Novel structure–activity relationships and selectivity profiling of cage dimeric 1,4-dihydropyridines as multidrug resistance (MDR) modulators

Coburger, Claudius; Wollmann, Jörg; Krug, Martin; Baumert, Christiane; Seifert, Marianne; Molnár, J; Lage, Hermann; Hilgeroth, Andreas

doi:10.1016/j.bmc.2010.06.004

Cited by 34 publications

(20 citation statements)

References 33 publications

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“…These compounds exhibit an optimal in vitro profile not only due to the lack of calcium channels antagonism and ability to inhibit ABC transporters, but also because they are neither inducers or substrates for P-gp [28][29][30]. Based on structural analysis of effective cage dimeric DHPs, Wollmann and co-workers suggested that a high degree of symmetry, but not necessarily a high degree of lipophilicity, are favourable for the P-gp inhibition (Fig.…”

Section: 4-dhps As Multi Drug Resistance Revertersmentioning

confidence: 97%

1,4-Dihydropyridine Scaffold in Medicinal Chemistry, The Story So Far And Perspectives (Part 2): Action in Other Targets and Antitargets

Carosati¹,

Ioan²,

Micucci³

et al. 2012

CMC

129

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1,4-Dihydropyridines were introduced in the last century for the treatment of coronary diseases. Then medicinal chemists decorated the 1,4-DHP nucleus, the most studied scaffold among L-type calcium channel blockers, achieving diverse activities at several receptors, channels and enzymes. We already described (Ioan et al. Curr. Med. Chem. 2011, 18, 4901-4922) the effects of 1,4-DHPs at ion channels and G-protein coupled receptors. In this paper we continue the analysis of the wide range of biological effects exerted by compounds belonging to this chemical class. In particular, focus is given to the ability of 1,4-DHPs to revert multi drug resistance that, after over 20 years of research, continues to be of great interest. We also describe activities on other targets and the action of 1,4-DHPs against several diseases. Finally, we report and review the interaction of 1,4-DHPs with the hERG channel, transporters and phase I metabolizing enzymes. This work is a starting point for further exploration of the 1,4-DHP core activities on targets, off-targets and antitargets.

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Section: 4-dhps As Multi Drug Resistance Revertersmentioning

confidence: 97%

1,4-Dihydropyridine Scaffold in Medicinal Chemistry, The Story So Far And Perspectives (Part 2): Action in Other Targets and Antitargets

Carosati¹,

Ioan²,

Micucci³

et al. 2012

CMC

129

View full text Add to dashboard Cite

show abstract

“…Interestingly, the widening of the torsion angle in biphenyl-substituted heterocyclic compounds with bulky ortho-substituents was identified to increase the inhibitory activity on ABCC2 (Lai et al 2007). In a set of dimeric 1,4-dihydropyridines, compounds with more lipophilic, aromatic benzyloxy substituents were poorer inhibitors of ABCC2 compared to the methoxy-substituted compounds (Coburger et al 2010). A larger study, based on 191 compounds including approved drugs, found ABCC2 inhibitors to be larger, more lipophilic and have more aromatic rings than non-inhibitors (Pedersen et al 2008).…”

Section: Introductionmentioning

confidence: 96%

A structure-activity relationship study of ABCC2 inhibitors

Wissel

Deng

Kudryavtsev

et al. 2017

European Journal of Pharmaceutical Sciences

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Multidrug resistance associated protein 2 (MRP2/ABCC2) is a membrane transport protein that can potentially affect the disposition of many substrate drugs and their metabolites. Recently, we studied the interaction of a library of 432 compounds with ABCC2, and the structure-activity relationship (SAR) of a subset of 64 compounds divided into four scaffolds (Wissel, G. et al., 2015. Bioorg Med Chem., 23(13), pp.3513–25). We have now expanded this test set by investigating 114 new compounds, of which 71 are representative of the previous four scaffolds and 43 compounds belong to a new scaffold. Interaction with ABCC2 was assessed by measuring the compounds effect on 5(6)-carboxy-2′,7′-dichlorofluorescein transport in the vesicular transport assay. In line with our previous study, we observed that anionic charge is not essential for inhibition of ABCC2 transport, even though it often increases the inhibitory activity within the analogue series. Additionally, we found that halogen substitutions often increase the inhibitory activity. The results confirm the importance of structural features such as aromaticity and lipophilicity for ABCC2 inhibitory activity.

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“…There was no significant change in inhibition activity with substitution of 2-chlorobenzyl (in A1) with 4-fluorobenzyl (A2). Previous studies have shown that the common feature of the transmembrane modulator is lipophilicity (Coburger et al, 2010). A1 and A2 are more lipophilic than B1, B2 (Table 2).…”

Section: P-gp and Bcrp Inhibition Profilementioning

confidence: 88%

P-gp and BCRP inhibition induced by some new 1,4-Dihydropyridine and Dihydropyrimidines

Hadizadeh

Mosaffa

Behravan

et al. 2017

IJBRA

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Abstract:Overexpression of ABC transporters leads to MDR (Multiple Drug Resistance). MDR is considered to be the major contributor to failure of chemotherapy in metastatic cancers. ABC transporters have protective role in normal cells by extruding xenobiotics of cytotoxic compounds from the cell. The development of selective inhibitors of P-gp, MRP1, MRP2, and BCRP has been a major goal of many research groups in the last few years. Previous studies have shown that 1,4-dihydropyridines could inhibit these transporters. In this study, some new 1,4-dihydropyridine and pyrimidine have been developed and their inhibitory effect on the resistant cancer cell lines was examined. In order to elucidate the binding mode of these compounds, a molecular docking and molecular dynamic simulation was performed for the protein-ligand complex. Dihydropyridines were more potent than dihydropyrimidines. However, one of the dihydropyrimidine derivatives selectively inhibited BCRP. The binding mode of these compounds showed that methoxy groups and heterocyclic rings could create hydrogen bonds with polar residues at the active sites. These regions were more stable during MD simulation.

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Novel structure–activity relationships and selectivity profiling of cage dimeric 1,4-dihydropyridines as multidrug resistance (MDR) modulators

Cited by 34 publications

References 33 publications

1,4-Dihydropyridine Scaffold in Medicinal Chemistry, The Story So Far And Perspectives (Part 2): Action in Other Targets and Antitargets

1,4-Dihydropyridine Scaffold in Medicinal Chemistry, The Story So Far And Perspectives (Part 2): Action in Other Targets and Antitargets

A structure-activity relationship study of ABCC2 inhibitors

P-gp and BCRP inhibition induced by some new 1,4-Dihydropyridine and Dihydropyrimidines

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