Synthesis and Cytotoxic Activity of Novel C7-Functionalized Spongiane Diterpenes Manuel Arno´, a Liliana Betancur-Galvis, b, * Miguel A. Gonza´lez, a, * Jelver Sierra b and Ramo´n J. Zaragoza´ a a Departamento de Quı´mica Orga ´nica, Universidad de Valencia, E-46100 Burjassot, Valencia, Spain b Grupo Infeccio ´n y Ca ´ncer, Universidad de Antioquia, A.A1226 Medellı´n, Colombia Received 31 January 2003; accepted 1 April 2003 Abstract—Based on two lead cytotoxic spongiane diterpenes, a new series of C7-oxygenated derivatives were synthesized and evaluated for their antitumor activity in vitro against the cancer cell lines HeLa and HEp-2. In general, introduction of either hydroxyl or acetoxy groups at C-7 did not improve the resultant cytotoxicity, while the presence of a butyrate ester led to more active compounds (CC 50 =4.0–9.5 mM). # 2003 Elsevier Science Ltd. All rights reserved. Introduction Spongiane diterpenoids are common metabolites found in marine organisms such as sponges and shell-less mollusks (nudibranchs). Nudibranchs are often conspicuously colored animals containing diet-derived natural products taken from the sponges. 1 These compounds are generally used in a defensive basis against predation and some of them have shown an interesting and wide profile of biological activity. 2 Despite the diverse biological prop- erties of this family of compounds, little effort has been made for their preparation and biological study, spe- cially of structural analogues. As a part of our research program towards the synthesis of bioactive terpene compounds starting from chiral building blocks such as podocarpenone 13, prepared from ()-abietic acid, and carvone, we have developed several routes leading to a variety of enantiopure spon- giane-type diterpenes, 3 and recently, we reported the synthesis of ()-spongian-16-oxo-17-al (1) and ()-acetyl- dendrillol-1 (12). 4 Then, we started a line of investi- gation in order to study the biological activity of most of the synthetic spongianes obtained by our group, as well as some derivatives and synthetic intermediates. For example, the antiherpetic activity of these com- pounds was studied against herpes simplex virus type 2 (HSV-2), but this was weak. However, several com- pounds exhibited significant cytotoxic activity against human cervix epitheloid carcinoma (HeLa) and human larynx epidermoid carcinoma (HEp-2) cancer cell lines (CC 50 3.5–37.5 mg/mL in 48 h assays). 5 These results prompted us to further study this structural class of molecules. Consequently, two leads for this family of compounds were selected, in particular, one for tetra- cyclic spongianes (1, spongian-16-oxo-17-al) and another for pentacyclic spongianes (7, dendrillol-1). A new series of C7-oxygenated derivatives was then designed and synthesized to determine their antitumor activity upon introduction/modification of a functional 0968-0896/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0968-0896(03)00230-X Bioorganic & Medicinal Chemistry 11 (2003) 3171–3177 Figure 1. Chemical structures of tested spongianes. *Corresponding authors. M.A. Gonza´lez tel.: +34-9635-44327; fax: +34-9635-44328; L. Betancur-Galvis tel.: +57-4510-6059; fax: +57- 4510-6062. E-mail: miguel.a.gonzalez@uv.es (M.A. Gonza´lez, chemi- cal aspects), labeta@catios.udea.edu.co (L. Betancur-Galvis, biologi- cal aspects).