Deconstruction of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety to separate P-glycoprotein (P-gp) activity from σ2 receptor affinity in mixed P-gp/σ2 receptor agents

Pati, Maria Laura; Abate, Carmen; Contino, Marialessandra; Ferorelli, Savina; Luisi, Renzo; Carroccia, Laura; Niso, Mauro; Berardi, Francesco

doi:10.1016/j.ejmech.2014.11.001

Cited by 13 publications

(12 citation statements)

References 33 publications

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“…Therefore, in Pip1, the piperidine ring has been replaced with a 6,7-dimethoxytetrahydroisoquinoline a moiety, which is widely present in modulators of P-gp including the third generation P-gp inhibitors (tariquidar and elacridar) (Fig. 1 ) 39 . This moiety is also present in the alkaloid tetrandrine, currently in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer

Syed

Arya

et al. 2017

Sci Rep

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P-glycoprotein (P-gp) is a drug transporter that effluxes chemotherapeutic drugs and is implicated in the development of resistance of cancer cells to chemotherapeutic drugs. To date, no drug has been approved to inhibit P-gp and restore chemotherapy efficacy. Moreover, majority of the reported inhibitors have high molecular weight and complex structures, making it difficult to understand the basic structural requirement for P-gp inhibition. In this study, two structurally simple, low molecular weight piperine analogs Pip1 and Pip2 were designed and found to better interact with P-gp than piperine in silico. A one step, acid-amine coupling reaction between piperic acid and 6,7-dimethoxytetrahydroisoquinoline or 2-(3,4-dimethoxyphenyl)ethylamine afforded Pip1 and Pip2, respectively. In vitro testing in drug resistant P-gp overexpressing KB (cervical) and SW480 (colon) cancer cells showed that both analogs, when co-administered with vincristine, colchicine or paclitaxel were able to reverse the resistance. Moreover, accumulation of P-gp substrate (rhodamine 123) in the resistant cells, a result of alteration of the P-gp efflux, was also observed. These investigations suggest that the natural product analog – Pip1 ((2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1 H)-yl)penta-2,4-dien-1-one) – is superior to piperine and could inhibit P-gp function. Further studies are required to explore the full potential of Pip1 in treating drug resistant cancer.

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Section: Introductionmentioning

confidence: 99%

Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer

Syed

Arya

et al. 2017

Sci Rep

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“…While F400 is devoid of sigma-2 receptor affinity [42], F421 and F397 respectively display a moderate (K i = 169 nM) [41] to a high affinity (K i = 5.34 nM) [28] towards sigma-2 receptors. Nevertheless, the involvement of a sigma-2 receptor-mediated effect was ruled out by the detection of a low density of sigma-2 receptors in A549 cells (data not shown).…”

Section: Collatateral Sensitivity Studymentioning

confidence: 97%

“…Therefore, we gathered inspiration from our library of sigma-2 receptors' ligands, that have been recently associated with CS [28,29,33,34]. Sigma-2 receptors, lately identified as TMEM97 proteins, are overexpressed in diverse types of cancers and their modulation leads to cell death upon the activation of a number of still investigated pathways [35][36][37][38][39][40][41][42][43][44][45]. Several sigma-2 receptor high-affinity ligands have been developed during recent decades (and lately reviewed), revealing cytotoxic activity through pathways that appear to be molecule-dependent and cell-type-dependent, with mechanisms that span from caspase-dependent apoptosis, autophagy, increase in ROS, and mithocondrial superoxide production [36,37,40,44].…”

