Pharmacophore modeling and 3D-QSAR studies of galloyl benzamides as potent P-gp inhibitors

Srivastava, Shubham; Choudhary, Bhanwar Singh; Sharma, Manish; Malik, Ruchi

doi:10.1007/s00044-016-1556-4

Cited by 3 publications

(4 citation statements)

References 18 publications

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“…Interestingly, all the polyoxygenated steroids investigated for antitumor [66], antibacterial [64], antifungal [64], and reversing MDR [62] activities contain the characteristic 3β,5α,6β-hydroxyl moiety. Among these derivatives are a spiroketal hippurinstanol (14), hippuristerone (15), which possesses a 3-keto group, and the cyclopropane-containing gorgosterols (16)(17)(18)(19)(20) (Figure 4) [62,64]. Polyoxygenated steroids 14-20 also differ in the side chains.…”

Section: Polyoxygenated Steroids and Derivativesmentioning

confidence: 99%

“…Among these derivatives are a spiroketal hippurinstanol (14), hippuristerone (15), which possesses a 3-keto group, and the cyclopropane-containing gorgosterols (16)(17)(18)(19)(20) (Figure 4) [62,64]. Polyoxygenated steroids 14-20 also differ in the side chains.…”

Section: Polyoxygenated Steroids and Derivativesmentioning

confidence: 99%

“…First generation of P-gp inhibitors referred to drugs already in clinical use or under investigation for therapeutic ability e.g., verapamil, quinidine, and cyclosporine A [19]. However, most of the first generation P-gp inhibitors were found to lack selectivity for P-gp and being substrates for other transporters and enzyme systems; this promiscuity resulted in unpredictable pharmacokinetic interactions in the presence of anticancer drugs [20].…”

Section: Introductionmentioning

confidence: 99%

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Marine Natural Products as Models to Circumvent Multidrug Resistance

et al. 2016

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Multidrug resistance (MDR) to anticancer drugs is a serious health problem that in many cases leads to cancer treatment failure. The ATP binding cassette (ABC) transporter P-glycoprotein (P-gp), which leads to premature efflux of drugs from cancer cells, is often responsible for MDR. On the other hand, a strategy to search for modulators from natural products to overcome MDR had been in place during the last decades. However, Nature limits the amount of some natural products, which has led to the development of synthetic strategies to increase their availability. This review summarizes the research findings on marine natural products and derivatives, mainly alkaloids, polyoxygenated sterols, polyketides, terpenoids, diketopiperazines, and peptides, with P-gp inhibitory activity highlighting the established structure-activity relationships. The synthetic pathways for the total synthesis of the most promising members and analogs are also presented. It is expected that the data gathered during the last decades concerning their synthesis and MDR-inhibiting activities will help medicinal chemists develop potential drug candidates using marine natural products as models which can deliver new ABC transporter inhibitor scaffolds.

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Section: Polyoxygenated Steroids and Derivativesmentioning

confidence: 99%

Section: Polyoxygenated Steroids and Derivativesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Marine Natural Products as Models to Circumvent Multidrug Resistance

et al. 2016

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“…QSAR has been widely used to determine whether a compound is an inhibitor of P-gp. Various studies have built the three-dimensional quantitative structure–activity relationships (3D-QSAR) model to investigate the inhibitory activity on P-gp [18,19,20]. The model is limited as it is based on the assumption that compounds all act on the same receptor.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Structure–Activity Relationships for the Flavonoid-Mediated Inhibition of P-Glycoprotein in KB/MDR1 Cells

et al. 2019

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P-glycoprotein (P-gp) serves as a therapeutic target for the development of inhibitors to overcome multidrug resistance (MDR) in cancer cells. In order to enhance the uptake of chemotherapy drugs, larger amounts of P-gp inhibitors are required. Besides several chemically synthesized P-gp inhibitors, flavonoids as P-gp inhibitors are being investigated, with their advantages including abundance in our daily diet and a low toxicity. The cytotoxicity of daunorubicin (as a substrate of P-gp) to KB/MDR1 cells and the parental KB cells was measured in the presence or absence of flavonoids. A two-dimensional quantitative structure–activity relationship (2D-QSAR) model was built with a high cross-validation coefficient (Q2) value of 0.829. Descriptors including vsurf_DW23, E_sol, Dipole and vsurf_G were determined to be related to the inhibitory activity of flavonoids. The lack of 2,3-double bond, 3′-OH, 4′-OH and the increased number of methoxylated substitutions were shown to be beneficial for the inhibition of P-gp. These results are important for the screening of flavonoids for inhibitory activity on P-gp.

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