title: Microfluidic platform for combinatorial synthesis in picolitre droplets.
abstract: This paper presents a droplet-based microfluidic platform for miniaturized combinatorial synthesis. As a proof of concept, a library of small molecules for early stage drug screening was produced. We present an efficient strategy for producing a 7 × 3 library of potential thrombin inhibitors that can be utilized for other combinatorial synthesis applications. Picolitre droplets containing the first type of reagent (reagents A(1), A(2), …, A(m)) were formed individually in identical microfluidic chips and then stored off chip with the aid of stabilizing surfactants. These droplets were then mixed to form a library of droplets containing reagents A(1-m), each individually compartmentalized, which was reinjected into a second microfluidic chip and combinatorially fused with picolitre droplets containing the second reagent (reagents B(1), B(2), …, B(n)) that were formed on chip. The concept was demonstrated with a three-component Ugi-type reaction involving an amine (reagents A(1-3)), an aldehyde (reagents B(1-7)), and an isocyanide (held constant), to synthesize a library of small molecules with potential thrombin inhibitory activity. Our technique produced 10(6) droplets of each reaction at a rate of 2.3 kHz. Each droplet had a reaction volume of 3.1 pL, at least six orders of magnitude lower than conventional techniques. The droplets can then be divided into aliquots for different downstream screening applications. In addition to medicinal chemistry applications, this combinatorial droplet-based approach holds great potential for other applications that involve sampling large areas of chemical parameter space with minimal reagent consumption; such an approach could be beneficial when optimizing reaction conditions or performing combinatorial reactions aimed at producing novel materials.
authors.affiliation: Institut de Science et d'Ingénierie Supramoléculaires (ISIS), Université de Strasbourg, CNRS UMR 7006, 8 Allée Gaspard Monge, 67083 Strasbourg Cedex, France.
authors.forename: Ashleigh B
authors.initials: AB
authors.lastname: Theberge
authors.forename: Estelle
authors.initials: E
authors.lastname: Mayot
authors.forename: Abdeslam
authors.initials: A
authors.lastname: El Harrak
authors.forename: Felix
authors.initials: F
authors.lastname: Kleinschmidt
authors.forename: Wilhelm T S
authors.initials: WT
authors.lastname: Huck
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Griffiths
mesh_terms: D000447:Aldehydes / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D003486:Cyanides / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D046210:Microfluidic Analytical Techniques / Q000295:instrumentation*; D008904:Miniaturization; D009821:Oils / Q000737:chemistry; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000447:Aldehydes; D000588:Amines; D003486:Cyanides; D004791:Enzyme Inhibitors; D009821:Oils; D013917:Thrombin