Nitrogen-containing naringenin derivatives for reversing multidrug resistance in cancer

Probing the allosteric modulation of P-glycoprotein: A medicinal chemistry approach towards the identification of non-competitive P-gp inhibitors.

“…These findings led the authors to suggest that this particular compound modulates P-gp drug efflux by a different mechanism. 19 Herein, and based on our findings, we hypothesize that compound 23 is able to act as an allosteric inhibitor by targeting the ICHs-NBD2 interface and impairing signal-transmission, thus blocking the efflux-related conformational changes that ultimately leads to drug efflux.…”

“…Finally, the possibility of compound 23 to act as a non-competitive inhibitor is reinforced by a previous published work made in our group using the same flavanone derivatives dataset. Quite interestingly, compound 23 -corresponding to compound 31 in previous work 19 -had much higher cytotoxicity in the ABCB1overexpressing L5178Y (L5178Y-MDR) than in parental cell lines (7.25 µM vs > 100 µM, respectively), but it was unable to promote R123 accumulation in resistant cells (FAR of 0.94 and 1.13 at 2.0 and 20 µM, respectively). Yet, it was still able to synergistically enhance doxorubicin cytotoxicity.…”

“…Moreover since it is an independent technique from the fragment-based molecular dynamics reported above, it can also provide a statistical check for results reliability. Based on the scaffolds found in each hotspot at the ICH-NBD interfaces, a small in-house library of thioxanthone 14 and flavanone derivatives [19][20] was selected for this purpose (Table S3). Additionally, since BUM and NPA were experimentally predicted to bind in a pocket located between the ICHs and Q-loop motif of NBDs, 18 these compounds were also included as references in our docking studies.…”

“…As anticipated, BUM, described as a potential ICH-NBD binder, 18 had a stronger impact on decreasing the verapamilstimulated ATPase activity than spiropedroxodiol, a potent efflux P-gp inhibitor that showed competition with Rhodamine-123 (R123) inside the DBP at the nanomolar range. 19,20 Interestingly, all the other compounds with lower ATPase inhibition rates (compounds 1-4, 6-15, 18, 19, 21, 22, 25 and 26) were previously described as competitive efflux modulators in the R123 accumulation assay, 19,20 with fluorescence activity ratios (FAR) ranging from 2.10 (7) up to 10.67 (8) at 2.0 µM. The only exceptions are compounds 27 (FAR, 4.06; ΔRLU, 1.2) and 28 (FAR, 3.08; ΔRLU, 0.6).…”

Pedrolane, a Polycyclic Diterpene Scaffold Containing a Bicyclo[2.2.1]heptane System, from Euphorbia pedroi

“…In our search for effective MDR reversers, − the phytochemical study of Euphorbia pedroi Molero and Rovira, an endemic plant of the western sea cliffs in Portugal, was performed . Herein a novel noncytotoxic tigliane-type diterpenoid was isolated from the methanol extract, with a previously unreported skeleton, which was evaluated for its ability to inhibit P-glycoprotein (P-gp/ABCB1).…”