Synthesis of novel spirochromane incorporating Schiff's bases, potential antiproliferative activity, and dual EGFR/HER2 inhibition: Cell cycle analysis and in silico study

Spirochromanes incorporating Schiff's bases and semicarbazones 4a-e and 5a-j were synthesizedand analyzed for their potential antiproliferative activity using four human cancer cell lines (MCF-7, HCT-116, PC3, and A549). Compounds 5a, 5b and 5g possessed the highest antiproliferative activity among the tested compounds,with an IC50 range of 1.154-9.09 mu M. Compound 5j selectively inhibited the PC3 cell proliferation (IC50 = 5.47 mu M). Spirochromanes 5a, 5b and 5g exhibited high inhibitory activity against EGFR (IC50 = 0.116, 0.132, and 0.077 mu M, respectively) and HER2 (IC50 = 0.055, 0.210 and 0.085 mu M, respectively) compared with the references, erlotinib (IC50 = 0.090 and 0.038 mu M, respectively) and gefitinib (IC50 = 0.052 and 0.072 mu M, respectively). Cell cycle analysis and apoptosis results showed that compounds 5a, 5b and 5g arrested growth inthe S phase, and the programmed cell death induced by these compounds was an apoptotic mechanism rather than a necrotic pathway. Molecular docking stud-ies of spirochromanes 5a, 5b and 5g to EGFR and HER2 binding sites were performed to explore the ori-entation mode and interaction.(c) 2023 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

Spirochromane compounds incorporating Schiff's bases and semicarbazones were synthesized and tested for their antiproliferative activity against four human cancer cell lines. Compounds 5a, 5b, and 5g showed the highest antiproliferative activity and exhibited high inhibitory activity against EGFR and HER2. The study also found that these compounds arrested cell growth in the S phase and induced programmed cell death.