Extending the structure−activity relationship study of marine natural ningalin B analogues as P-glycoprotein inhibitors

Yang, Chao; Wong, Iris L. K.; Peng, Kai; Liu, Zhen; Wang, Peng; Jiang, Tianyue; Jiang, Tao; Chow, Larry M.C.; Wan, Shengbiao

doi:10.1016/j.ejmech.2016.09.070

Cited by 17 publications

(20 citation statements)

References 38 publications

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“…The P-gp inhibitory activity of natural marine compounds including Ningalin B and terpenoids was comprehensively summarized in the review article by Long et al [ 43 ]. Ningalin B is a natural marine product isolated from the ascidian (sea squirt) family of the genus Didemnum [ 44 , 45 , 46 ]. In the earliest ningalin study a number of synthetic intermediates (e.g., O -methyl ningalin B, compounds 10, 11, 13 and 14) were synthesised from the ningalin isolate [ 44 ].…”

Section: Abcb1/p-gpmentioning

confidence: 99%

“…The P-gp overexpressed breast cancer cell line MDA435/LCC6MDR was used to investigate the most recently designed ningalin analogues by direct comparison with wild type MDA435/LCC6 ( Table 1 ) [ 45 , 50 , 51 , 52 ]. Doxorubicin accumulation assays showed that compounds 6, 25, 12, 23, 35 and 37 caused a 3.0, 2.1, 2.6, 2.4, 2.2 and 2.3-fold increase in doxorubicin accumulation in resistant cell lines, respectively ( Table 2 ) [ 45 , 50 , 52 ]. The potency of compounds based on the doxorubicin accumulation from the most to the least potent were as follows: 37 > 35 > 23 > 12 > 6 > 25 [ 45 , 50 , 52 ].…”

Section: Abcb1/p-gpmentioning

confidence: 99%

“…Doxorubicin accumulation assays showed that compounds 6, 25, 12, 23, 35 and 37 caused a 3.0, 2.1, 2.6, 2.4, 2.2 and 2.3-fold increase in doxorubicin accumulation in resistant cell lines, respectively ( Table 2 ) [ 45 , 50 , 52 ]. The potency of compounds based on the doxorubicin accumulation from the most to the least potent were as follows: 37 > 35 > 23 > 12 > 6 > 25 [ 45 , 50 , 52 ]. These compounds were also nontoxic towards normal human fibroblast L929 cells LCC6 [ 45 , 50 , 51 , 52 ].…”

Section: Abcb1/p-gpmentioning

confidence: 99%

“…The potency of compounds based on the doxorubicin accumulation from the most to the least potent were as follows: 37 > 35 > 23 > 12 > 6 > 25 [ 45 , 50 , 52 ]. These compounds were also nontoxic towards normal human fibroblast L929 cells LCC6 [ 45 , 50 , 51 , 52 ]. The combination of compounds 6 and 23 showed a greater response towards doxorubicin accumulation than when used individually [ 52 ].…”

Section: Abcb1/p-gpmentioning

confidence: 99%

“…Quantifying the accumulation levels of specific P-gp substrates within the cell correlates with the activity of the P-gp transporter [ 45 , 50 , 52 ]. Compounds 12 ( Figure 1 ) (2 µM) and 23 (2 µM) increased rhodamine 123 accumulation by 3.9 and 4.8-fold, respectively [ 45 , 51 ]. Compound 23 showed an EC 50 of 78 nM which was 4.7-fold less than the typical P-gp inhibitor verapamil [ 45 ].…”

Section: Abcb1/p-gpmentioning

confidence: 99%

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The Effects of Synthetically Modified Natural Compounds on ABC Transporters

et al. 2018

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Multidrug resistance (MDR) is a major hurdle which must be overcome to effectively treat cancer. ATP-binding cassette transporters (ABC transporters) play pivotal roles in drug absorption and disposition, and overexpression of ABC transporters has been shown to attenuate cellular/tissue drug accumulation and thus increase MDR across a variety of cancers. Overcoming MDR is one desired approach to improving the survival rate of patients. To date, a number of modulators have been identified which block the function and/or decrease the expression of ABC transporters, thereby restoring the efficacy of a range of anticancer drugs. However, clinical MDR reversal agents have thus far proven ineffective and/or toxic. The need for new, effective, well-tolerated and nontoxic compounds has led to the development of natural compounds and their derivatives to ameliorate MDR. This review evaluates whether synthetically modifying natural compounds is a viable strategy to generate potent, nontoxic, ABC transporter inhibitors which may potentially reverse MDR.

