The Morken Synthesis of (+)-Discodermolide

In 1990, the natural product discodermolide was isolated from a marine sponge and later found to have exceptional antiproliferative activity in cancer cells. Further studies showed discodermolide to stabilize microtubules via the taxoid binding site on beta-tubulin. Unlike paclitaxel, it is not a substrate for P-glycoprotein transport, is potent in paclitaxel-resistant cell lines with beta-tubulin mutations, exhibits better water solubility, and can act synergistically when combined with paclitaxel treatment. For this reason, discodermolide has been the focus of many synthetic and biological studies, culminating in a 60 gram-scale synthesis and Phase I/II clinical trials carried out by Novartis in 2004. Despite the great level of interest from the scientific community, much about this compound’s behavior in vivo is still unknown. An extended analysis of known structure-activity relationships for discodermolide is presented herein. Also reported are the syntheses of a series of discodermolide fragments, which are designed to enable the formation of a novel analogue library via late-stage multicomponent reactions. Fragments to be synthesized prior to coupling are streamlined alternatives to the discodermolide framework that have shown promise in prior analogue and HQSAR studies. Overall, these modifications have been designed to improve the efficiency of synthetic efforts and to represent a wholly unique series of analogues for biological study.

discodermolide: a marine natural product against cancer.

(+)-discodermolide: a marine natural product against cancer
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Discodermolide: Past, Present, and Future | SpringerLink

In 1990, the natural product discodermolide was isolated from a marine sponge and later found to have exceptional antiproliferative activity in cancer cells. Further studies showed discodermolide to stabilize microtubules via the taxoid binding site on beta-tubulin. Unlike paclitaxel, it is not a substrate for P-glycoprotein transport, is potent in paclitaxel-resistant cell lines with beta-tubulin mutations, exhibits better water solubility, and can act synergistically when combined with paclitaxel treatment. For this reason, discodermolide has been the focus of many synthetic and biological studies, culminating in a 60 gram-scale synthesis and Phase I/II clinical trials carried out by Novartis in 2004. Despite the great level of interest from the scientific community, much about this compound’s behavior in vivo is still unknown. An extended analysis of known structure-activity relationships for discodermolide is presented herein. Also reported are the syntheses of a series of discodermolide fragments, which are designed to enable the formation of a novel analogue library via late-stage multicomponent reactions. Fragments to be synthesized prior to coupling are streamlined alternatives to the discodermolide framework that have shown promise in prior analogue and HQSAR studies. Overall, these modifications have been designed to improve the efficiency of synthetic efforts and to represent a wholly unique series of analogues for biological study.

in the total synthesis of discodermolide.

(+)-Discodermolide was isolated in 1990 by Gunasekera et al. from the deep-water Caribbean sponge Discodermia dissoluta. It attacks cancer cells in a similar way to the successful cancer drug Taxol® that has become the best-selling anticancer drug in history. Taxol is also the first natural product described that stabilizes the microtubules involved in many aspects of cellular biology and that represent an important target of anticancer chemotherapeutics. However, (+)-discodermolide appears to be far more potent than Taxol® against tumors that have developed multiple-drug resistance, with an IC50 in the low nanomolar range. Due to these excellent results, this natural product was licensed to Novartis Pharmaceutical Corporation in early 1998. The present review covers the history, biological activity, total synthesis, and synthetic analogs of (+)-discodermolide.

A multi-gram total synthesis of discodermolide (133) was completed in order for Novartis to begin Phase I clinical trials.
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