Biology‐Oriented Synthesis of a Withanolide‐Inspired Compound Collection Reveals Novel Modulators of Hedgehog Signaling

Švenda, Jakub; Шеремет, М. І.; Kremer, Lea; Maier, Lukáš; Bauer, Jonathan O.; Strohmann, Carsten; Ziegler, Slava; Kumar, Kamal; Waldmann, Herbert

doi:10.1002/anie.201500112

Cited by 58 publications

(36 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We were intrigued by the possibility that hydrindane‐δ‐lactones ( 48 , Figure , eq. ii) which contain only the C‐D ring of the withanolides appended with a lactone ring may retain the neuritogenic activity . To our surprise and in fact disappointment, unlike the natural withanolides, the collection of hydrindane‐ δ ‐lactones was highly cytotoxic towards primary neurons even at low micromolar concentration.…”

Section: Nature Inspired Small Molecules and The Unforeseen Bioactivisupporting

confidence: 72%

Nature Inspired Small Molecules for Chemical Biology

Kumar

Waldmann

2018

Israel Journal of Chemistry

Self Cite

View full text Add to dashboard Cite

Chemical biology and drug discovery are instrumental sciences to address unmet medical needs and to gain a deeper understanding of normal and disease state biology in mammalian systems. Unlike most genetic tools, the small molecule modulation of biology is reversible, controllable in space, time and quantity, avoids the removal of gene products from cellular systems and thus enables perturbation of biology in its native state. Natural products, their derivatives as well as small molecules based on the core‐scaffolds of natural products including natural product fragments allow targeting unique, biologically relevant fractions of chemical space that may deliver quality tool compounds. In this essay, we discuss various synthesis approaches inspired by natural products to deliver biologically active small molecules. We argue and provide evidence that inspiration by natural product structure remains a powerful guiding principle for the development of novel approaches to the study biology by means of novel bioactive small molecules.

show abstract

Section: Nature Inspired Small Molecules and The Unforeseen Bioactivisupporting

confidence: 72%

Nature Inspired Small Molecules for Chemical Biology

Kumar

Waldmann

2018

Israel Journal of Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…21). 204 Although BIOS has been widely applied in medicinal chemistry and chemical biology, [206][207][208] successful examples in discovery of PPI inhibitors are rare. 204 Structural information and underlying scaffolds in complex NPs are embedded in the BIOS-derived compound collections and thus efficient synthetic methods are required to be developed.…”

Section: Synthetic Strategies To Discover Small Molecule Ppi Inhibitorsmentioning

confidence: 99%

State-of-the-art strategies for targeting protein–protein interactions by small-molecule inhibitors

et al. 2015

View full text Add to dashboard Cite

Targeting protein-protein interactions (PPIs) has emerged as a viable approach in modern drug discovery. However, the identification of small molecules enabling us to effectively interrupt their interactions presents significant challenges. In the recent past, significant advances have been made in the development of new biological and chemical strategies to facilitate the discovery process of small-molecule PPI inhibitors. This review aims to highlight the state-of-the-art technologies and the achievements made recently in this field. The "hot spots" of PPIs have been proved to be critical for small molecules to bind. Three strategies including screening, designing, and synthetic approaches have been explored for discovering PPI inhibitors by targeting the "hot spots". Although the classic high throughput screening approach can be used, fragment screening, fragment-based drug design and newly improved virtual screening are demonstrated to be more effective in the discovery of PPI inhibitors. In addition to screening approaches, design strategies including anchor-based and small molecule mimetics of secondary structures involved in PPIs have become powerful tools as well. Finally, constructing new chemically spaced libraries with high diversity and complexity is becoming an important area of interest for PPI inhibitors. The successful cases from the recent five year studies are used to illustrate how these approaches are implemented to uncover and optimize small molecule PPI inhibitors and notably some of them have become promising therapeutics.

show abstract

“…47–52 In addition to efforts targeting the well characterized protein aggregation process or other pathological hallmarks, re-establishment of damaged neuronal and synaptic network by neurotrophic agents has attracted extensive attention as an alternative and efficient way to treat neurodegenerative disorders and neuronal injuries. 53–56 Polyphenols and steroid analogs have been shown to induce neuronal differentiation and neurite outgrowth. 39, 57, 58 We thus examined whether our bivalent compounds provide neurotrophic activity to stimulate neurite outgrowth, which would add an additional layer of benefits to the scaffold.…”

Section: Resultsmentioning

confidence: 99%

Insights into the Impact of a Membrane-Anchoring Moiety on the Biological Activities of Bivalent Compounds As Potential Neuroprotectants for Alzheimer’s Disease

Li¹,

Jiang²,

Li³

et al. 2018

J. Med. Chem.

View full text Add to dashboard Cite

Bivalent compounds anchoring in different manners to the membrane were designed and biologically characterized to understand the contribution of the anchor moiety to their biological activity as neuroprotectants for Alzheimer’s disease. Our results established that the anchor moiety is essential and we identified a preference for diosgenin, as evidenced by 17MD. Studies in primary neurons and mouse brain mitochondria also identified 17MD as exhibiting activity on neuritic outgrowth and the state 3 oxidative rate of glutamate while preserving the coupling capacity of the mitochondria. Significantly, our studies demonstrated that the integrated bivalent structure is essential to the observed biological activities. Further studies employing bivalent compounds as probes in a model membrane also revealed the influence of the anchor moiety on how they interact with the membrane. Collectively, our results suggest diosgenin to be an optimal anchor moiety, providing bivalent compounds with promising pharmacology that have potential applications for Alzheimer’s disease.

show abstract

Biology‐Oriented Synthesis of a Withanolide‐Inspired Compound Collection Reveals Novel Modulators of Hedgehog Signaling

Cited by 58 publications

References 51 publications

Nature Inspired Small Molecules for Chemical Biology

Nature Inspired Small Molecules for Chemical Biology

State-of-the-art strategies for targeting protein–protein interactions by small-molecule inhibitors

Insights into the Impact of a Membrane-Anchoring Moiety on the Biological Activities of Bivalent Compounds As Potential Neuroprotectants for Alzheimer’s Disease

Contact Info

Product

Resources

About