The metabolite (–)-lomaiviticin A, which contains two diazotetrahydrobenzo[b]fluorene (diazofluorene) functional groups, inhibits the growth of cultured human cancer cells at nanomolar–picomolar concentrations; however, the mechanism responsible for the potent cytotoxicity of this natural product is not known. Here we report that (–)-lomaiviticin A nicks and cleaves plasmid DNA by an ROS- and iron-independent pathway and that the potent cytotoxicity of (–)-lomaiviticin A arises from induction of DNA double-strand breaks (dsbs). In a plasmid cleavage assay, the ratio of single-strand breaks (ssbs) to dsbs is 5.3±0.6:1. Labeling studies suggest this cleavage occurs via a radical pathway. The structurally related isolates (–)-lomaiviticin C and (–)-kinamycin C, which contain one diazofluorene, are demonstrated to be much less effective DNA cleavage agents, thereby providing an explanation for the enhanced cytotoxicity of (–)-lomaiviticin A compared to other members of this family.
Englerins A and B are guaiane sesquiterpenes that were isolated from the bark of Phyllanthus engleri, a plant indigenous to east Africa. The englerins consist of a 5-6-5 fused tricyclic structure with an ether bridge and two ester-bearing stereogenic centers, including a highly unusual glycolate residue. Englerin A is a potent and selective inhibitor of the growth of six human renal cancer cell lines. We report herein an efficient, eight-step synthesis of englerin A that leverages simple carbonyl-enabled carbon-carbon bond formations. Our route is amenable to the production of a diverse series of analogues for structure-function studies and determination of the mode of action of these natural products.
The development of enantioselective synthetic routes to (–)-kinamycin F (9) and (–)-lomaiviticin aglycon (6) is described. The diazotetrahydrobenzo[b]fluorene (diazofluorene) functional group of the targets was prepared by fluoride-mediated coupling of a β-trimethylsilylmethyl-α,β-unsaturated ketone (38) with an oxidized naphthoquinone (19), palladium-catalyzed cyclization (39→37), and diazo transfer (37→53). The D-ring precursors 60 and 68 were prepared from m-cresol and 3-ethylphenol, respectively. Coupling of the β-trimethylsilylmethyl-α,β-unsaturated ketone 60 with the juglone derivative 61, cyclization, and diazo transfer, provided the advanced diazofluorene 63, which was elaborated to (–)-kinamycin F (9) in three steps. The diazofluorene 87 was converted to the C2-symmetric lomaiviticin aglycon precursor 91 by enoxysilane formation and oxidative dimerization with manganese tris(hexafluoroacetylacetonate) (94, 26%). The stereochemical outcome is attributed to the steric bias engendered by the mesityl acetal of 87 and contact ion pairing of the intermediates. The coupling product 91 was deprotected (tert-butylhydrogen peroxide, trifluoroacetic acid–dichloromethane) to form the chain isomer of lomaiviticin aglycon 98, which cyclizes to (–)-lomaiviticin aglycon (6, 39–41% overall). The scope of the fluoride-mediated coupling process is delineated (nine products, average yield = 72%, Table 2); a related enoxysilane quinonylation reaction is also described (10 products, average yield = 77%, Table 1). We establish that dimeric diazofluorenes undergo hydrodediazotization 3-fold faster then related monomeric diazofluorenes (Table 6). The simple diazofluorene 103 is a potent inhibitor of ovarian cancer stem cells (IC50 = 500 nM).
Graphical Abstract In the decade since the discovery of englerin A (1) and its potent activity in cancer models, this natural product and its analogues have been the subject of numerous chemical, biological, and preclinical studies by many research groups. This review summarizes published findings and proposes further research directions required for entry of an englerin analogue into clinical trials for kidney cancer and other conditions.
The number of renal cancers has increased over the last ten years and patient survival in advanced stages remains very poor. Therefore, new therapeutic approaches for renal cancer are essential. Englerin A is a natural product with a very potent and selective cytotoxicity against renal cancer cells. This makes it a promising drug candidate that may improve current treatment standards for patients with renal cancers in all stages. However, little is known about englerin A's mode of action in targeting specifically renal cancer cells. Our study is the first to investigate the biological mechanism of englerin A action in detail. We report that englerin A is specific for renal tumor cells and does not affect normal kidney cells. We find that englerin A treatment induces necrotic cell death in renal cancer cells but not in normal kidney cells. We further show that autophagic and pyroptotic proteins are unaffected by the compound and that necrotic signaling in these cells coincided with production of reactive oxygen species and calcium influx into the cytoplasm. As the first study to analyze the biological effects of englerin A, our work provides an important basis for the evaluation and validation of the compound's use as an anti-tumor drug. It also provides a context in which to identify the specific target or targets of englerin A in renal cancer cells.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.