The Scripps Research Institute

Hans Vallberg

Kyriacos Costa Nicolaou

Yun He

Dionisios Vourloumis

Frank Roschangar

Sacha Ninkovic

Francisco Sarabia

Nigel Paul King

Nicolas Winssinger

Zhen Yang

Joaquin Pastor

M Ray Finlay

Maurice Raymond Verschoyle Finlay

Antony Bigot

N Paul King

Tianhu Li

Maruice Raymond Verschoyle Finlay

David Hepworth

The invention relates to epothilone analog represented by the formula I wherein(i) Ris absent or oxygen; 'a' can be either a single or double bond; 'b' can be either absent or a single bond; and &#x201c;c&#x201d; can be either absent or a single bond, with the proviso that if Ris oxygen then &#x201c;b&#x201d; and &#x201c;c&#x201d; are both a single bond and &#x201c;a&#x201d; is a single bond; if Ris absent then &#x201c;b&#x201d; and &#x201c;c&#x201d; are absent and &#x201c;a&#x201d; is a double bond; and if &#x201c;a&#x201d; is a double bond, then R, &#x201c;b&#x201d; and &#x201c;c&#x201d; are absent; These compounds have inter alia microtubuli depolymerisation inhibiting activity and are e.g. useful against proliferative diseases.

Epothilone derivatives and their synthesis and use

Epothilone A, epothilone B, analogs of epothilone and libraries of epothilone analogs are synthesized. Epothilone A and B are known anticancers agents that derive their anticancer activity by the prevention of mitosis through the induction and stabilization of microtubulin assembly. The analogs of epothilone are novel. Several of the analogs are demonstrated to have a superior cytotoxic activity as compared to epothilone A or epothilone B as demonstrated by their enhanced ability to induce the polymerization and stabilization of microtubules.

Epothilone analogs

Epothilone A, epothilone B, analogs of epothilone and libraries of epothilone analogs are synthesized. Epothilone A and B are known anticancers agents that derive their anticancer activity by the prevention of mitosis through the induction and stabilization of microtubule assembly. The analogs of epothilone are novel. Several of the analogs are demonstrated to have a superior cytotoxic activity as compared to epothilone A or epothilone B as demonstrated by their enhanced ability to induce the polymerization and stabilization of microtubules.

The invention relates to epothilone analog represented by formula (I) wherein (i) R is absent or oxygen; &ldquo;a&rdquo; can be either a single or double bond; &ldquo;b&rdquo; can be either absent or a single bond; and &ldquo;c&rdquo; can be either absent or a single bond, with the proviso that if R is oxygen then &ldquo;b&rdquo; and &ldquo;c&rdquo; are both a single bond and &ldquo;a&rdquo; is a single bond; if R is absent then &ldquo;b&rdquo; and &ldquo;c&rdquo; are absent and &ldquo;a&rdquo; is a double bond; and if &ldquo;a&rdquo; is a double bond, then R , &ldquo;b&rdquo; and &ldquo;c&rdquo; are absent; R is a radical selected from the group consisting of hydrogen; lower alkyl; &mdash;CH&boxH;CH ; &mdash;C&equiv;CH; &mdash;CH F; &mdash;CH Cl; &mdash;CH &mdash;OH; &mdash;CH &mdash;O&mdash;(C -C -alkyl); and &mdash;CH &mdash;S&mdash;(C -C -alkyl); R and R are independently selected from hydrogen, methyl or a protecting group; and R is as defined in the specification, or a salt of a compound of formula (I) where a salt-forming group is present. A further aspect of the invention is related to the synthesis of epothilone E. These compounds have inter alia microtubuli depolymerization inhibiting activity and are e.g. useful against proliferative diseases

Epothilone A, epothilone B, analogs of epothilone and libraries of epothilone analogs are synthesized. Epothilone A and B are known anticancer agents that derive their anticancer activity by the prevention of mitosis through the induction and stabilization of microtubulin assembly. The analogs of epothilone are novel. Several of the anlogs are demonstrated to have a superior cytotoxic activities as compared to epothilone A or epothilone B as demonstrated by their enhanced ability to induce the polymerization and stabilization of microtubules.

Novel analogs of epothilone A, epothilone B, and epothilone C are synthesized by Stille coupling thazole-stannanes to macrolactone intermediates. The synthetic epothilone analogs selectively prevent mitosis in cancer cells through the induction and stabilization of microtubulin assembly. Selected synthetic epothilone analogs are demonstrated to have greater bioactivity than their corresponding native compound.

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Huddinge, Sweden

Hans Vallberg