Structurally simplified macrolactone analogues of halichondrin B

Seletsky, Boris M.; Wang, Yuan; Hawkins, Lynn D.; Palme, Monica H.; Habgood, Gregory J.; DiPietro, Lucian; Towle, Murray J.; Salvato, Kathleen A.; Wels, Bruce F.; Aalfs, Kimberley K.; Kishi, Yoshito; Littlefield, Bruce A.; Yu, Melvin J.

doi:10.1016/j.bmcl.2004.08.068

Cited by 65 publications

(31 citation statements)

References 15 publications

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“…[13c] TheE isai Research Institute initiated in vitro and in vivo studies of synthetic halichondrin B, along with several analogues provided by the Kishi research group at Harvard University. [17] Surprisingly,t hey found that the C1-C38 macrolide,o rt he "eastern portion" of the molecule,demonstrated activities within an order of magnitude of the parent compound during an in vivo 3-4 day growth inhibition assay with aD LD-1h uman colon cancer cell line ( Figure 2). [8a, 18] They found that the macrolactone could be replaced by anonhydrolyzable ester bioisostere to prevent susceptibility toward nonspecific esterases.A ttempts to truncate further while retaining activity were unsuccessful.…”

Section: From Halichondrin Bt Oeribulinmentioning

confidence: 99%

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

2016

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Natural products have had an immense influence on science and have directly led to the introduction of many drugs. Organic chemistry, and its unique ability to tailor natural products through synthesis, provides an extraordinary approach to unlock the full potential of natural products. In this Review, an approach based on natural product derived fragments is presented that can successfully address some of the current challenges in drug discovery. These fragments often display significantly reduced molecular weights, reduced structural complexity, a reduced number of synthetic steps, while retaining or even improving key biological parameters such as potency or selectivity. Examples from various stages of the drug development process up to the clinic are presented. In addition, this process can be leveraged by recent developments such as genome mining, antibody–drug conjugates, and computational approaches. All these concepts have the potential to identify the next generation of drug candidates inspired by natural products.

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Section: From Halichondrin Bt Oeribulinmentioning

confidence: 99%

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

2016

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“…Similar results were obtained with COLO 205 colon carcinoma, LOX melanoma, and NIH:OVCAR-3 ovarian cancer xenografts. 119 Toxicity studies in Vitro showed no cytotoxicity at 1 µM eribulin in quiescent IMR-90 human fibroblasts. The mode of action of eribulin has also been studied.…”

Section: Preclinical Developmentmentioning

confidence: 98%

The Halichondrins and E7389

2009

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Katrina L. Jackson obtained her B.S. degree in biochemistry from Boston College in 2002, where she performed undergraduate research with Professor Shana O. Kelley. In 2007, she obtained her Ph.D. from the University of ColoradosBoulder under the direction of Professor Andrew J. Phillips for the total synthesis of norhalichondrin B. Currently, she is a postdoctoral researcher at Harvard University with Professor Yoshito Kishi. James A. Henderson received a B.Sc. in Biochemistry from Tennessee Technological University. After completing a M.S. degree in Chemistry at the same institution with Professor Jeffrey O. Boles, he moved to the University of Colorado at Boulder where he received his Ph.D. degree under the direction of Professor Andrew Phillips for the total synthesis of aburatubolactam A. In 2008, he moved to Harvard University where he is currently a postdoctoral researcher in the lab of Professor Yoshito Kishi. Scheme 3. The Initial Stages of the Kishi Synthesis of the C27-C38 Subunit Scheme 4. Completion of the Kishi Synthesis of the C27-C38 Subunit Scheme 5. The Kishi Halichondrin B C39-C54 Subunit Synthesis

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“…Therefore, scientists at the Eisai Research Institute produced a range of halichondrin B variants that are bioactive and structurally more stable than the natural parent compound. 13 Of all the analogs produced, eribulin mesylate appears to be the most promising.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Potential clinical applications of halichondrins in breast cancer and other neoplasms

Ortega¹,

Cortés²

2012

BCTT

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Halichondrin B is a large polyether macrolide found in a rare Japanese sponge, Halichondria okadai and has been shown to have anticancer activity. Eribulin mesylate is a completely synthetic analog of halichondrin B with a unique mechanism of action relative to other antimicrotubule agents. This new agent has demonstrated activity in preclinical studies, and it is being developed for the treatment of different tumor types. Eribulin has been approved by the United States Food and Drug Administration and the European Medicines Agency as lateline therapy for metastatic breast cancer patients previously treated with an anthracycline and a taxane. It has demonstrated superiority over other treatments in overall survival (OS) (hazard ratio: 0.81, P = 0.041), leading to its regulatory approbation for clinical practice use. Median OS for the eribulin-treated group was 13.1 months versus 10.6 months in the physician's treatmentof-choice group. Eribulin demonstrated a manageable toxicity profile. Most common adverse events associated with treatment were mild neutropenia and fatigue, mainly of grade 1 or 2. In contrast to other antimicrotubule agents, eribulin has a relatively low incidence of peripheral neuropathy and alopecia. Eribulin has been extensively studied in breast cancer and is currently being developed for treatment of other cancer types. Eribulin has demonstrated activity in Phase II trials in non-small cell lung cancer, pancreatic cancer, urothelial tract cancer, and sarcomas. Further studies in these cancers are ongoing. This article reviews pharmacology, mechanism of action, pharmacokinetics and efficacy of eribulin in breast cancer and other neoplasms.

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Structurally simplified macrolactone analogues of halichondrin B

Cited by 65 publications

References 15 publications

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

The Halichondrins and E7389

Potential clinical applications of halichondrins in breast cancer and other neoplasms

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