Structure-activity relationships and the binding mode of quinolinone-pyrimidine hybrids as reversal agents of multidrug resistance mediated by P-gp

JERONIMO LAIOLO; PRISCILA A. LANZA; OSCAR PARRAVICINI; CECILIA BARBIERI; DANIEL INSUASTY; JUSTO COBO; D. MARIANO A. VERA *; RICARDO D. ENRIZ *; MARÍA C. CARPINELLA *

Scientific Reports

Springer-Nature

Lugar: Basingstoke; Año: 2021 vol. 11 p. 16856 - 16856

P-gp-associatedmultidrug resistance (MDR) is a major impediment to the success ofchemotherapy. With the aim of finding non-toxic and effective P-gpinhibitors, we investigated a panel of quinolin-2-one-pyrimidinehybrids. Among the active compounds, two of them significantlyincreased intracellular doxorubicin and rhodamine 123 accumulation byinhibiting the efflux mediated by P-gp and restored doxorubicintoxicity at nanomolar range. Structure-activity relationships showedthat the number of methoxy groups, an optimal length of the moleculein its extended conformation, and at least one flexible methylenegroup bridging the quinolinone to the moiety bearing the pyrimidinefavored the inhibitory potency of P-gp. The best compounds showed asimilar binding pattern and interactions to those of doxorubicin andtariquidar, as revealed by MD and hybrid QM/MM simulations performedwith the recentexperimental structure of P-gp co-crystallized with paclitaxel.Analysis of the molecular interactions stabilizing the differentmolecular complexes determined by MD and QTAIM showed that binding tokey residues from TMH 4-7 and 12 is required for inhibition.p { margin-bottom: 0.25cm; direction: ltr; color: #000000; line-height: 115%; text-align: left; orphans: 2; widows: 2; background: transparent }p.western { font-family: "Calibri", serif; font-size: 11pt; so-language: es-AR }p.cjk { font-family: "Calibri"; font-size: 11pt; so-language: en-US }p.ctl { font-family: ; font-size: 11pt; so-language: ar-SA }a:link { color: #0563c1; text-decoration: underline }