Phytochemistry 96 (2013) 378–388

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Phytochemistry

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Scapiformolactones A–I: Germacrane sesquiterpenoids with an unusual D3-15,6-lactone moiety from scapiformis

Yongji Lai a,1, Yongbo Xue a,1, Mengke Zhang a, Jinwen Zhang b, Wei Tang c, Junjun Liu a, Liang Lei a, ⇑ ⇑ Juming Yan d, Zengwei Luo a, Jianping Zuo c, Yan Li d, Guangmin Yao a, , Yonghui Zhang a, a Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China b Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China c State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China d State Key Laboratory of Phytochemistry and Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, PR China article info abstract

Article history: Nine germacrane sesquiterpenoids with an unusual D3-15,6-lactone moiety, scapiformolactones A–I(1– Received 9 November 2012 9), and one known seco-germacrane sesquiterpenoid, 3,7,11-trimethyldodeca-l,6,9-triene-3,11-diol (10), Received in revised form 17 May 2013 were isolated from whole of Salvia scapiformis Hance. Their structures were elucidated by spectro- Available online 1 November 2013 scopic methods including HR-ESIMS, IR, UV, NMR, and CD, as well as by quantum mechanical calculations and chemical transformations. Structures of compounds 1–3 were also confirmed by single-crystal X-ray Keywords: diffraction analysis. Six germacrane 6,15-diol derivatives (11–16) were obtained by chemical transforma- Salvia scapiformis tion. Compounds 1–9 and 11–16 were evaluated for their in vitro immunomodulatory effects on T and B cells, as well as their in vitro cytotoxicity against five human cancer cell lines, HL-60, SMMC-7721, A-549, Germacrane sesquiterpene Conformation MCF-7, and SW480. Chemical transformation Ó 2013 Elsevier Ltd. All rights reserved. Quantum mechanical calculation Cytotoxicity Immunomodulatory activity

1. Introduction Salvia species, S. palaefolia (González et al., 1989), S. glutinosa (Rus- taiyan et al., 1992), S. roborowskii (Li et al., 2003; Liu et al., 2009), S. Salvia is one of the largest genera of the family Lamiaceae (for- nubicola (Ali et al., 2007), S. castanea (Xu et al., 2005, 2008), S. chin- merly Labiatae). It comprises of over 1000 species and is distrib- ensis (Wang et al., 2008), and S. trijuga (Pan et al., 2010). uted throughout tropical and temperate zones of the world; Salvia scapiformis Hance is widely distributed in Fujian, Guang- there are 84 species in China (Li and Ian, 1994). More than 1000 dong, Guangxi, Guizhou, Hunan, Jiangxi, Zhejiang, Taiwan, and as bioactive natural products including sesquiterpenoids, diterpe- well as the Philippines (Li and Ian, 1994). Whole plants of S. scap- noids, sesterterpenoids, steroids, triterpenoids, and phenolic com- iformis, known as a folk medicine ‘‘Bai-Bu-Yao’’ in China, are used pounds have also been isolated from 134 Salvia species (Wu et al., to treat cough, hemoptysis, traumatic injuries, traumatic hemor- 2012). Germacrane-type sesquiterpenoids are quite rare in Salvia rhage, dysentery, and furunculosis (Fang and Liao, 2006). However, species, however, although they are the most abundant among there have been no phytochemical investigations reported on any all known sesquiterpenoids. To date, there have been 24 germacra- part of this plant. In the course of searching for bioactive natural ne sesquiterpenoids reported belonging to four structural subtypes products from Chinese folk medicines, nine new germacran