From micrograms to grams: scale-up synthesis of eribulin mesylate

Yu, Melvin J.; Zheng, Wanjun; Seletsky, Boris M.

doi:10.1039/c3np70051h

Cited by 109 publications

(83 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This allowed the design, synthesis and evaluation of many analogs of the compound, one of which, eribulin (ER-086526, E7389, NSC-707389), is the subject of this review. The story of how the daunting 63-step chemical synthesis of eribulin was developed and made economically feasible was recently described (8). …”

Section: From Halichondrin B To Eribulinmentioning

confidence: 99%

Eribulin Mesylate: Mechanism of Action of a Unique Microtubule-Targeting Agent

Dybdal-Hargreaves

Risinger

Mooberry

2015

Clinical Cancer Research

180

145

View full text Add to dashboard Cite

Eribulin mesylate (eribulin), an analog of the marine natural product halichondrin B, is a microtubule-depolymerizing drug that has utility in the treatment of patients with breast cancer. Clinical trial results have demonstrated that eribulin treatment provides a survival advantage to patients with metastatic or locally advanced breast cancer previously treated with an anthracycline and a taxane. Furthermore, a pooled analysis of two pivotal phase III trials has demonstrated that eribulin also improves overall survival in several patient subgroups, including in women with human epidermal growth factor receptor 2 (HER2)-negative disease and triple-negative breast cancer. This review covers the preclinical research that led to the clinical testing and approval of eribulin, as well as subsequent research that was prompted by distinct and unexpected effects of eribulin in the clinic. Initial studies with halichondrin B, and then eribulin, demonstrated unique effects on tubulin binding that resulted in distinct microtubule-dependent events and antitumor actions. Consistent with the actions of the natural product, eribulin has potent microtubule-depolymerizing activities and properties that distinguish it from other microtubule targeting agents. Here, we review new results that further differentiate the effects of eribulin from other agents on peripheral nerves, angiogenesis, vascular remodeling and epithelial-to-mesenchymal transition. Together, these data highlight the distinct properties of eribulin and begin to delineate the mechanisms behind the increased survival benefit provided by eribulin for patients.

show abstract

Section: From Halichondrin B To Eribulinmentioning

confidence: 99%

Eribulin Mesylate: Mechanism of Action of a Unique Microtubule-Targeting Agent

Dybdal-Hargreaves

Risinger

Mooberry

2015

Clinical Cancer Research

180

145

View full text Add to dashboard Cite

show abstract

“…Generally, the synthetic pathway of 31 consists of preparation of two fragments, i.e., C-1-C-13 and C-14-C-26, as described by Kishi's group in 1992, and one key fragment (C-27 to C-35). The final assembly strategy is accomplished by the coupling reaction depicted in Scheme 6 [90,93]. Different methods for the synthesis, to obtain milligram to gram amounts of 31 have been reported [75,93].…”

Section: Halicondrin B and Derivativesmentioning

confidence: 99%

“…The final assembly strategy is accomplished by the coupling reaction depicted in Scheme 6 [90,93]. Different methods for the synthesis, to obtain milligram to gram amounts of 31 have been reported [75,93]. Generally, the synthetic pathway of 31 consists of preparation of two fragments, i.e., C-1-C-13 and C-14-C-26, as described by Kishi's group in 1992, and one key fragment (C-27 to C-35).…”

Section: Halicondrin B and Derivativesmentioning

confidence: 99%

Marine Natural Products as Models to Circumvent Multidrug Resistance

et al. 2016

View full text Add to dashboard Cite

Multidrug resistance (MDR) to anticancer drugs is a serious health problem that in many cases leads to cancer treatment failure. The ATP binding cassette (ABC) transporter P-glycoprotein (P-gp), which leads to premature efflux of drugs from cancer cells, is often responsible for MDR. On the other hand, a strategy to search for modulators from natural products to overcome MDR had been in place during the last decades. However, Nature limits the amount of some natural products, which has led to the development of synthetic strategies to increase their availability. This review summarizes the research findings on marine natural products and derivatives, mainly alkaloids, polyoxygenated sterols, polyketides, terpenoids, diketopiperazines, and peptides, with P-gp inhibitory activity highlighting the established structure-activity relationships. The synthetic pathways for the total synthesis of the most promising members and analogs are also presented. It is expected that the data gathered during the last decades concerning their synthesis and MDR-inhibiting activities will help medicinal chemists develop potential drug candidates using marine natural products as models which can deliver new ABC transporter inhibitor scaffolds.

show abstract

“…The potential of this approach was illustrated by eribulin, a highly potent analogue of halichondrin B (Scheme 2). [11] …”

Section: Contribution Of Natural Product Synthesis In Drug Discovementioning

confidence: 99%

Natural Product Synthesis at the Interface of Chemistry and Biology

Hong

2014

Chemistry A European J

View full text Add to dashboard Cite

Nature has evolved to produce unique and diverse natural products that possess high target affinity and specificity. Natural products have been the richest sources for novel modulators of biomolecular function. Since the chemical synthesis of urea by Wöhler, organic chemists have been intrigued by natural products, leading to the evolution of the field of natural product synthesis over the past two centuries. Natural product synthesis has enabled natural products to play an essential role in drug discovery and chemical biology. With the introduction of novel, innovative concepts and strategies for synthetic efficiency, natural product synthesis in the 21st century is well poised to address the challenges and complexities faced by natural product chemistry and will remain essential to progress in biomedical sciences.

show abstract

From micrograms to grams: scale-up synthesis of eribulin mesylate

Abstract: The synthesis of eribulin mesylate from microgram to multi-gram scale is described in this Highlight. Key coupling reactions include formation of the C30a to C1 carbon-carbon bond and macrocyclic ring closure through an intramolecular Nozaki-Hiyama-Kishi reaction.

Cited by 109 publications

References 12 publications

Eribulin Mesylate: Mechanism of Action of a Unique Microtubule-Targeting Agent

Eribulin Mesylate: Mechanism of Action of a Unique Microtubule-Targeting Agent

Marine Natural Products as Models to Circumvent Multidrug Resistance

Natural Product Synthesis at the Interface of Chemistry and Biology

Contact Info

Product

Resources

About