Structural characteristics of compounds that modulate P-glycoprotein-associated multidrug resistance

doi:10.1016/0065-2571(90)90026-X

Advances in Enzyme Regulation

Volume 30, 1990, Pages 357-373

https://doi.org/10.1016/0065-2571(90)90026-X Get rights and content

Abstract

Multidrug resistance is mediated by a membrane-bound protein, P-gp, that functions as an energy dependent efflux system to reduce the intracellular concentration of anticancer drugs by binding to these drugs and actively exporting them from the cell. Compounds that interact with P-gp and compete with anticancer drug binding modulate the degree of drug resistance and therefore enhance the cytotoxicity of anticancer drugs against the resistant cell. Effective modulators share certain physical and chemical properties including octanol/water partitioning and molecular size, but the physical properties of size and shape seem to correlate best with modulator effectiveness.

Using a photoactivatable analog of vinblastine as a probe, together with a semi-synthetic series of structurally homologous reserpine and yohimbine analogs, the need for two planar aromatic domains and a basic nitrogen atom was established within the structural context of these compounds. The use of three-dimensional comparisons was extended to examine important structural features in other modulator types such as the condensed-ring aromatics. This approach indicates that structural similarities between different classes of compounds are present in compounds recognized by the MDR phenotype.

These studies emphasize the importance of a ligand-receptor relationship for modulators of MDR, and begin to define the P-gp-binding pharmacophore. it is likely that this approach will be useful in directing the de novo synthesis of compounds that modulate MDR and help to further define the requirements for molecular recognition by this system.