Section: Introductionmentioning

confidence: 99%

“…Herein, we investigated the interaction of these compounds with MRP1 pumps in order to identify novel MRP1 modulators to be exploited as CS agents. Three compounds, derived from three different classes of sigma-2 receptor ligands ( Figure 1: [41]; and F400 6,7-dime thoxy-2-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propionyl]-1,2,3,4 tetrahydroisoquinoline) [42] emerged as MRP1 modulators in the preliminary screening and for this reason they were further evaluated in the appropriate MDR cell line models and in a preclinical in vivo model. affinity ligands have been developed during recent decades (and lately reviewed), revealing cytotoxic activity through pathways that appear to be molecule-dependent and cell-type-dependent, with mechanisms that span from caspase-dependent apoptosis, autophagy, increase in ROS, and mithocondrial superoxide production [36,37,40,44].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

MRP1-Collateral Sensitizers as a Novel Therapeutic Approach in Resistant Cancer Therapy: An In Vitro and In Vivo Study in Lung Resistant Tumor

Riganti

Giampietro

Kopecka

et al. 2020

IJMS

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Multidrug resistance (MDR) is the main obstacle to current chemotherapy and it is mainly due to the overexpression of some efflux transporters such as MRP1. One of the most studied strategies to overcome MDR has been the inhibition of MDR pumps through small molecules, but its translation into the clinic unfortunately failed. Recently, a phenomenon called collateral sensitivity (CS) emerged as a new strategy to hamper MDR acting as a synthetic lethality, where the genetic changes developed upon the acquisition of resistance towards a specific agent are followed by the development of hypersensitivity towards a second agent. Among our library of sigma ligands acting as MDR modulators, we identified three compounds, F397, F400, and F421, acting as CS-promoting agents. We deepened their CS mechanisms in the “pure” model of MRP1-expressing cells (MDCK-MRP1) and in MRP1-expressing/drug resistant non-small cell lung cancer cells (A549/DX). The in vitro results demonstrated that (i) the three ligands are highly cytotoxic for MRP1-expressing cells; (ii) their effect is MRP1-mediated; (iii) they increase the cytotoxicity induced by cis-Pt, the therapeutic agent commonly used in the treatment of lung tumors; and (iv) their effect is ROS-mediated. Moreover, a preclinical in vivo study performed in lung tumor xenografts confirms the in vitro findings, making the three CS-promoting agents candidates for a novel therapeutic approach in lung resistant tumors.

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Chemical molecular‐based approach to overcome multidrug resistance in cancer by targeting P‐glycoprotein (P‐gp)

Zhang

Ashby

et al. 2020

Medicinal Research Reviews

169

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Multidrug resistance (MDR) remains one of the major impediments for efficacious cancer chemotherapy. Increased efflux of multiple chemotherapeutic drugs by transmembrane ATP‐binding cassette (ABC) transporter superfamily is considered one of the primary causes for cancer MDR, in which the role of P‐glycoprotein (P‐gp/ABCB1) has been most well‐established. The clinical co‐administration of P‐gp drug efflux inhibitors, in combination with anticancer drugs which are P‐gp transport substrates, was considered to be a treatment modality to surmount MDR in anticancer therapy by blocking P‐gp‐mediated multidrug efflux. Extensive attempts have been carried out to screen for sets of nontoxic, selective, and efficacious P‐gp efflux inhibitors. In this review, we highlight the recent achievements in drug design, characterization, structure–activity relationship (SAR) studies, and mechanisms of action of the newly synthetic, potent small molecules P‐gp inhibitors in the past 5 years. The development of P‐gp inhibitors will increase our knowledge of the mechanisms and functions of P‐gp‐mediated drug efflux which will benefit drug discovery and clinical cancer therapeutics where P‐gp transporter overexpression has been implicated in MDR.

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Deconstruction of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety to separate P-glycoprotein (P-gp) activity from σ2 receptor affinity in mixed P-gp/σ2 receptor agents

Cited by 13 publications

References 33 publications

Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer

Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer

MRP1-Collateral Sensitizers as a Novel Therapeutic Approach in Resistant Cancer Therapy: An In Vitro and In Vivo Study in Lung Resistant Tumor

Chemical molecular‐based approach to overcome multidrug resistance in cancer by targeting P‐glycoprotein (P‐gp)

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