Design and synthesis of screening libraries based on the muurolane natural product scaffold

Barnes, Emma C.; Choomuenwai, Vanida; Andrews, Katherine Thea; Quinn, Ronald J.; Davis, Rohan A.

doi:10.1039/c2ob00029f

Cited by 34 publications

(54 citation statements)

References 47 publications

(113 reference statements)

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“…The structural features of natural-product scaffolds have long been widely used in drug development and in field of medicinal chemistry (234)(235)(236)(237). The structural features of natural-product scaffolds have long been widely used in drug development and in field of medicinal chemistry (234)(235)(236)(237).…”

Section: Modulators Of Potassium Channelsmentioning

confidence: 99%

Potassium Channels: Structures, Diseases, and Modulators

Tian

Zhu

et al. 2013

Chem Biol Drug Des

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Potassium channels participate in many critical biological functions and play important roles in a variety of diseases. In recent years, many significant discoveries have been made which motivate us to review these achievements. The focus of our review is mainly on three aspects. Firstly, we try to summarize the latest developments in structure determinants and regulation mechanism of all types of potassium channels. Secondly, we review some diseases induced by or related to these channels. Thirdly, both qualitative and quantitative approaches are utilized to analyze structural features of modulators of potassium channels. Our analyses further prove that modulators possess some certain natural-product scaffolds. And pharmacokinetic parameters are important properties for organic molecules. Besides, with in silico methods, some features that can be used to differentiate modulators are derived. There is no doubt that all these studies on potassium channels as possible pharmaceutical targets will facilitate future translational research. All the strategies developed in this review could be extended to studies on other ion channels and proteins as well.

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Section: Modulators Of Potassium Channelsmentioning

confidence: 99%

Potassium Channels: Structures, Diseases, and Modulators

Tian

Zhu

et al. 2013

Chem Biol Drug Des

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“…Briefly, the NPs in this collection have been isolated from endophytic fungi, [31] macrofungi, [32] plants, [33], and marine invertebrates (e.g., sponges [34] and ascidians [35]) with quantities ranging from 0.4 mg to >1 g. Approximately 15% of this library contains semisynthetic NP analogues, [32, 36] while a small percentage (~5%) of the library is known commercial drugs or synthetic compounds inspired by NPs. A substructure search on this NP-based library against the spermidine fragment identified five secondary metabolites as hits.…”

Section: Resultsmentioning

confidence: 99%

Natural Product Polyamines That Inhibit Human Carbonic Anhydrases

Davis

Vullo

Supuran

et al. 2014

BioMed Research International

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Natural product compound collections have proven an effective way to access chemical diversity and recent findings have identified phenolic, coumarin, and polyamine natural products as atypical chemotypes that inhibit carbonic anhydrases (CAs). CA enzymes are implicated as targets of variable drug therapeutic classes and the discovery of selective, drug-like CA inhibitors is essential. Just two natural product polyamines, spermine and spermidine, have until now been investigated as CA inhibitors. In this study, five more complex natural product polyamines 1–5, derived from either marine sponge or fungi, were considered for inhibition of six different human CA isozymes of interest in therapeutic drug development. All compounds share a simple polyamine core fragment, either spermine or spermidine, yet display substantially different structure activity relationships for CA inhibition. Notably, polyamines 1–5 were submicromolar inhibitors of the cancer drug target CA IX, this is more potent than either spermine or spermidine.

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“…78,79 Approximately 15% of the entries of this library were semisynthetic natural product analogues, 80,76 while a small percentage (∼5%) are known commercial drugs or synthetic compounds inspired by natural products. The Atanasov and Krenn databases consisted of 51 and 13 in-house available natural products, respectively, from the Department of Pharmacognosy at the University of Vienna, Austria.…”

Section: Methodsmentioning

confidence: 99%

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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Design and synthesis of screening libraries based on the muurolane natural product scaffold

Cited by 34 publications

References 47 publications

Potassium Channels: Structures, Diseases, and Modulators

Potassium Channels: Structures, Diseases, and Modulators

Natural Product Polyamines That Inhibit Human Carbonic Anhydrases

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

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