Design, synthesis and spectroscopic characterisation of a focused library based on the polyandrocarpamine natural product scaffold

Baron, Paul; Neve, Juliette Ellen; Camp, David Brian; Suraweera, Lekha; Lam, Ann; Lai, John; Jovanovic, Lidija; Nelson, Colleen C.; Davis, Rohan A.

doi:10.1002/mrc.3958

Cited by 6 publications

(6 citation statements)

References 27 publications

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“…All natural products from the Davis Compound Library were isolated from plants, marine invertebrates, or endophytic fungi archived at the Griffith Institute for Drug Discovery, Griffith University, Australia, or purchased from Sigma-Aldrich. The extraction and isolation of the natural products featured in this paper have been previously reported by Davis et al ,− The synthesis and characterization of the semisynthetic fungal analogues 13 – 18 have also been previously reported in the literature . All compounds from the Davis collection were analyzed for purity prior to screening and were shown by LC-MS or 1 H NMR analysis to have purities of >95%.…”

Section: Methodsmentioning

confidence: 82%

Potential Antiosteoporotic Natural Product Lead Compounds That Inhibit 17β-Hydroxysteroid Dehydrogenase Type 2

et al. 2017

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17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) converts the active steroid hormones estradiol, testosterone, and 5α-dihydrotestosterone into their weakly active forms estrone, Δ4-androstene-3,17-dione, and 5α-androstane-3,17-dione, respectively, thereby regulating cell- and tissue-specific steroid action. As reduced levels of active steroids are associated with compromised bone health and onset of osteoporosis, 17β-HSD2 is considered a target for antiosteoporotic treatment. In this study, a pharmacophore model based on 17β-HSD2 inhibitors was applied to a virtual screening of various databases containing natural products in order to discover new lead structures from nature. In total, 36 hit molecules were selected for biological evaluation. Of these compounds, 12 inhibited 17β-HSD2 with nanomolar to low micromolar IC50 values. The most potent compounds, nordihydroguaiaretic acid (1), IC50 0.38 ± 0.04 μM, (−)-dihydroguaiaretic acid (4), IC50 0.94 ± 0.02 μM, isoliquiritigenin (6), IC50 0.36 ± 0.08 μM, and ethyl vanillate (12), IC50 1.28 ± 0.26 μM, showed 8-fold or higher selectivity over 17β-HSD1. As some of the identified compounds belong to the same structural class, structure–activity relationships were derived for these molecules. Thus, this study describes new 17β-HSD2 inhibitors from nature and provides insights into the binding pocket of 17β-HSD2, offering a promising starting point for further research in this area.

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Section: Methodsmentioning

confidence: 82%

Potential Antiosteoporotic Natural Product Lead Compounds That Inhibit 17β-Hydroxysteroid Dehydrogenase Type 2

et al. 2017

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“…To extend these results we synthesized both polyandrocarpamines, as well as a series of derivatives [ 38 ] ( Figure 4 ), and tested them on a panel of 16 purified kinases. Synthesized ( Table 3 , PAC 1 and 2) and natural ( Table 3 , PAC 12 and 13) polyandrocarpamines showed very similar effects on the target kinases.…”

Section: Resultsmentioning

confidence: 99%

“…PAC1 to 11 were supplied by Rohan A. Davis The synthesis, purification and spectroscopic characterization of this focused polyandrocarpamine library has been described elsewhere [ 38 ].…”

Section: Methodsmentioning

confidence: 99%

Marine-Derived 2-Aminoimidazolone Alkaloids. Leucettamine B-Related Polyandrocarpamines Inhibit Mammalian and Protozoan DYRK & CLK Kinases

et al. 2017

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A large diversity of 2-aminoimidazolone alkaloids is produced by various marine invertebrates, especially by the marine Calcareous sponges Leucetta and Clathrina. The phylogeny of these sponges and the wide scope of 2-aminoimidazolone alkaloids they produce are reviewed in this article. The origin (invertebrate cells, associated microorganisms, or filtered plankton), physiological functions, and natural molecular targets of these alkaloids are largely unknown. Following the identification of leucettamine B as an inhibitor of selected protein kinases, we synthesized a family of analogues, collectively named leucettines, as potent inhibitors of DYRKs (dual-specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) and potential pharmacological leads for the treatment of several diseases, including Alzheimer’s disease and Down syndrome. We assembled a small library of marine sponge- and ascidian-derived 2-aminoimidazolone alkaloids, along with several synthetic analogues, and tested them on a panel of mammalian and protozoan kinases. Polyandrocarpamines A and B were found to be potent and selective inhibitors of DYRKs and CLKs. They inhibited cyclin D1 phosphorylation on a DYRK1A phosphosite in cultured cells. 2-Aminoimidazolones thus represent a promising chemical scaffold for the design of potential therapeutic drug candidates acting as specific inhibitors of disease-relevant kinases, and possibly other disease-relevant targets.

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“…The transcription factor Nrf2 is a potential target of RAD618. Other naphthoquinones have been shown to stimulate the activity of nuclear factor (erythroid-derived 2)-like 2(Nrf2) in other cell types 33,34 . Nrf2 regulates cell cycle transition from G2 to M phase 35 .…”

Section: Rad618 Induces Cell Cycle Alterations In Gfp-moecs Consistenmentioning

confidence: 99%

The plant natural product 2-methoxy-1,4-naphthoquinone stimulates therapeutic neural repair properties of olfactory ensheathing cells

Chen

Vial

Gee

et al. 2020

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Olfactory ensheathing cells (OECs) are crucial for promoting the regeneration of the primary olfactory nervous system that occurs throughout life. Transplantation of OECs has emerged as a promising therapy for nervous system injuries, in particular for spinal cord injury repair. Functional outcomes in both animals and humans are, however, highly variable, primarily because it is difficult to rapidly obtain enough OECs for transplantation. Compounds which can stimulate OEC proliferation without changing the phenotype of the cells are therefore highly sought after. Additionally, compounds which can stimulate favourable cell behaviours such as migration and phagocytic activity are desirable. We conducted a medium-throughput screen testing the Davis open access natural product-based library (472 compounds) and subsequently identified the known plant natural product 2-methoxy-1,4naphthoquinone as a stimulant of OEC viability. We showed that 2-methoxy-1,4-naphthoquinone: (i) strongly stimulates proliferation over several weeks in culture whilst maintaining the OEC phenotype; (ii) stimulates the phagocytic activity of OECs, and (iii) modulates the cell cycle. We also identified the transcription factor Nrf2 as the compound's potential molecular target. From these extensive investigations we conclude that 2-methoxy-1,4-naphthoquinone may enhance the therapeutic potential of OECs by stimulating proliferation prior to transplantation.

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Design, synthesis and spectroscopic characterisation of a focused library based on the polyandrocarpamine natural product scaffold

Cited by 6 publications

References 27 publications

Potential Antiosteoporotic Natural Product Lead Compounds That Inhibit 17β-Hydroxysteroid Dehydrogenase Type 2

Potential Antiosteoporotic Natural Product Lead Compounds That Inhibit 17β-Hydroxysteroid Dehydrogenase Type 2

Marine-Derived 2-Aminoimidazolone Alkaloids. Leucettamine B-Related Polyandrocarpamines Inhibit Mammalian and Protozoan DYRK & CLK Kinases

The plant natural product 2-methoxy-1,4-naphthoquinone stimulates therapeutic neural repair properties of olfactory ensheathing cells

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