline] exhibited low nanomolar potency (5.2 nm) and had a peculiar activity profile, acting both as a positive allosteric modulator and as a substrate of the transporter. A new and more efficient synthesis of MC70 is also described.

References

Jan 31, 2002·Annual Review of Medicine·Michael M Gottesman
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Mar 7, 2006·Nature Reviews. Drug Discovery·Gergely SzakácsMichael M Gottesman
Oct 16, 2007·Bioorganic & Medicinal Chemistry·Nicola Antonio ColabufoAngelo Paradiso
Feb 16, 2008·Bioorganic & Medicinal Chemistry·Nicola Antonio ColabufoAngelo Paradiso
Jun 18, 2009·Journal of Medicinal Chemistry·Aren van WaardeNicola A Colabufo
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Jan 31, 2014·Frontiers in Oncology·Laura ZinziNicola Antonio Colabufo

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Citations

Jun 13, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Iris Chiara SalaroglioChiara Riganti
Feb 6, 2020·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Jinyun DongJiang-Jiang Qin

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