Phorboxazole compounds and methods of their preparation

This application is a divisional of Ser. No. 11/408,573, filed on Apr. 20, 2006, and also claims priority to U.S. Provisional Application Ser. No. 60/674,004, filed Apr. 21, 2005, the disclosure of each is incorporated herein by reference in its entirety.

Certain of the inventors were supported by National Institutes of Health Grant CA019033.

The invention relates to compounds which mimic the chemical and/or biological activity of Phorboxazole, compositions containing such compounds, and to methods useful in their preparation. More particularly, the present invention relates to novel Phorboxazole analogs that may be useful as pharmaceuticals in inducing apoptosis in cancer cells.

In 1995, Searle and Molinski (J. Am. Chem. Soc. 1995, 117, 8126-8131; J. Am. Chem. Soc. 1996, 118, 9422-9423; Tetrahedron Lett. 1996, 37, 7879-7880) isolated (+)-Phorboxazole A (1) and B (2) from a methanolic extract of the sponge Phorbas sp. In vitro bioassay against the National Cancer Institute\'s (NCI) panel of 60 human tumor cell lines revealed extraordinary anti-proliferative activity against the entire panel; a mean GI₅₀ value of 1.58×10⁻⁹ M for both (+)-Phorboxazole A and B.

While (1) and (2) remain promising anticancer medicinal agents, their architectural complexity warrants exploration of simplified synthetic analogs. Initial structure activity relationship (SAR) studies conducted by Uckun (WO 01/36048 A1) and Forsyth (Bioorg. Med. Chem. Lett. 2001, 11, 1181-1183) disclosed the discovery of two (+)-Phorboxazole A analogues which displayed anticancer activity in leukemia, breast cancer, and brain tumor cancer cell lines.

Several groups have been actively involved in devising synthetic routes to Phorboxazole A and/or Phorboxazole B. Forsyth, et al. (J. Am. Chem. Soc. 1998, 120, 5597) have reported a linear synthetic sequence of 100 total steps to Phorboxazole A in 0.4% overall yield. Smith, et al., (J. Am. Chem. Soc. 2001, 123, 4834) have prepared Phorboxazole A in an overall yield of 3%. Pattenden, et al., (Angew. Chem. Int. Ed. 2003, 42, 1255) have provided Phorboxazole A in 0.18% overall yield. A 2.4% overall yield of Phorboxazole A was reported by Williams, et al. (Angew. Chem. Int. Ed. 2003, 42, 1258). Evans, et al (Angew. Chem. Int. Ed. 2000, 39, 2533, 2536) have developed a route to Phorboxazole B of 71 total steps in 12.6% overall yield.

There is therefore a need for improved synthetic methods which provide high yield and high selectivity, and at a relatively high rate of reaction, using better, more convenient and/or less expensive process methodology than many processes known heretofore for the preparation of Phorboxazole A, Phorboxazole B, their synthetic intermediates, and for compounds, analogs or derivatives having similar chemical and/or biological activity. The present invention is directed to these and other important ends.

Accordingly, the present invention is directed in part to novel methods for the preparation of Phorboxazole A, Phorboxazole B, and their synthetic intermediates. In certain aspects, the invention is directed to new analogs and derivatives of Phorboxazole A and Phorboxazole B having useful chemical and/or biological activity. In other aspects, the invention is directed to methods of preparation for, compositions containing, and methods of use of analogs or derivatives of Phorboxazole A or Phorboxazole B.