Design, synthesis and bioactivity study on oxygen-heterocyclic-based pyran analogues as effective P-glycoprotein-mediated multidrug resistance in MCF-7/ADR cell

• Published in: Scientific reports Vol. 14; no. 1; p. 7589
• Main Authors: Abd El-Wahab, Ashraf H. F., Borik, Rita M. A., Al-Dies, Al-Anood M., Fouda, Ahmed M., Mohamed, Hany M., El-Eisawy, Raafat A., Mora, Ahmed, El-Nassag, Mohammed A. A., Abd elhady, Ahmed M., Elhenawy, Ahmed A., El-Agrody, Ahmed M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31-03-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154; 631/45; 639/638/309; 639/638/403; 639/638/45; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; ATP Binding Cassette Transporter, Subfamily B - metabolism; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Bioavailability; Biological activity; Blood-brain barrier; Cell cycle; Doxorubicin - pharmacology; Drug resistance; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Glycoproteins; Humanities and Social Sciences; Humans; MCF-7 Cells; Molecular Docking Simulation; multidisciplinary; Multidrug resistance; Nitrogen dioxide; Oxygen - metabolism; P-Glycoprotein; Pharmacokinetics; S phase; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-56197-w

P
-glycoprotein (
P
-gp) imparts multi-drug resistance (MDR) on the cancers cell and malignant tumor clinical therapeutics. We report a class of newly designed and synthesized oxygen-heterocyclic-based pyran analogues
(4a–l)
bearing different aryl/hetaryl-substituted at the 1-postion were synthesized, aiming to impede the
P
-gp function. These compounds (
4a–l
) have been tested against cancerous PC-3, SKOV-3, HeLa, and MCF-7/ADR cell lines as well as non-cancerous HFL-1 and WI-38 cell lines to determine their anti-proliferative potency.The findings demonstrated the superior potency of
4a–c
with 4-F, 2-Cl, and 3-Cl derivatives and
4h,g
with 4-NO
2
, 4-MeO derivatives against PC-3, SKOV-3, HeLa, and MCF-7/ADR cell lines.Compounds
4a–c
were tested for
P
-gp inhibition and demonstrated significant vigour against MCF-7/ADR cells with IC
50
 = 5.0–10.7 μM. The Rho123 accumulation assay showed that compounds
4a–c
adequately inhibited
P
-gp function, as predicted. Furthermore,
4a
or
4b
administration resulted in MCF-7/ADR cell accumulation in the S phase, while compound
4c
induced apoptosis by causing cell cycle arrest at G2/M. The molecular docking was applied to understand the likely modes of action and guide us in the rational design of more potent analogs. The investigate derivatives showed their good binding potential for
p
-gp active site with excellent docking scores and interactions. Finally, the majority of investigated derivatives
4a–c
derivatives showed high oral bioavailability, but they did not cross the blood–brain barrier. These results suggest that they have favorable pharmacokinetic properties. Therefore, these compounds could serve as leads for designing more potent and stable drugs in the future.