New cytotoxic diterpenylnaphthohydroquinone derivatives obtained from a natural diterpenoid Jose ´ M. Miguel del Corral, a, * M. Angeles Castro, a M. Lucena Rodrı ´guez, a Pablo Chamorro, a Carmen Cuevas b and Arturo San Feliciano a a Departamento de Quı ´ mica Farmace ´utica, Facultad de Farmacia, Universidad de Salamanca, E-37007 Salamanca, Spain b PharmaMar S.A., Avda. de los Reyes, 1 P.I. La Mina-Norte, 28770 Colmenar Viejo, Madrid, Spain Received 5 March 2007; revised 31 May 2007; accepted 5 June 2007 Available online 8 June 2007 Abstract—Diterpenylquinone/hydroquinone derivatives were prepared through Diels–Alder cycloaddition between natural myrce- communic acid or its methyl ester and p-benzoquinone (p-BQ), using BF 3 ÆEt 2 O as catalyst or under microwave (Mw) irradiation. Acetyl, methyl and benzyl derivatives of several diterpenylnaphthohydroquinone were prepared from cycloadducts following two basic synthetic strategies, either protection before aromatisation or viceversa. Some of them were further functionalised at the B-ring of the decaline core. Most of the new compounds were evaluated and some of them resulted cytotoxic against several tumour cell lines with IC 50 values under the lM level. Ó 2007 Elsevier Ltd. All rights reserved. 1. Introduction Terpenylquinones constitute an interesting group of marine natural products, 1 for which a wide variety of biological activities have been described, including anti-inflammatory, antifungal, anti-HIV and most often antineoplastic activities. Their cytotoxicity has been jus- tified on their ability for undergoing redox cycling and on the generation of reactive oxygen species, which would damage tumour cells. 2 Most of these meroterpe- noids are characterised by possessing a benzoquinone (BQ) fragment attached to a terpenoid, which usually in- cludes a decaline core, mostly without other functions, as in the case of avarol and avarone (Fig. 1), which pres- ent cytotoxic and antiviral activities. 3 A few reported examples present oxygenated functions at the decaline moiety, as it is the case of the cytotoxic drimanoid yahazunol 4 (Fig. 1). The 1,4-naphthoquinone system (1,4-NQ) is ubiquitously distributed in nature 5 and it is also present in numerous biologically active com- pounds, such as menadione (vitamin K 3 ) and drugs like the antiparasitic atovaquone (Fig. 1). 6 Both facts prompted us, a few years ago, to study the influence of the terpenyl and quinone sizes and functionalities on the bioactivity of this type of meroterpenoids. Thus, sev- eral monoterpenylbenzo-, 7 naphtho- 8 and anthraqui- nones 8d,9 (AQ) with different functions in the side chain and in the quinone ring were prepared and their antineoplastic cytotoxicity assayed. Additionally, sev- eral diterpenyl-NQ and AQs were also synthesised. 10 In those studies it became clear that all the compounds 0968-0896/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2007.06.005 Keywords: Terpenylquinones; Myrcecommunic acid; Allylic oxidation; Cytotoxicity. * Corresponding author. Tel.: +34 923 294528; fax: +34 923 294515; e-mail: jmmcs@usal.es H HO OH H O O OH O O Cl O O Avarol Avarone Atovaquone Menadione OH HO OH H Yahazunol Figure 1. Structures of biologically active quinones. Bioorganic & Medicinal Chemistry 15 (2007) 5760–5774