Arylamino Esters As P‐Glycoprotein Modulators: SAR Studies to Establish Requirements for Potency and Selectivity

Teodori, Elisabetta; Dei, Silvia; Floriddia, Elisa; Perrone, Maria Grazia; Manetti, Dina; Romanelli, Maria Novella; Contino, Marialessandra; Colabufo, Nicola Antonio

doi:10.1002/cmdc.201500143

Cited by 11 publications

(6 citation statements)

References 27 publications

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“…To explore the consequences of varying the amide function, we also synthesized corresponding isosteric ester derivatives 7 – 12 and analogues 13 – 16 containing an alkylamine function (Figure ). The inserted aryl moieties were chosen because they were present in compounds previously studied and proved to be very potent multidrug resistance reversers …”

Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationship Studies on 6,7‐Dimethoxy‐2‐phenethyl‐1,2,3,4‐tetrahydroisoquinoline Derivatives as Multidrug Resistance Reversers

et al. 2017

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A series of derivatives were synthesized and studied with the aim to investigate the structure–activity relationships of the two P‐glycoprotein (P‐gp) modulators elacridar and tariquidar. Then, different aryl‐substituted amides were inserted, and to explore the effects of varying the amide function, the corresponding isosteric ester derivatives and some alkylamine analogues were synthesized. The new compounds were studied to evaluate their P‐gp interaction profile and selectivity toward the two other ABC transporters, multidrug‐resistance‐associated protein‐1 (MRP‐1) and breast cancer resistance protein (BCRP). Investigation of the chemical stability of the amide and ester derivatives toward spontaneous or enzymatic hydrolysis showed that these compounds were stable in phosphate‐buffered saline and human plasma. This study allowed us to evaluate the selectivity of the three series on the three efflux pumps and to propose the structural requirements that define the P‐gp interaction profile. We identified two P‐gp substrates, a P‐gp inhibitor, and three ester derivatives that were active on BCRP, which opens a new scenario in the development of ligands active toward this pump.

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Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationship Studies on 6,7‐Dimethoxy‐2‐phenethyl‐1,2,3,4‐tetrahydroisoquinoline Derivatives as Multidrug Resistance Reversers

et al. 2017

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“…Numerous moieties can be used as linkers, such as ester bonds, alkyl chains, and ketone functional groups. However, the compounds with amide bonds had relatively poor potency 103 . In addition, the length of the spacer was also adjustable (ranging from 1 to 10s of atoms).…”

Section: P‐gp Inhibitorsmentioning

confidence: 99%

“…However, the compounds with amide bonds had relatively poor potency. 103 In addition, the length of the spacer was also adjustable (ranging from 1 to 10s of atoms). A variety of aromatic rings have been observed in the structure of potent and selective P-gp inhibitors, 63,96,100 such as the phenyl moiety, diphenyl moiety, and a 9-anthracene nucleus.…”

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confidence: 99%

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

Zhang

Ashby

et al. 2020

Medicinal Research Reviews

202

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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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“…Continuing their previous researches on derivatives of the natural alkaloid Pervilleine A, and based on the polyvalency approach, Teodori et al . [ 181 ] synthesized a set of basic molecules carrying aryl moieties connected to the N -containing linker through ester functions. The nature of the spacer (dicyclohexylamine or dialkylamine) and of the aryl moieties was modified to investigate their interacting mechanism with the ABC transporters and their selectivity [Figure 24] .…”

Section: Othersmentioning

confidence: 99%

Recent advances in the search of BCRP- and dual P-gp/BCRP-based multidrug resistance modulators

Dei¹,

Braconi²,

Romanelli³

et al. 2019

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The development of multidrug resistance (MDR) is one of the major challenges to the success of chemotherapy treatment of cancer. This phenomenon is often associated with the overexpression of the ATP-binding cassette (ABC) transporters P-gp (P-glycoprotein, ABCB1), multidrug resistance-associated protein 1, ABCC1 and breast cancer resistance protein, ABCG2 (BCRP). These transporters are constitutively expressed in many tissues playing relevant protective roles by the regulation of the permeability of biological membranes, but they are also overexpressed in malignant tissues. P-gp is the first efflux transporter discovered to be involved in cancer drug resistance, and over the years, inhibitors of this pump have been disclosed to administer them in combination with chemotherapeutic agents. Three generations of inhibitors of P-gp have been examined in preclinical and clinical studies; however, these trials have largely failed to demonstrate that coadministration of pump inhibitors elicits an improvement in therapeutic efficacy of antitumor agents, although some of the latest compounds show better results. Therefore, new and innovative strategies, such as the fallback to natural products and the discover of dual activity ligands emerged as new perspectives. BCRP is the most recently ABC protein identified to be involved in multidrug resistance. It is overexpressed in several haematological and solid tumours together with P-gp, threatening the therapeutic effectiveness of different chemotherapeutic drugs. The chemistry of recently described BCRP inhibitors and dual P-gp/BCRP inhibitors, as well as their preliminary pharmacological evaluation are discussed, and the most recent advances concerning these kinds of MDR modulators are reviewed.

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Arylamino Esters As P‐Glycoprotein Modulators: SAR Studies to Establish Requirements for Potency and Selectivity

Cited by 11 publications

References 27 publications

Structure–Activity Relationship Studies on 6,7‐Dimethoxy‐2‐phenethyl‐1,2,3,4‐tetrahydroisoquinoline Derivatives as Multidrug Resistance Reversers

Structure–Activity Relationship Studies on 6,7‐Dimethoxy‐2‐phenethyl‐1,2,3,4‐tetrahydroisoquinoline Derivatives as Multidrug Resistance Reversers

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

Recent advances in the search of BCRP- and dual P-gp/BCRP-based multidrug resistance modulators

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