System and method for solid-phase parallel synthesis of a combinatorial collection of compounds

• US 6,083,682 A
• Filed: 12/19/1997
• Issued: 07/04/2000
• Est. Priority Date: 12/19/1997
• Status: Expired due to Fees

• Current Assignee: Smithkline Beecham Corporation (GSK plc)
• Original Assignee: Glaxo Group Limited (GSK plc)
• Inventors: Campbell, David A., Selick, Harold E., Antonenko, Valery V.
• Primary Examiner(s): Celsa, Bennett
• Assistant Examiner(s): RICIGLIANO, JOSEPH W
• Application Number:
  US08/994,802
• Time in Patent Office: 928 Days
• Field of Search: 422/130, 422/129, 422/131, 422/134, 422/101, 422/98, 436/578, 435/4, 435/DIG. 49
• US Class Current: 435/4
• CPC Class Codes: B01J 19/0046 Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays synthesis methods per se C40B50/00
• CPC Class Codes: B01J 2219/00313 the reactor vessels being formed by arrays of wells in blocks
• CPC Class Codes: B01J 2219/00319 the blocks being mounted in stacked arrangements
• CPC Class Codes: B01J 2219/00353 Pumps
• CPC Class Codes: B01J 2219/00391 Rotary valves
• CPC Class Codes: B01J 2219/00423 using filtration, e.g. through porous frits
• CPC Class Codes: B01J 2219/00495 Means for heating or cooling the reaction vessels
• CPC Class Codes: B01J 2219/005 Beads
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/0059 Sequential processes
• CPC Class Codes: B01J 2219/00596 Solid-phase processes
• CPC Class Codes: B01J 2219/00664 Three-dimensional arrays
• CPC Class Codes: B01J 2219/00689 using computers
• CPC Class Codes: C40B 60/14 for creating libraries
• CPC Class Codes: Y10T 436/25 including sample preparation

Abstract

The invention provides a system and method for synthesizing chemicals onto supports in a parallel manner to produce a combinatorial collection of compounds. The system includes a plurality of middle plates, with each middle plate defining a plurality of reaction zones arranged in a two dimensional array. The reaction zones are adapted to receive a solid support, such as a sheet of membrane, and the middle plates are stackable on each other to form a three dimensional array of reaction zones. The system also includes a pair of end plates, where the middle plates are located between the end plates, and where the end plates include an array of fluid guides corresponding to the array of reaction zones, to allow for selective routing of reagents through the reaction zones.

Claims

1. A system for synthesizing chemicals on membrane supports in a parallel manner, the system comprising:

a plurality of middle plates, with each middle plate comprising a plurality of holes arranged in a two dimensional array having x and y axes, wherein the middle plates are stackable on each other and adapted to receive a plurality of interleaving sheets of membrane to form a three dimensional array of reaction zones having x, y and z axes and defining Z (x,y) reaction planes, wherein each Z(x,y) reaction plane has a different sheet of membrane; and

a pair of end plates, wherein the middle plates are located between the end plates, and wherein the end plates include an array of fluid guides corresponding to said array of reaction zones, to allow for selective routing of reagents through the reaction zones such that the same reagent passes through the reaction zones having a common z axis.

2. The system of claim 1, wherein the middle plates form a stack which is rotatable relative to the end plates to align the fluid guides with selected reaction zones.

3. The system of claim 2 wherein the fluid guides in at least one of the end plates include an array of manifolds, where each manifold is aligned with one group of reaction zones when the end plate is in a first orientation and with a different group of reaction zones when the end plate is in a second orientation.

4. The system of claim 1, wherein at least some of the fluid guides include a narrowing orifice to control the flow of chemicals through the reaction zones.

5. The system of claim 1, wherein the middle plates are formed of polytetrafluoroethylene (PTFE) sheets.

6. The system of claim 1, wherein said middle plates have a thickness of between about 0.005" and 0.1".

7. The system of claim 1, further comprising a compression means effective to compress the end plates together with sufficient force to isolate reaction zones in each (x,y) reaction plane from one another by a fluid-tight seal.

8. The system of claim 7, wherein the compression means is a hydraulic press.

9. The system of claim 7, further comprising

a reagent vessel,

at least one length of tubing connecting a subset of said fluid guides with said reagent vessel, and

a pressure source for delivering fluid from said reagent vessel to said fluid guides by way of said tubing.

10. A method of synthesizing a library of compounds, comprising

providing a plurality of middle plates, each middle plate comprising a plurality of holes arranged in a two dimensional array having x and y axes when the plates are aligned;

interposing, between said plurality of middle plates, a sheet of membrane capable of serving as a solid support for chemical synthesis, wherein the sheet of membrane is a continuous sheet disposed across said holes;

compressing said plates together to form an array comprised of a plurality of sheets of membranes interposed between a plurality of middle plates, resulting in an array of discrete reaction zones corresponding to the array of holes, where each reaction zone contains a portion of each said continuous sheet of membrane, and where said compressing creates a fluid-tight seal between adjacent reaction zones;

delivering a first building block to the reaction zones;

delivering a second building block to the reaction zones such that zones having a common x coordinate value receive the same second building block; and

delivering a third building block to the reaction zones such that zones having a common y coordinate value are contacted with the same third building block; and

wherein a library of compounds is formed by the reaction of the second and third building blocks in the different reaction zones.

