A landmark in drug discovery based on complex natural product synthesis

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.

Old and Modern Antibiotic Structures with Potential for Today’s Infections

“…As an example of what can be done today by competent synthetic chemists, the recent review by Nicolaou and Rigel shows some of the capabilities of experts in this field [ 51 ]. To this review can be added the work referred to earlier on the total synthesis of a derivative of halichondrin B E7130 (MW 1111, 6 ) producing 10 grams of a cGMP product [ 10 ], together with the production of 1 gram of cGMP Bryostatin 1 by the Wender group [ 52 ].…”

“…It should be emphasized at this juncture that synthetic organic chemists have succeeded in the last few years in producing large quantities of cGMP-quality, partial or complete natural products that have either become drugs, eribulin (4) MW 730 being the prime example utilizing data from the Kishi synthesis of halichondrin B (5) MW 1111. Or nowadays as potential leads to drugs, with the total synthesis of a derivative of halichondrin B E7130 (6); MW 1111 at the 10-gram level, reported by the same Eisai group that synthesized eribulin [10], which is currently in Phase I clinical trials. These structures are shown in Figure 2.…”

Natural Product Based Antibody Drug Conjugates: Clinical Status as of November 9, 2020

“…Interestingly, there are ADCs that are using compounds that have already been approved as single antitumor agents (or their close relatives) with the underlying idea that if directly targeted by means of a specific mAb, the off- target toxicity of these agents may be ameliorated. Eribulin, which is derived from halichondrin B and was the most complex natural product based molecule to undergo production by total synthesis, has now had its "claim" eclipsed by work reported in 2019 from Eisai, 48 where over 10 g of halichondrin B and other "improved" derivatives (structures not shown) have been synthesized and obtained at >99% purity, on effectively an industrial scale. The eribulin-ADC is currently in phase II/I under the auspices of Eisai with the code name Morab-202 (44).…”

The quest for supernatural products: the impact of total synthesis in complex natural products medicinal chemistry

“…1), a C52-amine analogue of 2, exhibiting subnanomolar in vitro antiproliferative activity (IC 50 0.1-0.01 nM) against human cancer cell lines and potent in vivo antitumor activity. 33 Importantly, the in vivo efficacy of E7130 is highlighted by a more sustained tumor regression and amelioration of the tumor microenvironment by increasing intratumoral microvessel density for improved drug delivery and location. Currently a Phase I study to investigate E7130 in a solid tumor is underway in Japan by Eisai Co., Ltd.…”

“…Vinblastine (32) and vincristine (33) represent the most important members of the Vinca alkaloid family natural products. 107,108 They exhibit potent antitumor activity derived from inhibition and perturbation of microtubule formation and dynamics.…”