Uvaridacols E-H, Highly Oxygenated Antiausterity Agents from Uvaria dac Suresh Awale,* ,†,‡ Jun-ya Ueda, †,‡ Sirivan Athikomkulchai, § Dya Fita Dibwe, ‡ Sherif Abdelhamed, ‡ Satoru Yokoyama, ‡ Ikuo Saiki, ‡ and Ryuta Miyatake ⊥ † Frontier Research Core for Life Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan ‡ Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan § Faculty of Pharmacy, Srinakharinwirot University, Nakhon Nayok, 26120, Thailand ⊥ Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan * S Supporting Information ABSTRACT: Chemical investigation of the stems of Uvaria dac yielded four new highly oxygenated cyclohexene derivatives named uvaridacols E-H(1-4). Their structures were established through NMR and circular dichroism spectroscopic analysis. Uvaridacols E (1), F (2), and H (4) displayed weak preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrition-deprived conditions in a concentration-dependent manner, without causing toxicity in normal nutrient-rich conditions. T he plant Uvaria dac Pierre ex Finet & Gagnep belongs to the Annonaceae family and is a woody tree found mainly in Southeast Asian countries such as Thailand, Burma, and Vietnam. In a continued study on the antiausterity strategy- based screening of medicinal plants, 1-9 the CH 2 Cl 2 extract of the stems of U. dac from Thailand showed preferential cytotoxic activity against the PANC-1 human pancreatic cancer cell line. The observed preferential cytotoxicity has been attributed to (+)-grandifloracin and cyclohexene derivatives. 10 Further study on this bioactive extract resulted in the isolation of four new highly oxygenated cyclohexenyl derivatives, named uvaridacols E-H(1-4). We report herein the structure of these new compounds and their preferential cytotoxic activity against the PANC-1 human pancreatic cancer cell line. Uvaridacol E (1) was isolated as a white, amorphous solid. Its molecular formula was determined by HRFABMS to be C 21 H 20 O 7 [m/z 385.1278 (M + H) + ]. The IR spectrum of 1 showed the absorptions due to hydroxy (3446 cm -1 ), ester carbonyl (1636 cm -1 ), and aromatic ring (1601, 1452 cm -1 ) functionalities. The 1 H NMR spectrum of 1 showed signals due to three oxymethines (δ H 4.17, H-2; 4.50, H-4; 5.44, H-3), an oxymethylene (δ H 4.50, 4.72, H 2 -7), and two olefinic methines (δ H 5.79, H-6; 5.89, H-5), together with those for two benzoyl groups (Table 1). In turn, the 13 C NMR spectrum showed 21 carbon signals including those for five oxygenated sp 3 carbons (δ C 67.1, 70.1, 74.5, 74.7, and 78.1), two olefinic carbons (δ C 129.5 and 130.0), and two benzoyl groups (Table 2). Analysis of the 1 H- 1 H COSY and HMQC spectra revealed the partial connectivities (bold line) between C-2-C-3-C-4-C-5-C-6, which were connected further based on long-range HMBC correlations (Figure 1a). In the HMBC spectrum of 1, the long- range correlations from the oxymethylene protons at δ H 4.50, 4.72 (H 2 -7) to the oxymethine carbon at δ C 78.1 (C-2), the olefinic methine carbon at δ C 129.5 (C-6), and the quaternary oxygenated carbon at δ 74.7 (C-1) suggested the connectivity of C-2, C-6, and C-7 via the quaternary carbon C-1. Furthermore, significant correlations of the H 2 -7 oxymethylene protons and the aromatic protons at δ H 8.07 (H-2′,6′) with the ester carbonyl carbon at δ C 165.9, and of the oxymethine proton at δ H 5.44 (H-3) and the aromatic protons at δ H 8.12 (H-2″,6″) with the ester carbonyl carbon at δ C 166.9, indicated the locations of the two benzoyl groups to be at C-3 and C-7, Received: August 31, 2012 Published: October 23, 2012 Note pubs.acs.org/jnp © 2012 American Chemical Society and American Society of Pharmacognosy 1999 dx.doi.org/10.1021/np300596c | J. Nat. Prod. 2012, 75, 1999-2002