Design and Syntheses of Permethyl Ningalin B Analogues: Potent Multidrug Resistance (MDR) Reversal Agents of Cancer Cells

Abstract

A series of novel N-arylalkyl-3,4-diaryl-substituted pyrrole-2,5-diones were synthesized. They exhibited promising P-gp modulating activity in a P-gp overexpressing breast cancer cell line (LCC6MDR). Compound 6 (with three methoxy groups at D-ring) displayed the highest P-gp modulating activity. 6 at 1 microM can sensitize LCC6MDR cells toward paclitaxel by 18.2-fold. Interestingly, a synergy on modulating P-gp was noted when 6 and 25 were used together (fractional inhibitory concentration index FICI = 0.42). Combination of 6 (0.5 microM) and 25 (0.5 microM) resulted in a 66-fold sensitization of LCC6MDR cells toward paclitaxel. They also reversed P-gp mediated doxorubicin (DOX) and vincristine resistance. Kinetic characterization suggests that permethyl ningalin B analogues likely act as a noncompetitive inhibitor of P-gp-mediated DOX transport (K(i) = 5.4-5.8 microM). The present study demonstrates that synthetic analogues of permethyl ningalin B can be employed as effective and safe modulators of P-gp-mediated drug resistance in cancer cells.

Marine Natural Products as Models to Circumvent Multidrug Resistance

“…The amide analogs of 48 enhanced the MDR activity, while amine derivatives (dimers) were inactive as MDR reversal compounds [115]. The synthetic analog of 46, 1-[2-(4-methoxyphenyl)-2-oxoetyl]-3,4-bis(3,4-dimethoxyphenyl)-1H-pyrrole-2,5-dione (52) which was designed from permethyl ningalin B showed a remarkable enhancement of MDR reversal abilities in concentrations up to 1 µM [117,118]. Compound 53, having a methoxy group on the D-ring, showed a 18.2-fold increase in cell sensitization towards paclitaxel at 1 µM concentration, and a 66 fold one when 0.5 µM of 53 was combined with 0.5 µM of 54 [117].…”

“…The synthetic analog of 46, 1-[2-(4-methoxyphenyl)-2-oxoetyl]-3,4-bis(3,4-dimethoxyphenyl)-1H-pyrrole-2,5-dione (52) which was designed from permethyl ningalin B showed a remarkable enhancement of MDR reversal abilities in concentrations up to 1 µM [117,118]. Compound 53, having a methoxy group on the D-ring, showed a 18.2-fold increase in cell sensitization towards paclitaxel at 1 µM concentration, and a 66 fold one when 0.5 µM of 53 was combined with 0.5 µM of 54 [117]. It was found that increasing the number of methoxy groups on ring B of the ningalin scaffold showed only low to moderate P-gp-modulating activity, while the addition of a benzyloxy group on the D ring enhanced the P-gp modulating activity [119].…”

“…It was found that increasing the number of methoxy groups on ring B of the ningalin scaffold showed only low to moderate P-gp-modulating activity, while the addition of a benzyloxy group on the D ring enhanced the P-gp modulating activity [119]. SAR studies of a series of novel N-substituted derivatives of 45 on breast P-gp-overexpressing tumor cell line (LCC6MDR) showed that analogs containing one methoxy group and one benzyloxy group on ring C are the most potent P-gp modulators (1 µM desensitized cell line by 42.7 folds) without showing cytotoxicity IC 50 for L929 fibroblast >100 µM) [117,119,120]. The analog 55 containing dimethoxy groups on rings A and B, and trisubstitution with o-methoxyethylmorpholine, m-bromo and p-benzyloxyl on ring D showed an effect compatible with P-gp modulation with an effective concentration (EC 50 ) of 423 µM in reversing paclitaxel resistance [118].…”

Potent and Nontoxic Chemosensitizer of P-Glycoprotein-Mediated Multidrug Resistance in Cancer: Synthesis and Evaluation of Methylated Epigallocatechin, Gallocatechin, and Dihydromyricetin Derivatives

“…Examples include methylated quercetin with side chain modifications (compounds 1 and 2 shown in Chart 1) 36 and permethyl ningalin B and its synthetic analogues (compounds 3 and 4 shown in Chart 1). 49,50 They displayed significantly better P-gp modulating activity than the parental compounds. These results suggest that the methylation of polyphenolic compounds is a reasonable and important modification to improve P-gp modulating activity.…”

Optimization of permethyl ningalin B analogs as P-glycoprotein inhibitors

“…16 Recent rational modification of polyphenols has provided us promising lead compounds of P-gp inhibitor including flavonoid dimers, quercetin derivatives, curcumin derivatives and methylated ningalin B analogs. 4,[25][26][27][28][29][30][31][32][33] In our previous structureactivity relationship study of methylated ningalin B analogs, two potent hit compounds 1 and 2 ( Fig. 1) were found to be effective P-gp-specific inhibitor.…”