Synergistic Effects of Stereochemistry and Appendages on the Performance Diversity of a Collection of Synthetic Compounds

Target- and phenotype-agnostic assessments of biological activity have emerged as viable strategies for prioritizing scaffolds, structural features, and synthetic pathways in screening sets, with the goal of increasing performance diversity. Here, we describe the synthesis of a small library of func...

Full description

Saved in:
Bibliographic Details
Published inJournal of the American Chemical Society Vol. 140; no. 37; pp. 11784 - 11790
Main Authors Melillo, Bruno, Zoller, Jochen, Hua, Bruce K, Verho, Oscar, Borghs, Jannik C, Nelson, Shawn D, Maetani, Micah, Wawer, Mathias J, Clemons, Paul A, Schreiber, Stuart L
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 19.09.2018
Amer Chemical Soc
Subjects
appendages
Azetidines - chemical synthesis
Azetidines - chemistry
bioactive properties
cell biology
Cell Line, Tumor
Chemistry
Chemistry, Multidisciplinary
Humans
image analysis
Molecular Conformation
Optical Imaging
Physical Sciences
Science & Technology
screening
Small Molecule Libraries - chemical synthesis
Small Molecule Libraries - chemistry
stereochemistry
Stereoisomerism
synergism
LIBRARIES
TIME BIOLOGICAL ANNOTATION
SMALL MOLECULES
SIMILARITY
AZETIDINE
DRUG DISCOVERY
Online AccessGet full text
ISSN0002-7863
1520-5126
1520-5126
DOI10.1021/jacs.8b07319

Cover

More Information
Summary:Target- and phenotype-agnostic assessments of biological activity have emerged as viable strategies for prioritizing scaffolds, structural features, and synthetic pathways in screening sets, with the goal of increasing performance diversity. Here, we describe the synthesis of a small library of functionalized stereoisomeric azetidines and its biological annotation by “cell painting,” a multiplexed, high-content imaging assay capable of measuring many hundreds of compound-induced changes in cell morphology in a quantitative and unbiased fashion. Using this approach, we systematically compare the degrees to which a core scaffold’s biological activity, inferred from its effects on cell morphology, is affected by variations in stereochemistry and appendages. We show that stereoisomerism and appendage diversification can produce effects of similar magnitude, and that the concurrent use of these strategies results in a broader sampling of biological activity.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
These authors contributed equally to this work.
ISSN:0002-7863
1520-5126
1520-5126
DOI:10.1021/jacs.8b07319