ABSTRACT
E7130 is a novel drug candidate with an exceedingly complex chemical structure of the halichondrin class, discovered by a total synthesis approach through joint research between the Kishi group at Harvard University and Eisai. Only 18 months after completion of the initial milligram-scale synthesis, ten-gram-scale synthesis of E7130 was achieved, providing the first good manufacturing practice (GMP) batch to supply clinical trials. This paper highlights the challenges in developing ten-gram-scale synthesis from the milligram-scale synthesis.
Subject(s)
Antineoplastic Agents , Humans , Antineoplastic Agents/pharmacologyABSTRACT
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.
Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Breast Neoplasms/drug therapy , Carcinoma, Squamous Cell/drug therapy , Ethers, Cyclic/chemical synthesis , Head and Neck Neoplasms/drug therapy , Macrolides/chemical synthesis , Tubulin Modulators/chemical synthesis , Actins/genetics , Actins/metabolism , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Combined Chemotherapy Protocols , Biological Products/chemical synthesis , Biological Products/pharmacology , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Cancer-Associated Fibroblasts/drug effects , Cancer-Associated Fibroblasts/metabolism , Cancer-Associated Fibroblasts/pathology , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Cetuximab/pharmacology , Drug Discovery , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Endothelial Cells/pathology , Ethers, Cyclic/pharmacology , Female , Gene Expression/drug effects , Head and Neck Neoplasms/mortality , Head and Neck Neoplasms/pathology , Humans , Macrolides/pharmacology , Mice , Mice, Inbred BALB C , Platelet Endothelial Cell Adhesion Molecule-1/genetics , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Survival Analysis , Tubulin Modulators/pharmacology , Tumor Burden/drug effects , Xenograft Model Antitumor AssaysABSTRACT
The first successful effort to replicate the beginning of the Taxol oxidase phase in the laboratory is reported, culminating in the total synthesis of taxuyunnanine D, itself a natural product. Through a combination of computational modeling, reagent screening, and oxidation sequence analysis, the first three of eight C-H oxidations (at the allylic sites corresponding to C-5, C-10, and C-13) required to reach Taxol from taxadiene were accomplished. This work lays a foundation for an eventual total synthesis of Taxol capable of delivering not only the natural product but also analogs inaccessible via bioengineering.
