Synthesis and preliminary biological evaluation of truncated zoanthenol analogues Go Hirai, a Hiroki Oguri, a, * Masahiko Hayashi, b Koji Koyama, a Yuuki Koizumi, a Sameh M. Moharram a and Masahiro Hirama a, * a Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan b Kitasato Institute for Life Sciences, Tokyo 108-8641, Japan Received 14 January 2004; accepted 13 February 2004 Abstract—Zoanthamines are a family of marine alkaloids that have complex heptacyclic structures and are reported to be inter- leukin-6 modulators. While the structure of zoanthamines, especially the ABC-ring portion, is similar to that of steroids, the CDEFG-ring portion, composed of aminoacetal and lactone core, is a unique structural element. In this report, we designed and synthesized ABC-ring 6 and CDEFG-ring 7, which are truncated analogues of the northern and southern hemispheres of zoanthenol 5, respectively, and which incorporate all of the functionality of each hemisphere. A preliminary SAR study suggested that the hydrochloride of the CEFG-ring portion is an active pharmacophore for suppressing the growth of interleukin-6-dependent MH60 cells. Ó 2004 Elsevier Ltd. All rights reserved. 1. Introduction Zoanthamines (1, 2, 5) are a family of marine alkaloids isolated from the zoanthid Zoanthus sp. and possess a unique array of skeletal and stereochemical complexi- ties. 1 Zoanthamines have several pharmacological properties, 1;2 and their activity as a possible osteoporosis drug is of particular interest. Uemura and co-workers reported that norzoanthamine hydrochloride 4 sup- pressed the loss of bone weight and strength in ovari- ectomized mice. 3 Unlike estrogens, serious side effects, such as an increase in uterine weight, are not observed. Therefore, the mode of action of 4 on osteoporosis appears to be different from that of estrogen. 3c;4 In addition, norzoanthamine and its hydrochloride are reported to suppress interleukin-6 (IL-6) production. 3 Because IL-6 is known as a mediator of bone resorption in osteoporosis, 5 it is likely that the activity as an IL-6 modulator might be associated with its effects on osteo- porosis 6;7 (Fig. 1). The structure of zoanthamines, especially the ABC-ring portion, is similar to that of steroids. On the other hand, the CDEFG-ring portion, composed of an aminoacetal and a lactone, is a unique structural element. We thus hypothesized that the CDEFG-ring portion and its hydrochloride might be a pharmacophore of the zoanthamines. To date, neither the total synthesis of zoanthamines 8;9 nor the structure–activity relationship (SAR) study using synthetic analogues has been reported, although SAR study using natural product derivatives has been described. 1e In this report, we designed the ABC-ring 6 and the CDEFG-ring 7, which are truncated analogues of the northern and southern hemispheres of zoanthenol 5, respectively, and which incorporate all of the function- ality of each hemisphere. We report herein the synthesis and the preliminary biological evaluation of these truncated analogues. 2. Synthesis As outlined in Scheme 1, we planned the synthesis of the truncated analogues (6, 7) to allow the total synthesis of zoanthenol 5. A fully functionalized ABC-ring moiety 10 was designed as a key intermediate that could be * Corresponding authors. Tel.: +81-22-217-6563; fax: +81-22-217-6566 (M.H.); e-mail addresses: oguri@ykbsc.chem.tohoku.ac.jp; hirama@ ykbsc.chem.tohoku.ac.jp 0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2004.02.064 Bioorganic & Medicinal Chemistry Letters 14 (2004) 2647–2651