SAR Studies on Tetrahydroisoquinoline Derivatives: The Role of Flexibility and Bioisosterism To Raise Potency and Selectivity toward P-glycoprotein

Capparelli, Elena; Zinzi, Laura; Cantore, Mariangela; Contino, Marialessandra; Perrone, Maria Grazia; Luurtsema, Gert; Berardi, Francesco; Perrone, Roberto; Colabufo, Nicola Antonio

doi:10.1021/jm501640e

Cited by 26 publications

(44 citation statements)

References 26 publications

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“…All compounds have been tested to establish their P‐gp interacting mechanism by evaluating: (i) the inhibition of calcein‐AM probe in MDCK cells overexpressing P‐gp ; (ii) apparent permeability determination ( P app ) in Caco‐2 cells monolayer . The first assay allows to define the potency of the interaction of each compound toward P‐gp; the second assay permits to distinguish between an inhibitor ( P app < 2) or a substrate ( P app > 2) .…”

Section: Resultsmentioning

confidence: 99%

Functionalized Coumarine Fragment to Obtain Fluorescent and Selective P‐Glycoprotein Ligands

Capparelli

Contino

Perrone

et al. 2016

Archiv der Pharmazie

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Starting from our lead compound MC70 displaying high P-glycoprotein (P-gp) inhibition activity but low selectivity, a new class of coumarine derivatives was studied to develop selective and fluorescent P-gp ligands. In this series, the biphenyl moiety of MC70 was replaced with the coumarine fluorophore as a bioisostere of the biphenyl nucleus in order to improve the selectivity toward P-gp and the fluorescent properties for in vitro studies. Moreover, the presence and position of substituents on the coumarine nucleus were probed to develop suitable fluorescent probes to study the expression and activity of P-gp in living cells. The best result was found for compound 4c, which exerts a good P-gp activity profile (EC50 = 13 μM) as substrate and a high selectivity toward the pump since it is inactive toward MRP1.

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Section: Resultsmentioning

confidence: 99%

Functionalized Coumarine Fragment to Obtain Fluorescent and Selective P‐Glycoprotein Ligands

Capparelli

Contino

Perrone

et al. 2016

Archiv der Pharmazie

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“…-(3-((4-phenyl-1,2,5-oxadiazol-3-yl) (quin, J = 5.9 Hz, 2H). 13 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 …”

Section: Methodsmentioning

confidence: 99%

“…26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 solubilized using 100 µL of DMSO and the absorbance values at 570 and 630 nm were determined on the microplate reader Victor3 from PerkinElmer Life Sciences.…”

Section: -Methoxy-4-(phenylsulfonylmentioning

confidence: 99%

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Structure–Activity Relationship Studies on Tetrahydroisoquinoline Derivatives: [4′-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-4-ol] (MC70) Conjugated through Flexible Alkyl Chains with Furazan Moieties Gives Rise to Potent and Selective Ligands of P-glycoprotein

et al. 2016

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P-glycoprotein (P-gp) is a well-known membrane transporter expressed in a number of strategic biological barriers, where it exerts a protective effect of paramount importance. Conversely it is one of the main causes of multidrug resistance (MDR), being capable of effluxing many chemotherapeutics. In a development of previous research, a small library of compounds was created conjugating diversely substituted furazan rings with MC70, a well-known P-gp inhibitor. These compounds were assessed for their potency against P-gp and another transporter (MRP1), for their apparent permeability (Papp) and for their ability to induce ATPase activity, thus delineating a complete functional profile. They displayed a substrate mechanism of action and high selectivity toward P-gp, unlike the lead compound. Data relating to their activity range from low micromolar to sub-nanomolar EC50, the most interesting compounds being 15 (0.97 nM), 19 (1.3 nM), 25 (0.60 nM), and 27 (0.90 nM).

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“…THIQ) is as tructuralk ey element of elacridar andt ariquidar (two P-gp saturating substrates or inhibitor-like compounds). [13][14][15][16] Indomethacin, P6, and mofezolac were then linked to either aR h6Go r6 ,7-DM-THIQm oiety to first explore the COX inhibitor recognitiona nd,s econdly, to verify if such new molecules retain P-gp substrate/inhibitor activity.…”

Section: Introductionmentioning

confidence: 99%

Isoxazole‐Based‐Scaffold Inhibitors Targeting Cyclooxygenases (COXs)

et al. 2016

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A new set of cyclooxygenase (COX) inhibitors endowed with an additional functionality was explored. These new compounds also contained either rhodamine 6G or 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, two moieties typical of efflux pump substrates and inhibitors, respectively. Among all the synthesized compounds, two new COX inhibitors with opposite selectivity were discovered: compound 8 [N-(9-{2-[(4-{2-[3-(5-chlorofuran-2-yl)-4-phenylisoxazol-5-yl]acetamido}butyl)carbamoyl]phenyl-6-(ethylamino)-2,7-dimethyl-3H-xanthen-3-ylidene}ethanaminium chloride] was found to be a selective COX-1 inhibitor, whereas 17 (2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]-1-[6,7-dimethoxy-3,4-dihydroisoquinolin-2-(1H)-yl]ethanone) was found to be a sub-micromolar selective COX-2 inhibitor. However, both were shown to interact with P-glycoprotein. Docking experiments helped to clarify the molecular aspects of the observed COX selectivity.

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SAR Studies on Tetrahydroisoquinoline Derivatives: The Role of Flexibility and Bioisosterism To Raise Potency and Selectivity toward P-glycoprotein

Cited by 26 publications

References 26 publications

Functionalized Coumarine Fragment to Obtain Fluorescent and Selective P‐Glycoprotein Ligands

Functionalized Coumarine Fragment to Obtain Fluorescent and Selective P‐Glycoprotein Ligands

Structure–Activity Relationship Studies on Tetrahydroisoquinoline Derivatives: [4′-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-4-ol] (MC70) Conjugated through Flexible Alkyl Chains with Furazan Moieties Gives Rise to Potent and Selective Ligands of P-glycoprotein

Isoxazole‐Based‐Scaffold Inhibitors Targeting Cyclooxygenases (COXs)

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