Recruitment of hexahydroquinoline as anticancer scaffold targeting inhibition of wild and mutants EGFR (EGFR<sup>WT</sup>, EGFR<sup>T790M</sup>, and EGFR<sup>L858R</sup>)
Creators: name: Al-Hamd, Mahmoud G. Abo
name: Tawfik, Haytham O.
name: Abdullah, Omeima
name: Yamaguchi, Koki
name: Sugiura, Masaharu
name: Mehany, Ahmed B. M.
name: El-Hamamsy, Mervat H.
name: El-Moselhy, Tarek F.
Publisher: name: Taylor & Francis
Year: 2023
Subjects: Biochemistry
Cell Biology
Pharmacology
Biotechnology
Chemical Sciences not elsewhere classified
Biological Sciences not elsewhere classified
Developmental Biology
Marine Biology
Cancer

description: Hexahydroquinoline (HHQ) scaffold was constructed and recruited for development of new series of anticancer agents. Thirty-two new compounds were synthesised where x-ray crystallography was performed to confirm enantiomerism. Thirteen compounds showed moderate to good activity against NCI 60 cancer cell lines, with GI % mean up to 74% for <b>10c</b>. Expending erlotinib as a reference drug, target compounds were verified for their inhibiting activities against EGFR<sup>WT</sup>, EGFR<sup>T790M</sup>, and EGFR<sup>L858R</sup> where compound <b>10d</b> was the best inhibitor with IC<sub>50</sub> = 0.097, 0.280, and 0.051 µM, respectively, compared to erlotinib (IC<sub>50</sub> = 0.082 µM, 0.342 µM, and 0.055 µM, respectively). Safety profile was validated using normal human lung (IMR-90) cells. <b>10c</b> and <b>10d</b> disrupted cell cycle at pre-G1 and G2/M phases in lung cancer, HOP-92, and cell line. Molecular docking study was achieved to understand the potential binding interactions and affinities in the active sites of three versions of EGFRs. New 32 hexahydroquinoline (HHQ) analogues <b>6a–i</b>, <b>8a–m</b>, <b>10a–d</b>, and <b>12a–f</b> having the same features of EGFR inhibitors were synthesised in racemic mixtures.The antiproliferative activities were assessed towards 60 cancer cell lines which were efficiently inhibited by compound <b>10c</b>.Compound <b>10d</b> remarkably inhibited EGFR<sup>WT</sup>, EGFR<sup>T790M</sup>, and EGFR<sup>L858R</sup>.Cell cycle analysis and Annexin V-based flow cytometry in the HOP-92 lung cancer cells were performed.The safety profile of compounds <b>10c</b> and <b>10d</b> was validated using normal human lung (IMR-90) cells.Molecular docking studies revealed that the <i>S</i>-isomers exhibited higher affinity than <i>R</i>-isomers to active sites. New 32 hexahydroquinoline (HHQ) analogues <b>6a–i</b>, <b>8a–m</b>, <b>10a–d</b>, and <b>12a–f</b> having the same features of EGFR inhibitors were synthesised in racemic mixtures. The antiproliferative activities were assessed towards 60 cancer cell lines which were efficiently inhibited by compound <b>10c</b>. Compound <b>10d</b> remarkably inhibited EGFR<sup>WT</sup>, EGFR<sup>T790M</sup>, and EGFR<sup>L858R</sup>. Cell cycle analysis and Annexin V-based flow cytometry in the HOP-92 lung cancer cells were performed. The safety profile of compounds <b>10c</b> and <b>10d</b> was validated using normal human lung (IMR-90) cells. Molecular docking studies revealed that the <i>S</i>-isomers exhibited higher affinity than <i>R</i>-isomers to active sites.