Design, synthesis and cytotoxic studies on the simplified oxy analog of eleutherobin q S. Chandrasekhar, a, * V. Jagadeshwar, a Ch. Narsihmulu, a M. Sarangapani, b D. R. Krishna, b J. Vidyasagar, b Dolly Vijay c and G. Narahari Sastry c, * a Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India b Cancer and Aging Research Division, University College of Pharmaceutical Sciences, Kakatiya University, Warangal 506 009, India c Molecular Modelling Group, Organic Chemical Sciences, Indian Institute of Chemical Technology, Hyderabad 500 007, India Received 18 March 2004; revised 7 May 2004; accepted 10 May 2004 Available online Abstract—A straight forward entry into nine membered B ring of eleutherobin as oxy analog and its cyctotoxic properties on HBL cell lines is described. Molecular modeling studies were carried out to ascertain the binding of the model compound to the active site of b-tubulin. Ó 2004 Elsevier Ltd. All rights reserved. Eleutherobin (1) and Sarcodictyins A and B (2) 1 (gen- erally referred as Eleutheside family of microtubule stabilizing natural products) are derived from mem- brane precursors having common 4,7-oxaeunicellane oxatricyclic ring system. These compounds have shown highest activity against paclitaxel resistant tumor cell lines and are likely to lead second generation microtu- bule stabilizing anti-cancer drugs. 2 The scarce avail- ability of these complex diterpene natural products has initiated major programmes of total synthesis across the world. Even though the total synthesis of eleutherobin and sarcodictyins is achieved by the groups of Nicolaou et al., 3 Danishefsky and co-workers, 4 and several syn- thetic approaches by various groups, 5 none of the methods are useful for a large scale synthesis (Fig. 1). While Eleutherobin is a potent b-tubulin inhibitor molecule, it has a complex architecture and the unde- sirable aspect of the available synthetic procedures is that they fail to provide quantitative yields. Therefore, we felt that attempts towards designing simpler analogs of eleutherobin are worthwhile. As part of a project aimed to synthesize eleutheside and their analogs, we were interested in synthesizing simple and easily acces- sible tricyclic core, so that large quantities of potent cytotoxic molecules would be accessible for further studies. Herein our preliminary studies on synthesis of oxy-B-ring analog grafted into A-ring benzene and furano-C-ring with appendages for further analoging is reported. Keeping in view the complex 6–9–5 natural eleuthe- robin, we conceived a simple 6–9–5 scaffold 3. In this approach, the five membered furan ring is originated from glucofuranose, the six membered cyclohexyl moi- ety was replaced with benzene ring and the nine mem- bered B ring was grafted with –O– link. We employed the in vitro cytotoxicity studies and molecular modeling approaches to validate whether such an analog retains the biological activity. O O H H Me O OMe O AcO OH OH O N N CH 3 O O H H Me CO 2 R OMe O N N CH 3 O O O O OH H H R=Me:Sarcodictyin A R=Et:Sarcodictyin B 1 3 2 Eleutherobin Oxy analog Figure 1. q IICT Communication No.: 040502. * Corresponding authors. Tel.: +91-40-27193434; fax: +91-40- 27160512; e-mail addresses: srivaric@iict.res.in; gnsastry@iict.res.in 0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2004.05.017 Bioorganic & Medicinal Chemistry Letters 14 (2004) 3687–3689