Polyisoprenylated benzophenone derivatives from the fruits of Garcinia cambogia and their absolute configuration by quantum chemical circular dichroism calculations Milena Masullo, Carla Bassarello, Giuseppe Bifulco * , Sonia Piacente * Dipartimento di Scienze Farmaceutiche, Universita ` degli Studi di Salerno, via Ponte Don Melillo, 84084 Fisciano (SA), Italy article info Article history: Received 28 July 2009 Received in revised form 19 October 2009 Accepted 5 November 2009 Available online 10 November 2009 Keywords: Polyisoprenylated benzophenones Oxy-guttiferones CD Quantum chemical calculations abstract Three new tetracyclic polyisoprenylated xanthones, named oxy-guttiferones M, K2, and I, along with oxy-guttiferone K and guttiferone M, have been isolated from the fruits of Garcinia cambogia. Their structures were elucidated by MS and NMR spectroscopic experiments. The absolute configurations of oxy-guttiferone K, taken as a model of tetracyclic xanthones, and guttiferone M, as a model of poly- isoprenylated benzophenones, have been determined by comparison of their experimentally measured circular dichroism (CD) curves with the TDDFT-predicted curves. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction Garcinol, also known as camboginol, is a polyisoprenylated benzophenone derivative occurring in Garcinia indica and Garcinia cambogia. 1 This compound is reported to possess scavenging ac- tivity, playing an important role in the treatment of gastric ulcers caused by the hydroxyl radical 1,2 or by a chronic infection with Helicobacter pylori. 3 Garcinol shows antibiotic activity against methicillin-resistant Staphylococcus aureus comparable to that of vancomycin 4 and it inhibits topoisomerases I and II at concentra- tions comparable to that of etoposide. 5 Furthermore, garcinol has reported to possess antitumor activity against human leukemia HL- 60 cells, through cytochrome c release and activation of caspases 6–8 and to inhibit histone acetyltransferases and p300/CPB-associated factor, both of which modulate gene expression. 9 Garcinol is also able to suppress colonic aberrant crypt foci (ACF) formation in rats and to modulate tyrosine phosphorylation of FAK and subsequently to induce apoptosis in human colon cancer cells. 10 Other polyisoprenylated benzophenones, named guttiferones, have shown interesting biological properties. Guttiferones A, B, E, C, and D, the latter two isolated as an inseparable mixture, were tested for anti-HIV biological activity. 11 In a different study, guttiferone F showed both cytoprotection against HIV-1 in vitro and cytotoxicity to the host cells. 12 Guttiferone I is reported to in- hibit the binding activity of a-liver X receptor (LXRa) but is less effective against b-receptor (LXRb). 13 Our previous phytochemical study of the fruits of G. cambogia has shown the presence of garcinol and guttiferones K, I, J, M, N, along with oxy-guttiferone K. 14 Continuing our investigation, here we report the isolation of further new oxy-guttiferones, namely oxy-guttiferones M, K2, and I (1–3) (see Fig. 1). Oxy-guttiferones are tetracyclic xanthones derived from the oxidation of the corresponding polyisoprenylated benzophenones. Sang et al. 15 have recently reported the structure of some oxidation products of garcinol by DPPH and have proposed the mechanism for the formation of these products. The reaction of garcinol with the stable DPPH radical generates a conjugated radical whose cyclization involving the catechol ring leads to the tetracyclic xanthone derivatives. The natural occurrence of oxy-guttiferones K, K2, I, and M together with the corresponding guttiferones could be in agreement with the mechanism of cyclization proposed by Sang et al. for garcinol. Examination of the NMR spectroscopic data ( 1 H and 13 C) allows the relative stereochemistry of guttiferones to be established. The relative orientation of the C(6) substituent (axial or equatorial) can be determined on the basis of the coupling constant of H-7ax, the chemical shifts of the methyl groups at C-5, and the carbon reso- nance of C-7. Moreover, ROESY correlations are useful to confirm and determine the relative stereochemistry of guttiferones. 3 So far, * Corresponding authors. Tel.: þ39 089 969741; fax: þ39 089 969602 (G.B); tel.: þ39 089 969763; fax: þ39 089 969602 (S.P.). E-mail addresses: bifulco@unisa.it (G. Bifulco), piacente@unisa.it (S. Piacente). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2009.11.034 Tetrahedron 66 (2010) 139–145