Structurally diverse (9β-H)-pimarane derivatives with six frameworks from the leaves of Icacina oliviformis and their cytotoxic activities

Mingming Xu; Di Di; Lu Fan; Yingrun Ma; Xinyi Wei; Er-Xin Shang; Monday M Onakpa; Oluwatosin O Johnson; Jin-Ao Duan; Chun-Tao Che; Junfei Zhou; Ming Zhao

doi:10.1016/j.phytochem.2023.113804

Structurally diverse (9β-H)-pimarane derivatives with six frameworks from the leaves of Icacina oliviformis and their cytotoxic activities

Phytochemistry. 2023 Oct:214:113804. doi: 10.1016/j.phytochem.2023.113804. Epub 2023 Aug 2.

Authors

Mingming Xu¹, Di Di¹, Lu Fan², Yingrun Ma¹, Xinyi Wei¹, Er-Xin Shang¹, Monday M Onakpa³, Oluwatosin O Johnson⁴, Jin-Ao Duan¹, Chun-Tao Che⁵, Junfei Zhou⁶, Ming Zhao⁷

Affiliations

¹ Jiangsu Collaborative Innovation Centre of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resource Industrialization and Formulae Innovative Medicine, Key Laboratory of Chinese Medicinal Resource Recycling Utilization Under National Administration of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, School of Pharmacy, Nanjing, Jiangsu, 210023, People's Republic of China.
² School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, People's Republic of China.
³ Department of Veterinary Pharmacology and Toxicology, University of Abuja, Abuja, 920001, Nigeria.
⁴ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Lagos, CMUL Campus, Lagos, 100254, Nigeria.
⁵ Department of Pharmaceutical Sciencesollege of Pharmacy, the University of Illinois at Chicago, Chicago, IL, 60612, United States.
⁶ Jiangsu Collaborative Innovation Centre of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resource Industrialization and Formulae Innovative Medicine, Key Laboratory of Chinese Medicinal Resource Recycling Utilization Under National Administration of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, School of Pharmacy, Nanjing, Jiangsu, 210023, People's Republic of China. Electronic address: 300524@njucm.edu.cn.
⁷ Jiangsu Collaborative Innovation Centre of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resource Industrialization and Formulae Innovative Medicine, Key Laboratory of Chinese Medicinal Resource Recycling Utilization Under National Administration of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, School of Pharmacy, Nanjing, Jiangsu, 210023, People's Republic of China; Department of Pharmaceutical Sciencesollege of Pharmacy, the University of Illinois at Chicago, Chicago, IL, 60612, United States. Electronic address: mingzhao@njucm.edu.cn.

PMID: 37541354
DOI: 10.1016/j.phytochem.2023.113804

Abstract

Thirteen previously undescribed (9β-H)-pimarane derivatives, icacinolides A-G (1-7) and oliviformislactones C-H (8-13), together with four known analogs (14-17), were isolated from the leaves of Icacina oliviformis. Their structures were constructed by extensive spectroscopic analysis, ¹³C NMR-DP4+ analysis, ECD calculation, single-crystal X-ray diffraction, and chemical methods. These structurally diverse isolates were classified into six framework types: rearranged 3-epi-17-nor-(9β-H)-pimarane, rearranged 17-nor-(9β-H)-pimarane, 16-nor-(9β-H)-pimarane, 17-nor-(9β-H)-pimarane, 17,19-di-nor-(9β-H)-pimarane, and (9β-H)-pimarane. Among them, compounds 1, 5, and 7 were the first examples of three rearranged 3-epi-17-nor-(9β-H)-pimaranes featuring a unique (11S)-carboxyl-9-oxatricyclo[5.3.1.0^2,7]dodecane motif with contiguous stereogenic centers, whereas their C-3 epimers, compounds 2-4 and 6 were the second examples of four rearranged 17-nor-(9β-H)-pimaranes. Additionally, compounds 8 and 12/13 represented the second examples of a 16-nor-(9β-H)-pimarane and two 17,19-di-nor-(9β-H)-pimaranes, respectively. In cytotoxic bioassay, compound 2 exhibited significant cytotoxic against HT-29 with IC₅₀ values of 7.88 μM, even stronger than 5-fluorouracil, and 15 showed broad-spectrum cytotoxic activities against HepG2, HT-29, and MIA PaCa-2 with IC₅₀ values of 11.62, 9.77, and 4.91 μM, respectively. Meanwhile, a preliminary structure-activity relationship suggested that 3,20-epoxy, 6,19-lactone, 2-OH, 7-OH, and 8-OH in (9β-H)-pimarane derivatives might be active groups, whereas ring C aromatization may decrease the cytotoxic activities.

Keywords: (9β-H)-Pimarane; Cytotoxic activities; Icacina oliviformis (Icacinaceae); Structural elucidation; Structure-activity relationship.