Abstract
Despite their outstanding antitumour activity in mice, the limited supply from the natural sources has prevented drug discovery/development based on intact halichondrins. We achieved a total synthesis of C52-halichondrin-B amine (E7130) on a >10 g scale with >99.8% purity under GMP conditions. Interestingly, E7130 not only is a novel microtubule dynamics inhibitor but can also increase intratumoural CD31-positive endothelial cells and reduce α-SMA-positive cancer-associated fibroblasts at pharmacologically relevant compound concentrations. According to these unique effects, E7130 significantly augment the effect of antitumour treatments in mouse models and is currently in a clinical trial. Overall, our work demonstrates that a total synthesis can address the issue of limited material supply in drug discovery/development even for the cases of complex natural products.
Highlights
Despite their outstanding antitumour activity in mice, the limited supply from the natural sources has prevented drug discovery/development based on intact halichondrins
We recognized that our recent studies in the total syntheses of halichondrins could solve the problem of limited material supply via chemical synthesis
As the candidate for the downstream effector in α-SMA-positive cancer-associated fibroblasts (CAFs), which can account for its tumour-promoting function, we examined the expression of tenascin-C and EDA-fibronectin, extracellular matrix (ECM) proteins[23,24]
Summary
Despite their outstanding antitumour activity in mice, the limited supply from the natural sources has prevented drug discovery/development based on intact halichondrins. Halichondrins are known to exhibit exceptional in vivo antitumour activities in mice in addition to excellent in vitro activities towards a variety of human cancer cell types These compounds are novel inhibitors of microtubule dynamics, but their mode of action is distinctly different from those of other microtubule-targeted drugs such as paclitaxel[9,10,11]. Halichondrin B was shown to be more effective than vinblastine, another type of microtubule-targeted drug, in the LOX melanoma bone marrow metastasis model in nude rats, while no difference in antitumour activity was observed in the subcutaneous (s.c.) xenograft model with the same melanoma cell line[12] Despite their extraordinarily potent and unique anticancer activities, to date, intact halichondrins have not been studied as anticancer drugs in humans because the material could not be secured via either isolation from natural sources or chemical synthesis[13]. Its exceptional in vivo antitumour activity in mouse xenograft models may suggest that halichondrins are not microtubule-targeted drugs, thereby having encouraged us to undertake drug development efforts using intact halichondrins
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