2. Academic Validation
  3. Scaffold hopping of N-benzyl-3,4,5-trimethoxyaniline: 5,6,7-Trimethoxyflavan derivatives as novel potential anticancer agents modulating hippo signaling pathway

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

  • Eur J Med Chem. 2023 Aug 5;256:115421. doi: 10.1016/j.ejmech.2023.115421.
Ahmed H E Hassan 1,  Cai Yi Wang 2,  Hyo Jong Lee 3,  Su Jin Jung 3,  Yeon Ju Kim 3,  Soo Bin Cho 3,  Chae Hyeon Lee 3,  Gyeongpyo Ham 3,  Taegeun Oh 3,  Sang Kook Lee 4,  Yong Sup Lee 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt; Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea.
  • 2 Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
  • 3 Department of Fundamental Pharmaceutical Sciences, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea.
  • 4 Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea. Electronic address: [email protected].
  • 5 Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea; Department of Fundamental Pharmaceutical Sciences, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea. Electronic address: [email protected].
PMID: 37163949 DOI: 10.1016/j.ejmech.2023.115421
Abstract

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 temozolomide, 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 findings present compound 8q as a potential Anticancer lead compound for further development of potential agents.

Keywords

Apoptosis; Cancer; Cell cycle arrest; Flavan; Hippo signaling; Natural products derivatives.

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