11. The method of claim 10, wherein the sheets of membrane are pre-derivatized with a first building block, and said library of compounds is formed by the reaction of the first, second and third building blocks in the different reaction zones.

12. The method of claim 10, wherein said sheets of membrane are selected from the group consisting of polypropylene membrane, polyethylene membrane, polytetrafluoroethylene (PTFE) polyacrylate terpolymer membrane, PTFE polyacrylamide terpolymer membrane, and fluoropolymer membrane grafted with styrene, acrylate, or acrylamide.

13. The method of claim 10, wherein said membrane is a PTFE polyacrylate terpolymer membrane or a polyvinylidene fluoride membrane.

14. The method of claim 10, wherein said middle plates are formed of polytetrafluoroethylene (PTFE) sheets.

15. The method of claim 10, wherein said middle plates have a thickness of between about 0.005" and 0.1".

16. The method of claim 10, wherein the middle plates and sheets of membrane form a stack, said method further includes providing a pair of end plates flanking said stack, and said compressing includes compressing the end plates together.

17. The method of claim 16, wherein the end plates include an array of fluid guides corresponding to said array of reaction zones, to allow for selective routing of reagents through the reaction zones.

18. The method of claim 10, wherein said compressing is accomplished using a pneumatic or hydraulic press.

19. The method of claim 10, wherein said compressing is accomplished using a clamp or set of bolts.

20. A method of synthesizing a library of compounds, comprising

providing at least three middle plates, each middle plate comprising a plurality of holes arranged in a two dimensional array having x and y axes when the plates are aligned;

interposing, between adjacent ones of said plates, a separate sheet of membrane capable of serving as a solid support for chemical synthesis, wherein each sheet of membrane is a continuous sheet positioned across multiple holes of said plates;

compressing said plates together to form a three dimensional array of discrete reaction zones having x, y, and z axes and defining Z (x,y) reaction planes, wherein Z equals at least two, where each reaction zone contains a portion of said sheet of membrane, and where said compressing creates a fluid-tight seal between adjacent reaction zones;

delivering a second building block to the reaction zones such that zones having a common x and z coordinate value receive the same second building block; and

delivering a third building block to the reaction zones such that zones having a common y and z coordinate value are contacted with the same third building block; and

wherein a library of compounds is formed by the reaction of the second and third building blocks in the different reaction zones.

21. The method of claim 20, wherein each sheet of membrane is pre-derivatized with a different first building block, and said library of compounds is formed by the reaction of the first, second and third building blocks in the different reaction zones.

22. The method of claim 20, wherein said membranes are selected from the group consisting of polypropylene membrane, polyethylene membrane, polytetrafluoroethylene (PTFE) polyacrylate terpolymer membrane, PTFE polyacrylamide terpolymer membrane, and fluoropolymer membrane grafted with styrene, acrylate, or acrylamide.

23. The method of claim 20, wherein said membranes are a PTFE polyacrylate terpolymer membrane or a polvinylidene fluoride membrane.

24. The method of claim 20, wherein said middle plates are formed of polytetrafluoroethylene (PTFE) sheets.

25. The method of claim 20, wherein said middle plates have a thickness of between about 0.005" and 0.1".

26. The method of claim 20, wherein the middle plates and sheets of membrane form a stack, said method further includes providing a pair of end plates flanking said stack, and said compressing includes compressing the end plates together.

27. The method of claim 26, wherein the end plates include an array of fluid guides corresponding to said array of reaction zones, to allow for selective routing of reagents through the reaction zones.

28. A method of synthesizing a library of compounds, comprising

providing at least three middle plates, each middle plate comprising a plurality of holes arranged in a two dimensional array having x and y axes when the plates are aligned;

interposing, between adjacent ones of said plates, a separate sheet of membrane capable of serving as a solid support for chemical synthesis, wherein each sheet of membrane is pre-derivatized with a different first building block and wherein each sheet of membrane is a continuous sheet positioned across multiple holes of said plates;

compressing said plates together to form a three dimensional array of discrete reaction zones having x, y, and z axes and defining Z (x,y) reaction planes;

wherein Z equals at least two, where each reaction zone contains a portion of said sheet of membrane, and where said compressing creates a fluid-tight seal between adjacent reaction zones;

delivering a second building block to the reaction zones such that zones having a common x and z coordinate value receive the same second building block; and

delivering a third building block to the reaction zones such that zones having a common y and z coordinate value are contacted with the same third building block; and

wherein a library of compounds is formed by the reaction of the first, second and third building blocks in the different reaction zones.