Total Synthesis and Antitumor Activity of ZK‐EPO: The First Fully Synthetic Epothilone in Clinical Development

Abstract

Going to trial: From about 350 active epothilone analogues synthesized by a highly convergent synthesis, one (ZK‐EPO, see picture) has been chosen for clinical development on the basis of its outstanding preclinical data. This compound exhibits higher activity and efficacy than taxanes (e.g. paclitaxel) and second‐generation epothilones, a fast and efficient cellular uptake, no recognition by efflux mechanisms, and an improved therapeutic window.

Epothilones

“…65 Out of 350 epothilone analogs produced at Schering AG (now Bayer) by total synthesis up to 2006, the side chain-modified analog sagopilone (also known as ZK-EPO, 3; Figure 3.2) was chosen as a clinical candidate, since it combined high activity and efficacy with fast and efficient cellular uptake and was not recognized by drug efflux pumps. 66,67 In comparison with natural Epo B, sagopilone (3) features a benzothiazole-derived side chain and an allyl substituent at position 6; the former type of modification has independently been investigated by the group at Novartis/ETH Zürich (vide infra). Key steps in the synthesis of sagopilone (3) are a non-selective Wittig reaction (E/Z ratio of 1/1) between methyl ketone 4 and phosphonium salt 5 to install the double bond at C12-C13, a stereoselective aldol reaction between a-chiral aldehyde 6 and ketone 7 to establish the stereocenters at C6 and C7, and the macrolactonization of seco acid 9 (Figure 3.2, Scheme 3.1), to produce the fully protected macrolactone core structure.…”

“…Key steps in the synthesis of sagopilone (3) are a non-selective Wittig reaction (E/Z ratio of 1/1) between methyl ketone 4 and phosphonium salt 5 to install the double bond at C12-C13, a stereoselective aldol reaction between a-chiral aldehyde 6 and ketone 7 to establish the stereocenters at C6 and C7, and the macrolactonization of seco acid 9 (Figure 3.2, Scheme 3.1), to produce the fully protected macrolactone core structure. 66,67 Overall, the synthesis of sagopilone (3) comprises 39 steps with the longest linear sequence being 22 steps. The synthesis depicted in Scheme 3.1 has been scaled up (with some modifications) 68 to deliver API (active pharmaceutical ingredient) for clinical studies.…”

Selected hybrid natural products as tubulin modulators

“…This compound differs from epothilone B for the allyl group at the sixth position and for the thiazole ring replaced with the benzothiazole system. The compound was called ZK-EPO and is also known as Sagopilone [24].…”

Anticancer Drugs Targeting Tubulin and Microtubules

“…84 Sagopilone (ZK-EPO) is a promising, fully synthetic epothilone that was designed to overcome multidrug resistance. 85 This compound, currently under clinical assays, 86 exhibited significant activity across a broad spectrum of preclinical tumor models, including those resistant to widely used chemotherapeutic agents, because it is not recognized by cellular efflux pumps. It is also more water soluble than taxanes and does not require a formulating agent such as Cremophor.…”