A device that enables the combinatorial synthesis of small molecule libraries

A method for combinatorial synthesis of small molecule libraries on a single substrate using a device with a plurality of microfluidic channels, said method using building blocks with reactive groups and comprising the steps of:

• a) with the synthesis plate and microfluidic patterning plate sandwiched in a first orientation, flowing a selected known building block through a first selected microfluidic channel and binding covalently said selected building block to the substrate delineated by the walls of the selected channel;
• and
• b) flowing a known building block through a different selected microfluidic channel and binding covalently said building block to the substrate delineated by the walls of the selected channel;
• and
• c) repeating step b) wherein selected building blocks are flowed through other selected microfluidic channels and bound covalently to other delineated regions of the synthesis plate until a diversity of building blocks are arrayed on the single substrate;
• and
• d) flowing wash solutions through selected microfluidic channels;
• and
• e) disassembling the sandwich, rotating the microfluidic patterning plate relative to the synthesis plate, and reassembling the sandwich so as to create a plurality of new fully sealed microfluidic channels in a second orientation in which this second series of channels are non-parallel to the first series of channels used in steps a)-d), creating intersections between the first and second series of channels, with one outlet and one inlet for each channel;
• and
• f) repeating steps a)-d) once such that covalent coupling between building blocks occurs at each intersection that receives a building block through the first orientation of channels and a building block through the second orientation of channels, until a diversity of synthetic small molecule products is arrayed on the single substrate,
• wherein the device is a device for the combinatorial synthesis of small molecule libraries on a single substrate, said device comprised of:
• A′) a synthesis plate with a plurality of vias (through-holes), in which the vias are patterned in arrays and the total number of vias on the plate will be between 2-100,000;
• and
• B′) a microfluidic patterning plate, with a series of open-faced channels that are aligned with some or all the vias on the synthesis plate such that, when the two plates are sandwiched together, a plurality of fully sealed microfluidic channels are created with one outlet and one inlet for each channel;
• C′) wherein the synthesis plate and the microfluidic patterning plate are separate;
• and
• D′) optionally, wherein the synthesis plate has a face that is in contact with the microfluidic patterning plate and is coated with a functionality that enables solid phase synthesis to be executed on the substrate.

A method for combinatorial synthesis of small molecule libraries on a single substrate using a device with a plurality of microfluidic channels, said method using building blocks with reactive groups and comprising the steps of:

• a) with the synthesis plate and microfluidic patterning plate sandwiched in a first orientation, flowing a selected known building block through a first selected microfluidic channel and binding covalently said selected building block to the substrate delineated by the walls of the selected channel;
• and
• b) flowing a known building block through a different selected microfluidic channel and binding covalently said building block to the substrate delineated by the walls of the selected channel;
• and
• c) repeating step b) wherein selected building blocks are flowed through other selected microfluidic channels and bound covalently to other delineated regions of the substrate plate until a diversity of building blocks are arrayed on the single substrate;
• and
• d) flowing wash solutions through selected microfluidic channels;
• and
• e) flowing a selected known building block through each of the selected microfluidic channels used in steps a)-d) such that covalent coupling between building blocks occurs within this first selected series of channels;
• and
• f) flowing wash solutions through selected microfluidic channels;
• and
• g) disassembling the sandwich, rotating the microfluidic patterning plate relative to the synthesis plate, and reassembling the sandwich to create a plurality of new fully sealed microfluidic channels in a second orientation in which this second series of channels are non-parallel to the first series of channels used in steps a)-f), creating intersections between the first and second series of channels, with one outlet and one inlet for each channel;
• and
• h) repeating steps a)-d) once such that covalent coupling between molecules occurs at each intersection that received building blocks occurs at each intersection that received a building block through the first orientation of channels and a building block through the second orientation of channels, until a diversity of synthetic small molecule products is arrayed on the single substrate,
• wherein the device is a device for the combinatorial synthesis of small molecule libraries on a single substrate, said device comprised of:
• A′) a synthesis plate with a plurality of vias (through-holes), in which the vias are patterned in arrays and the total number of vias on the plate will be between 2-100,000;
• and
• B′) a microfluidic patterning plate with a series of open-faced channels that are aligned with some or all the vias on the synthesis plate such that, when the two plates are sandwiched together, a plurality of fully sealed microfluidic channels are created with one outlet and one inlet for each channel;
• C′) wherein the synthesis plate and the microfluidic patterning plate are separate;
• and
• D′) optionally, wherein the synthesis plate has a face that is in contact with the microfluidic patterning plate and is coated with a functionality that enables solid phase synthesis to be executed on the substrate.