Synthesis and Bioactivity Evaluation of Nepetaefolin F and Its Analogues

Xu-Dong Mao; Ting-Ting Du; Qi Gu; Li Yang; Hai-Lian Shi; Ran Hong; Gui-Xin Chou

doi:10.1021/acsomega.3c01319

Synthesis and Bioactivity Evaluation of Nepetaefolin F and Its Analogues

ACS Omega. 2023 Apr 12;8(16):14830-14840. doi: 10.1021/acsomega.3c01319. eCollection 2023 Apr 25.

Authors

Xu-Dong Mao^{1

2}, Ting-Ting Du^{1

2}, Qi Gu³, Li Yang¹, Hai-Lian Shi¹, Ran Hong³, Gui-Xin Chou^{1

2}

Affiliations

¹ The MOE Key Laboratory of Standardization of Chinese Medicines and SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica (ICMM), Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai 201203, P. R. China.
² Shanghai R&D Center for Standardization of Chinese Medicines, Shanghai 201203, P. R. China.
³ CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. China.

Abstract

Nepetaefolin F (5), an abietane diterpenoid, showed significant inhibitory activity against human cancer cells in vitro with an IC₅₀ value of 6.3 μM. The syntheses of nepetaefolin F and its analogues are presented herein. The cytotoxicity against various cancer cell lines was evaluated; notably, the cyclopropanecarboxylate ester 42 displayed significant antitumor activity against MGC 803 cells with an IC₅₀ value of 20.9 μM. Further studies revealed that 42 could upregulate the expression of p62, microtubule-associated protein 1 light-chain 3 β (LC3 B-I), cleaved caspase-3, and cleaved caspase-9 and downregulate the expression of Beclin-1 and LC3B-II. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that 42 could modulate multiple signaling pathways, especially for peroxisome proliferator-activated receptor (PPAR) and AMP-activated protein kinase (AMPK), which are closely related to autophagy. These results suggested that compound 42 is a promising lead by inhibiting cell proliferation and autophagy, as inducing cell apoptosis in MGC 803 cells.