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Substrates share little consistent chemical, pharmacological or structural features and the pharmacophore of interaction is not completely understood. Attempts to define the pharmacophore have been restricted to physical features including hydrophobicity, planarity and the presence of a cationic nitrogen group [1,2]. P-gp expression in cancer cells is associated with a multidrug resistance phenotype and its impacts on patient survival, the incidence of remission and contribution to the failure of chemotherapy are compelling.
A mechanistic understanding of how P-glycoprotein (Pgp) is able to bind and transport its astonishing range of substrates remains elusive. Pharmacological data demonstrated the presence of at least four distinct binding sites, but their locations have not been fully elucidated. The combination of biochemical and structural data suggests that initial binding may occur in the central cavity or at the lipid-protein interface. Our objective was to define the binding sites for two transported substrates of Pgp; the anticancer drug vinblastine and the fluorescent probe rhodamine 123. A series of mutations was generated in positions proximal to previously defined drug-interacting residues on Pgp. The protein was purified and reconstituted into styrene-maleic acid lipid particles (SMALPs) to measure the apparent drug binding constant or into liposomes for assessment of drug-stimulated ATP hydrolysis. The biochemical data were reconciled with structural models of Pgp using molecular docking. The data indicated that the binding of rhodamine 123 occurred predominantly within the central cavity of Pgp. In contrast, the significantly more hydrophobic vinblastine bound to both the lipid-protein interface and within the central cavity. The data suggest that the initial interaction of vinca alkaloids with Pgp occurs at the lipid interface followed by internalisation into the central cavity, which also provides the transport conduit. This model is supported by recent structural observations with Pgp and early biophysical and cross-linking approaches. Moreover, the proposed model illustrates that the broad substrate profile for Pgp is underpinned by a combination of multiple initial interaction sites and an accommodating transport conduit.
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Nanomedicine, the application of nanotechnology to treatment and prevention of diseases, is an emerging form of drug therapy that utilizes nanomaterials as drug carriers for enhancing treatment efficacy while reducing detrimental side effects to normal tissues. Nanomaterials, with their size range (1–100 nm) that corresponds to basic biological materials such as DNA and vastly increased surface area, have a wide range of applications from drug and gene delivery to biomedical imaging. The major advantages of using nanomaterials as a carrier for anticancer agents are the possibility of targeted delivery to the tumor, tumor imaging, their ability to hold thousands of molecules of a drug, and also their ability to overcome solubility, stability, and resistance issues. Currently, there are several nanotechnology-enabled diagnostic and therapeutic agents undergoing clinical trials, and a few are already approved by the US Food and Drug Administration (FDA) and European Medicine Agency (EMA). Targeted delivery of anticancer agents is achieved by “Enhanced Permeation and Retention Effect” (EPR effect) and/or active targeting. This review provides an update on FDA-approved cancer nanomedicines and those in nanoplatforms that have reached an advanced stage of clinical development utilizing liposomes, albumin nanospheres, micelles, and gold nanoparticles.
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Our previous QSAR analysis with 41 structurally-different compounds revealed that two carbocyclic systems with at least one aromatic ring and ring-linking groups containing one carbon atom were important for stimulating ABCB1-dependent ATPase activity (Sakurai et al., 2007). On the other hand, other investigations have indicated important structural features of molecules that modulate the function of ABCB1, namely two planar aromatic domains and a basic nitrogen atom within an extended aliphatic chain, a bulky aromatic ring system with a heteroatom in the third position toward the anthranilamide nucleus at the opposite end of the tetrahydroquinoline group, hydrophobicity, and nitrogen or hydrogen bond acceptor groups (Chiba et al., 1996; Ecker et al., 1999; Globisch et al., 2006; Klopman et al., 1997; Pearce et al., 1989, 1990; Zamora et al., 1988). Furthermore, previous studies of pharmacophore identification of ABCB1-related drugs have pointed to hydrophobic and hydrogen bond-acceptor interactions as the most likely to be involved in ligand binding to ABCB1 (Ekins et al., 2002; Garrigues et al., 2002; Pajeva and Wiese, 2002; Penzotti et al., 2002).
The Pterogyne nitens (Fabaceae) tree, native to South America, has been found to produce guanidine alkaloids as well as bioactive flavonols such as kaempferol, quercetin, and rutin. In the present study, we examined the possibility of interaction between human ATP-binding cassette (ABC) transporter ABCB1 and four guanidine alkaloids isolated from P. nitens (i.e., galegine, nitensidine A, pterogynidine, and pterogynine) using human T cell lymphoblast-like leukemia cell line CCRF-CEM and its multi-drug resistant (MDR) counterpart CEM/ADR5000. In XTT assays, CEM/ADR5000 cells were resistant to the four guanidine alkaloids compared to CCRF-CEM cells, although the four guanidine alkaloids exhibited some level of cytotoxicity against both CCRF-CEM and CEM/ADR5000 cells. In ATPase assays, three of the four guanidine alkaloids were found to stimulate the ATPase activity of ABCB1. Notably, nitensidine A was clearly found to stimulate the ATPase activity of ABCB1 as strongly as the control drug, verapamil. Furthermore, the cytotoxic effect of nitensidine A on CEM/ADR5000 cells was synergistically enhanced by verapamil. Nitensidine A inhibited the extrusion of calcein by ABCB1. In the present study, the possibility of interaction between ABCB1 and two synthetic nitensidine A analogs (nitensidine AT and AU) were examined to gain insight into the mechanism by which nitensidine A stimulates the ATPase activity of ABCB1. The ABCB1-dependent ATPase activity stimulated by nitensidine A was greatly reduced by substituting sulfur (S) or oxygen (O) for the imino nitrogen atom (N) in nitensidine A. Molecular docking studies on human ABCB1 showed that, guanidine alkaloids from P. nitens dock to the same binding pocket as verapamil. Nitensidine A and its analogs exhibit similar binding energies to verapamil. Taken together, this research clearly indicates that nitensidine A is a novel substrate for ABCB1. The present results also suggest that the number, binding site, and polymerization degree of the isoprenyl moiety in the guanidine alkaloids and the imino nitrogen atom cooperatively contribute to their stimulation of ABCB1's ATPase activity.
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The relatively low uptake of [11C]6 in whole brain and D3 receptor-rich regions was unexpected since previous studies have shown 6 (i.e., WC-10) to be pharmacologically active in behavioral studies [26,44]. P-gp has a high affinity for lipophilic molecules of moderate weight and size that contain cationic centers and planar aromatic domains [51–53]. CycA, a nonspecific competitive inhibitor of P-gp, reduces P-glycoprotein-dependent drug efflux from the CNS.
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Precursors were synthesized, and the four D₃ selective benzamide analogs were radiolabeled. The tissue distribution and brain uptake of the four compounds were evaluated in control rats and rats pretreated with cyclosporin A, a modulator of P-glycoprotein and an inhibitor of other ABC efflux transporters that contribute to the blood brain barrier. Micro-positron emission tomographic (PET) imaging was carried out for [¹¹C]6 in a control and a cyclosporin A pretreated rat.
All four compounds showed low brain uptake in control rats at 5 and 30 min post-injection; despite recently reported rat behavioral studies conducted on analogs 6 (WC-10) and 7 (WC-44). Following administration of cyclosporin A, increased brain uptake was observed with all four PET radiotracers at both 5 and 30 min post-intravenous injection. An increase in brain uptake following modulation/inhibition of the ABC transporters was also observed in the microPET study.
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Some groups have been able to define a structure‐activity relationship and models for P‐gp inhibition based around large numbers of structurally similar analogues known to be inhibitors, such as phenothiazines,157 propafenone inhibitors,158 or diverse inhibitors of ATPase activity.159 These models suggested the importance of aromatic rings and a basic nitrogen atom in P‐gp modulation.160,161 A subsequent, more extensive study with 232 phenothiazines and structurally related compounds indicated that molecules with a carbonyl group that was part of an amide functionality, together with a tertiary amine, were active P‐gp inhibitors.162
Enaminones, enamines of β‐dicarbonyl compounds, have been known for many years. Their early use has been relegated to serving as synthetic intermediates in organic synthesis and of late, in pharmaceutical development. Recently, the therapeutic potential of these entities has been realized. This review provides the background and current research in this area with emphasis of these agents as potential anticonvulsants, their proposed mechanisms of action, and as potential modulators of multidrug resistance (MDR). © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 2509–2531, 2007

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Structural characteristics of compounds that modulate P-glycoprotein-associated multidrug resistance

Abstract

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

Biochem. Pharmacol.

Biochem. Biophys. Res. Commun.

Biochem. Pharmacol.

Amplification of dihydrofolate reductase genes in methotrexate-resistant cultured mouse cells

Cross-resistance to intercalating agents in an epipodophyllotoxin-resistant Chinese hamster ovary cell line: Evidence for a common intracellular target

Cancer Res.

Glutathione-S-transferases in nitrogen mustard-resistant and -sensitive cell lines

Mol. Pharmacol.

Multiple-drug resistance in human cancer

New Engl. J. Med.

Multidrug resistance

J. Natl. Cancer Inst.

ATP-binding properties of P-glycoprotein from multidrug-resistant KB cells

FASEB J.