scholarly journals Realisation of small molecule libraries based on frameworks distantly related to natural products

2018 ◽  
Vol 16 (17) ◽  
pp. 3160-3167 ◽  
Author(s):  
Anthony Aimon ◽  
George Karageorgis ◽  
Jacob Masters ◽  
Mark Dow ◽  
Philip G. E. Craven ◽  
...  
Keyword(s):  
Natural Products ◽  
Small Molecule ◽  
Molecular Properties ◽  
Design And Synthesis ◽  
Compound Libraries ◽  
Small Molecule Libraries

Design and synthesis of compound libraries with focused molecular properties, based on NP-like scaffolds.

Post Glycosylation Diversification (PGD): An Approach for Assembling Collections of Glycosylated Small Molecules

2018 ◽  
Author(s):  
Zachary Cannone ◽  
Ala Shaqra ◽  
Chris Lorenc ◽  
Liza Henowitz ◽  
Santosh Keshipeddy ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
T Cell Activation ◽  
Cell Activation ◽  
De Novo ◽  
Protein Translation ◽  
Compound Libraries ◽  
Activation Assay ◽  
Small Molecule Libraries ◽  
New Compounds

Many small molecule natural products with are adorned with a carbohydrate as part of their molecular structure that acts to mediate key interactions with the target, attenuate physicochemical properties, or both. Facile incorporation of a carbohydrate group on de novo small molecules would enable these valuable properties to be leveraged in the evaluation of focused compound libraries. Here we report a new approach for the synthesis of glycosylated small molecule libraries that puts the glycosylation early in the synthesis of library compounds. Functionalized aglycones subsequently participate in chemoselective diversification reactions distal to the carbohydrate. A number of desosaminyl glycosides were prepared from only a few starting glycosides, using click cycloadditions, acylations, and Suzuki couplings as diversification reactions. New compounds were characterized for their inhibition of bacterial protein translation, bacterial growth, and in a T-cell activation assay.

Post Glycosylation Diversification (PGD): An Approach for Assembling Collections of Glycosylated Small Molecules

2018 ◽  
Author(s):  
Zachary Cannone ◽  
Ala Shaqra ◽  
Chris Lorenc ◽  
Liza Henowitz ◽  
Santosh Keshipeddy ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
T Cell Activation ◽  
Cell Activation ◽  
De Novo ◽  
Protein Translation ◽  
Compound Libraries ◽  
Activation Assay ◽  
Small Molecule Libraries ◽  
New Compounds

Many small molecule natural products with are adorned with a carbohydrate as part of their molecular structure that acts to mediate key interactions with the target, attenuate physicochemical properties, or both. Facile incorporation of a carbohydrate group on de novo small molecules would enable these valuable properties to be leveraged in the evaluation of focused compound libraries. Here we report a new approach for the synthesis of glycosylated small molecule libraries that puts the glycosylation early in the synthesis of library compounds. Functionalized aglycones subsequently participate in chemoselective diversification reactions distal to the carbohydrate. A number of desosaminyl glycosides were prepared from only a few starting glycosides, using click cycloadditions, acylations, and Suzuki couplings as diversification reactions. New compounds were characterized for their inhibition of bacterial protein translation, bacterial growth, and in a T-cell activation assay.

scholarly journals A small molecule HIF-1α stabilizer that accelerates diabetic wound healing

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Guodong Li ◽  
Chung-Nga Ko ◽  
Dan Li ◽  
Chao Yang ◽  
Wanhe Wang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Small Molecule ◽  
Hypoxia Inducible Factor ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Impaired Wound Healing ◽  
Von Hippel Lindau ◽  
Design And Synthesis

AbstractImpaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design and synthesis of a cyclometalated iridium(III) metal complex 1a as a stabilizer of hypoxia-inducible factor-1α (HIF-1α). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL–HIF-1α interaction. Furthermore, the compound accumulates HIF-1α levels in cellulo and activates HIF-1α mediated gene expression, including VEGF, GLUT1, and EPO. In in vivo mouse models, the compound significantly accelerates wound closure in both normal and diabetic mice, with a greater effect being observed in the diabetic group. We also demonstrate that HIF-1α driven genes related to wound healing (i.e. HSP-90, VEGFR-1, SDF-1, SCF, and Tie-2) are increased in the wound tissue of 1a-treated diabetic mice (including, db/db, HFD/STZ and STZ models). Our study demonstrates a small molecule stabilizer of HIF-1α as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1α interaction.

scholarly journals Screening of DNA-Encoded Small Molecule Libraries inside a Living Cell

2021 ◽  
Vol 143 (7) ◽  
pp. 2751-2756
Author(s):  
Lars K. Petersen ◽  
Allan B. Christensen ◽  
Jacob Andersen ◽  
Charlotta G. Folkesson ◽  
Ole Kristensen ◽  
...  
Keyword(s):  
Small Molecule ◽  
Living Cell ◽  
Small Molecule Libraries

Synthetic Strategies to Access Heteroatomic Spirocentres Embedded in Natural Products

Synthesis ◽  
2021 ◽  
Author(s):  
Michael P. Badart ◽  
Bill C. Hawkins
Keyword(s):  
Natural Products ◽  
Heterocyclic Compound ◽  
Chemical Space ◽  
Three Dimensional ◽  
Coupling Reactions ◽  
Conjugate Additions ◽  
Biological Targets ◽  
Compound Libraries ◽  
The Common ◽  
Significant Attention

AbstractThe spirocyclic motif is abundant in natural products and provides an ideal three-dimensional template to interact with biological targets. With significant attention historically expended on the synthesis of flat-heterocyclic compound libraries, methods to access the less-explored three-dimensional medicinal-chemical space will continue to increase in demand. Herein, we highlight by reaction class the common strategies used to construct the spirocyclic centres embedded in a series of well-studied natural products.1 Introduction2 Cycloadditions3 Palladium-Catalysed Coupling Reactions4 Conjugate Additions5 Imines, Aminals, and Hemiaminal Ethers6 Mannich-Type Reactions7 Oxidative Dearomatisation8 Alkylation9 Organometallic Additions10 Conclusions

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