Innovative approaches to the design and synthesis of small molecule libraries

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.

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

Journal of the American Chemical Society ◽

10.1021/jacs.0c09213 ◽

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

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Towards drugging the ‘undruggable’: enhancing the scaffold diversity of synthetic small molecule screening collections using diversity-oriented synthesis

Diversity Oriented Synthesis ◽

10.2478/dos-2013-0001 ◽

2013 ◽

Vol 1 (1) ◽

Cited By ~ 5

Author(s):

Warren R.J.D. Galloway ◽

David R. Spring

Keyword(s):

Small Molecule ◽

Structural Diversity ◽

Library Size ◽

Diversity Oriented Synthesis ◽

Biological Targets ◽

Small Molecule Screening ◽

Chemistry Research ◽

Large Numbers ◽

Small Molecule Libraries ◽

Scaffold Diversity

AbstractMedicinal chemistry research has traditionally focused upon a limited set of biological targets. Many other human disease-related targets have been termed ‘undruggable’ as they have proved largely impervious to modulation by small molecules. However, it is becoming increasingly evident that such targets can indeed be modulated; they are simply being challenged with the wrong types of molecules. Traditionally, screening libraries were composed of large numbers of structurally similar compounds. However, library size is not everything; the structural diversity of the library, which is largely dictated by the range of molecular scaffolds present, is crucial. Diversity-oriented synthesis (DOS) generates small molecule libraries with high levels of scaffold, and thus structural, diversity. Such collections should provide hits against a broad range of targets with high frequency, including ‘undruggable’ targets. Examples in the area of scaffold diversity generation taken from the author’s laboratories are given.

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