Scaffold hopping of N-benzyl-3,4,5-trimethoxyaniline: 5,6,7-Trimethoxy- flavan derivatives as novel potential anticancer agents modulating hippo signaling pathway

Scaffold hopping of N-benzyl-3,4,5-trimethoxyaniline afforded 5,6,7-trimethoxyflavan derivatives that were efficiently synthesized in four linear steps. As lung cancer is the most lethal cancer, twenty-three synthesized compounds were evaluated against a panel of lung cancer cells. Amongst, compounds 8q and 8e showed interesting activity. Hence, compounds 8q and 8e were evaluated against panels of diverse cancers. Compounds 8q and 8e showed broad spectrum anticancer activity. However, compound 8q was more effective and, hence, was advanced for potency evaluation and characterization. Compound 8q showed comparable potencies to gefitinib, and oxaliplatin against lung and colorectal cancers, respectively, and superior potencies to temozo-lomide, dacarbazine, cisplatin, enzalutamide, methotrexate, imatinib against brain, skin, ovary, prostate, breast, and blood cancers, respectively. Compound 8q increased cleaved PARP, caspase 3, and 7 inducing apoptosis. In addition, it inhibited cyclins A, B1, H and cdc25c, and increased p53 triggering cell cycle arrest in G2/M phase. Moreover, it decreased YAP and increased LATS1 and p-mob1/mob1 activating hippo signaling. Furthermore, it decreased p-PI3K/PI3k, p-mTOR/mTOR and p-P70S6K/P70S6K inhibiting PI3k pathway. Together, these find-ings present compound 8q as a potential anticancer lead compound for further development of potential agents.

Automated summary

Scaffold hopping of N-benzyl-3,4,5-trimethoxyaniline yielded 5,6,7-trimethoxyflavan derivatives synthesized in four linear steps. Compounds 8q and 8e showed interesting activity against a panel of cancer cells. Compound 8q displayed comparable potencies to gefitinib and oxaliplatin against lung and colorectal cancers, and superior potencies to several other drugs against various cancers. In addition, it induced apoptosis, triggered cell cycle arrest, and activated hippo signaling while inhibiting the PI3k pathway. Compound 8q shows potential as a lead compound for further development of anticancer agents.