Discovery of Anticancer Agents of Diverse Natural Origin

Kinghorn, A. Douglas; Blanco, Esperanza J. Carcache de; Lucas, David M.; Rakotondraibe, L. Harinantenaina; Orjala, Jimmy; Soejarto, Djaja D.; Oberlies, Nicholas H.; Pearce, Cedric J.; Wani, Mansukh C.; Stockwell, Brent R.; Burdette, Joanna E.; Swanson, Steven M.; Fuchs, James R.; Phelps, Mitch A.; Xu, Lihui; Zhang, Xiaoli; Shen, Yongchun

doi:10.21873/anticanres.11146

Cited by 108 publications

(134 citation statements)

References 103 publications

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“…1,2 Of these, about 4700 are halogenated, 3 and just 5 contain a fluorine atom, 4−7 with no reports of natural fluorometabolites derived from fungi. Nature has been a fertile source for drug leads, particularly in the realms of anticancer and antimicrobial agents.…”

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confidence: 99%

Biosynthesis of Fluorinated Peptaibols Using a Site-Directed Building Block Incorporation Approach

et al. 2017

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Synthetic biological approaches, such as site-directed biosynthesis, have contributed to the expansion of the chemical space of natural products, making possible the biosynthesis of unnatural metabolites that otherwise would be difficult to access. Such methods may allow the incorporation of fluorine, an atom rarely found in nature, into complex secondary metabolites. Organofluorine compounds and secondary metabolites have both played pivotal roles in the development of drugs; however, their discovery and development are often via nonintersecting tracks. In this context, we used the biosynthetic machinery of Trichoderma arundinaceum (strain MSX70741) to incorporate a fluorine atom into peptaibol-type molecules in a site-selective manner. Thus, fermentation of strain MSX70741 in media containing ortho- and meta-F-phenylalanine resulted in the biosynthesis of two new fluorine-containing alamethicin F50 derivatives. The fluorinated products were characterized using spectroscopic (1D and 2D NMR, including 19F) and spectrometric (HRESIMS/MSn) methods, and their absolute configurations were established by Marfey’s analysis. Fluorine-containing alamethicin F50 derivatives exhibited potency analogous to the nonfluorinated parent when evaluated against a panel of human cancer cell lines. Importantly, the biosynthesis of fluorinated alamethicin F50 derivatives by strain MSX70741 was monitored in situ using a droplet–liquid microjunction–surface sampling probe coupled to a hyphenated system.

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confidence: 99%

Biosynthesis of Fluorinated Peptaibols Using a Site-Directed Building Block Incorporation Approach

et al. 2017

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“…El-Elimat et al (2012) studied the chemical space of 105 compounds isolated from filamentous fungi using nine molecular descriptors, and compared them to other natural products and FDA-approved anticancer drugs. In that work it was concluded that fungal metabolites had a high overlap with the chemical space of anticancer drugs, which was an encouraging finding for the ongoing efforts to discover active anticancer compounds of fungal origin (Kinghorn et al, 2016). Gonzalez-Medina et al (2016) analyzed a larger data set with 207 fungal isolates, adding more information on structural complexity and diversity of the fungal metabolites.…”

Section: Introductionmentioning

confidence: 92%

Scaffold Diversity of Fungal Metabolites

González-Medina

Owen²,

El‐Elimat

et al. 2017

Front. Pharmacol.

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Many drug discovery projects rely on commercial compounds to discover active leads. However, current commercial libraries, with mostly synthetic compounds, access a small fraction of the possible chemical diversity. Natural products, in contrast, possess a vast structural diversity and have proven to be an outstanding source of new drugs. Several chemoinformatic analyses of natural products have demonstrated their diversity and structural complexity. However, to our knowledge, the scaffold content and structural diversity of fungal secondary metabolites have never been studied. Herein, the scaffold diversity of 223 fungal metabolites was measured and compared to the diversity of approved drugs and commercial libraries for HTS containing natural, synthetic, and semi-synthetic compounds. In addition, the global diversity of the fungal isolates was assessed and compared to other reference data sets using Consensus Diversity Plots, a chemoinformatic tool recently developed. It was concluded that fungal secondary metabolites are cyclic systems with few ramifications and more diverse than the commercial libraries with natural products and semi-synthetic compounds. The fungal metabolites data set was one of the most structurally diverse, containing a large proportion of different and unique scaffolds not found in the other compound data sets including ChEMBL. Therefore, fungal metabolites offer a rich source of molecules suited for identifying diverse candidates for drug discovery.

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“…Decisive advances in cellular and molecular biology have led to the improvement of chemotherapeutic management of cancer, but further efforts to discover new anticancer agents to overcome resistance and toxicity concerns, are still necessary. Because natural products are one of the major sources for lead compounds, exhibiting various modes of cytostatic action, in the last decades, interest has been focused on the use of natural products or their derivative with the aim of developing more efficacious chemotherapeutic agents …”

Section: Introductionmentioning

confidence: 99%

Anticancer Activity of Stilbene‐Based Derivatives

et al. 2017

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Stilbene is an abundant structural scaffold in nature, and stilbene-based compounds have been widely reported for their biological activity. Notably, (E)-resveratrol and its natural stilbene-containing derivatives have been extensively investigated as cardioprotective, potent antioxidant, anti-inflammatory, and anticancer agents. Starting from its potent chemotherapeutic activity against a wide variety of cancers, the stilbene scaffold has been subject to synthetic manipulations with the aim of obtaining new analogues with improved anticancer activity and better bioavailability. Within the last decade, the majority of new synthetic stilbene derivatives have demonstrated significant anticancer activity against a large number of cancer cell lines, depending on the type and position of substituents on the stilbene skeleton. This review focuses on the structure-activity relationship of the key compounds containing a stilbene scaffold and describes how the structural modifications affect their anticancer activity.

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Discovery of Anticancer Agents of Diverse Natural Origin

Cited by 108 publications

References 103 publications

Biosynthesis of Fluorinated Peptaibols Using a Site-Directed Building Block Incorporation Approach

Biosynthesis of Fluorinated Peptaibols Using a Site-Directed Building Block Incorporation Approach

Scaffold Diversity of Fungal Metabolites

Anticancer Activity of Stilbene‐Based Derivatives

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