Flavonoid dimers as bivalent modulators for P-glycoprotein-based multidrug resistance: synthetic apigenin homodimers linked with defined-length poly(ethylene glycol) spacers increase drug retention and enhance chemosensitivity in resistant cancer cells.

Much effort has been spent on searching for better P-glycoprotein- (P-gp-) based multidrug resistance (MDR) modulators. Our approach was to target the binding sites of P-gp using dimers of dietary flavonoids. A series of apigenin-based flavonoid dimers, linked by poly(ethylene glycol) chains of various lengths, have been synthesized. These flavonoid dimers modulate drug chemosensitivity and retention in breast and leukemic MDR cells with the optimal number of ethylene glycol units equal to 2-4. Compound 9d bearing four ethylene glycol units increased drug accumulation in drug-resistant cells and enhanced cytotoxicity of paclitaxel, doxorubicin, daunomycin, vincristine, and vinblastine in drug-resistant breast cancer and leukemia cells in vitro, resulting in reduction of IC50 by 5-50 times. This compound also stimulated P-gp's ATPase activity by 3.3-fold. Its modulating activity was presumably by binding to the substrate binding sites of P-gp and disrupting drug efflux.

Flavonoid dimers as novel, potent antileishmanial agents.

The present study found that synthetic flavonoid dimers with either polyethylene glycol linker or amino ethyleneglycol linker have marked leishmanicidal activity. Compound 39 showed very consistent and promising leishmanicidal activity for both extracellular promastigotes (IC50 ranging from 0.13 to 0.21 µM) and intracellular amastigotes (IC50 = 0.63 µM) irrespective of the drug-sensitivity of parasites. Moreover, compound 39 displayed no toxicity toward macrophage RAW 264.7 cells (IC50 > 100 µM) and primary mouse peritoneal elicited macrophages (IC50 > 88 µM). Its high value of therapeutic index (>140) was better than other highly potent antileishmanials such as amphotericin B (therapeutic index = 119). Compound 39 is therefore a new, safe, and effective antileishmanial candidate compound which is even effective against drug-refractory parasites.

Amine linked flavonoid dimers as modulators for P-glycoprotein-based multidrug resistance: structure-activity relationship and mechanism of modulation.

Here we report a great improvement in reversal potency of cancer drug resistance when flavonoid dimers possess a functionally substituted aminopolyethylene glycol linker. The most potent compound, 18, contains a N-benzyl group at the linker. It has many advantages including (1) high potencies in reversing P-glycoprotein (P-gp) mediated resistance in LCC6MDR cells to various anticancer drugs with EC(50) in the nanomolar range, (2) low toxicity and high therapeutic index, and (3) preferential inhibition of P-gp over multidrug resistance protein 1 and breast cancer resistance protein. Compound 18 stimulates P-gp-ATPase activity by 2.7-fold and mediates a dose-dependent inhibition of doxorubicin (DOX) transport activity. Lineweaver-Burk and Dixon plots suggest that 18 is a competitive inhibitor to DOX in binding to P-gp with a K(i) of 0.28-0.34 µM and a Hill coefficient of 1.17. Moreover, the LCC6MDR cell displays about 2.1-fold lower intracellular accumulation of 18 compared to the wild type, suggesting that 18 is a P-gp substrate as well.