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Section: Abcb1/p-gpmentioning

confidence: 99%

Section: Abcb1/p-gpmentioning

confidence: 99%

Section: Abcb1/p-gpmentioning

confidence: 99%

Section: Abcb1/p-gpmentioning

confidence: 99%

Section: Abcb1/p-gpmentioning

confidence: 99%

See 3 more Smart Citations

The Effects of Synthetically Modified Natural Compounds on ABC Transporters

et al. 2018

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Ningalins, Pyrrole‐Bearing Metabolites Isolated from Didemnum spp. Synthesis and MDR‐Reversion Activity in Cancer Therapy

Segura‐Quezada,

Hernández‐Velázquez,

Corrales‐Escobosa

et al. 2024

Chemistry & Biodiversity

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Multi‐Drug Resistance (MDR) is one of the most frequent problems observed in the course of cancer chemotherapy. Cells under treatment, tend to develop survival mechanisms to drug‐action thus generating drug‐resistance. One of the most important mechanism to get it is the over expression of P‐gp glycoprotein, which acts as an efflux‐pump releasing the drug outside of the cancer cell. A strategy for a succesfull treatment consists in the co‐administration of one compound that acts against P‐gp and another which acts against the cell during chemotherapy. Ningalins are pyrrole‐containing naturally occurring compounds isolated mainly from the marine tunicate Didemnum spp and also they are some of the top reversing agents in MDR treatment acting on P‐gp. Considering the relevance displayed for some of these isolated alkaloids or their core as a drug for co‐administration in cancer therapy, all the total synthesis described to date for the members of ningalins family are reviewed herein.

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Synthesis of 5‐Hydroxy‐3′,4′,7‐trimethoxyflavone and Related Compounds and Elucidation of Their Reversal Effects on BCRP/ABCG2‐Mediated Anticancer Drug Resistance

et al. 2018

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3',4',7-Trimethoxyflavone (TMF) has been reported to show a potent reversal effect on drug resistance mediated by breast cancer resistance protein (BCRP)/ATP-binding cassette subfamily G member 2 (ABCG2). In this study, we designed and synthesized five derivatives with either a hydroxy group or a fluorine atom at C-5 and several kinds of capping moiety at the C-7 hydroxy group, on the same 3',4'-dimethoxy-substituted flavone skeleton. We subsequently evaluated the efficacies of these compounds against BCRP-expressing human leukaemia K562/BCRP cells. Reversal of drug resistance was expressed as the concentration of compound causing a twofold reduction in drug sensitivity (RI ). Of the synthesized compounds, the reversal effect of 5-hydroxy-3',4',7-trimethoxyflavone (HTMF, RI 7.2 nm) towards 7-ethyl-10-hydroxycamptothecin (SN-38) was stronger than that of TMF (RI 18 nm). Fluoro-substituted 5-fluoro-3',4',7-trimethoxyflavone (FTMF, RI 25 nm) and monoglycosylated 7-(β-glucosyloxy)-5-hydroxy-3',4'-dimethoxyflavone (GOHDMF, 91 nm) also exhibited reversal effects, whereas the di- and triglycoside derivatives did not. TMF, HTMF and FTMF at 0.01-10 μm upregulated the K562/BCRP cellular accumulation of Hoechst 33342 nuclear staining dye. In addition, western blotting revealed that treatment of K562/BCRP cells with 0.1 μm TMF, HTMF or FTMT suppressed the expression of BCRP. HTMF showed the strongest inhibition of BCRP-mediated efflux and suppression of BCRP expression of the three effective synthesized flavones.

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Extending the structure−activity relationship study of marine natural ningalin B analogues as P-glycoprotein inhibitors

Cited by 17 publications

References 38 publications

The Effects of Synthetically Modified Natural Compounds on ABC Transporters

The Effects of Synthetically Modified Natural Compounds on ABC Transporters

Ningalins, Pyrrole‐Bearing Metabolites Isolated from Didemnum spp. Synthesis and MDR‐Reversion Activity in Cancer Therapy

Synthesis of 5‐Hydroxy‐3′,4′,7‐trimethoxyflavone and Related Compounds and Elucidation of Their Reversal Effects on BCRP/ABCG2‐Mediated Anticancer Drug Resistance

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