An entirely chromium-free synthesis of eribulin, a fully synthetic macrocyclic ketone analogue of the marine natural product halichondrin B, was achieved through iterative sulfone fragment couplings followed by an intramolecular Prins reaction involving a C.26 homoallenyl alcohol and a C.27 aldehyde acetal. A notable feature of this new macrocyclization is the employment of a β-ketosulfone at C.15/14 as an acid-stable progenitor of the notoriously acid-sensitive polycyclic ketal moiety, characteristic of the halichondrins.
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Microtubule acetylation and PERK activation facilitate eribulin-induced mitochondrial calcium accumulation and cell death.
Cell Mol Life Sci
December 2024
Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea.
Over the past few decades, microtubules have been targeted by various anticancer drugs, including paclitaxel and eribulin. Despite their promising effects, the development of drug resistance remains a challenge. We aimed to define a novel cell death mechanism that targets microtubules using eribulin and to assess its potential in overcoming eribulin resistance.
View Article and Find Full Text PDFEribulin Induction of Immunogenic Cell Death (ICD): Comparison With Other Cytotoxic Agents and Temporal Relationship of ICD Biomarkers.
Anticancer Res
January 2025
Eisai Inc., Cambridge, MA, U.S.A.
Background/aim: Preclinical studies were undertaken to investigate whether eribulin's known cytotoxic antimitotic effects are characterized by immunogenic cell death (ICD) as assessed by three established ICD biomarkers: extracellular released ATP, released HMGB1 and cell surface calreticulin.
Materials And Methods: Using BT-549, Hs578T and MCF-7 breast cancer cell lines, antiproliferative IC's of eribulin, five other microtubule targeting agents (MTAs; ER-076349, vinblastine, vinorelbine, paclitaxel, docetaxel) and three DNA damaging agents (DDAs; doxorubicin, cisplatin, oxaliplatin) were determined.
Results: Treatment of cells with 10×IC concentrations of all drugs in serum-free media resulted in time-dependent induction of cytotoxicity over DMSO controls.
Total Synthesis of Eribulin, a Macrocyclic Ketone Analogue of Halichondrin B, via Prins Macrocyclization.
Org Lett
December 2024
Eisai Inc. G2D2, 35 Cambridgepark Drive, Cambridge, Massachusetts 02140, United States.
An entirely chromium-free synthesis of eribulin, a fully synthetic macrocyclic ketone analogue of the marine natural product halichondrin B, was achieved through iterative sulfone fragment couplings followed by an intramolecular Prins reaction involving a C.26 homoallenyl alcohol and a C.27 aldehyde acetal.
View Article and Find Full Text PDFTargeted and cytotoxic inhibitors used in the treatment of breast cancer.
Pharmacol Res
December 2024
Blue Ridge Institute for Medical Research, 221 Haywood Knolls Drive, Hendersonville, NC 28791, United States. Electronic address:
Breast cancer is the most commonly diagnosed malignancy and the fifth leading cause of cancer deaths worldwide. Surgery and radiation therapy are localized therapies for early-stage and metastatic breast cancer. The management of breast cancer is determined in large part by the HER2 (human epidermal growth factor receptor 2), HR (hormone receptor), ER (estrogen receptor), and PR (progesterone receptor) status.
View Article and Find Full Text PDFAn intracerebral microdialysis study to determine the neuropharmacokinetics of eribulin in patients with metastatic or primary brain tumors.
Cancer Chemother Pharmacol
December 2024
City of Hope Comprehensive Cancer Center, Department of Medical Oncology and Therapeutics Research, Duarte, CA, USA.
Article Synopsis
- Eribulin is a microtubule dynamics inhibitor that shows potential for managing brain tumors, especially breast cancer brain metastases, due to its lower protein binding and resistance to P-glycoprotein extrusion.
- A clinical study involved administering eribulin to cancer patients post-tumor removal, with samples analyzed to measure its concentrations in the brain and plasma.
- Results indicated higher concentrations of eribulin in areas where the blood-brain barrier was disrupted, but overall levels in the brain were not enough to confirm consistent clinical effectiveness against brain tumors.
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