title: A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products.
abstract: High-throughput screening is the dominant method used to identify lead compounds in drug discovery. As such, the makeup of screening libraries largely dictates the biological targets that can be modulated and the therapeutics that can be developed. Unfortunately, most compound-screening collections consist principally of planar molecules with little structural or stereochemical complexity, compounds that do not offer the arrangement of chemical functionality necessary for the modulation of many drug targets. Here we describe a novel, general and facile strategy for the creation of diverse compounds with high structural and stereochemical complexity using readily available natural products as synthetic starting points. We show through the evaluation of chemical properties (which include fraction of sp(3) carbons, ClogP and the number of stereogenic centres) that these compounds are significantly more complex and diverse than those in standard screening collections, and we give guidelines for the application of this strategy to any suitable natural product.
authors: Department of Chemistry, Roger Adams Laboratory, University of Illinois, 600 South Mathews, Urbana, Illinois 61801, USA.
authors: Robert W
authors: RW
authors: Huigens
authors: Karen C
authors: KC
authors: Morrison
authors: Robert W
authors: RW
authors: Hicklin
authors: Timothy A
authors: TA
authors: Flood
authors: Michelle F
authors: MF
authors: Richter
authors: Paul J
authors: PJ
authors: Hergenrother
mesh_terms: D000736:Androstenes / Q000737:chemistry; D001688:Biological Products / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic / Q000379:methods*; D015195:Drug Design; D005875:Gibberellins / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D011803:Quinine / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013678:Technology, Pharmaceutical
chemical_list: D000736:Androstenes; D001688:Biological Products; D005875:Gibberellins; D011803:Quinine; C011657:adrenosterone; C007842:gibberellic acid