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

• US 6,168,914 B1
• Filed: 12/18/1998
• Issued: 01/02/2001
• Est. Priority Date: 12/19/1997
• Status: Expired due to Fees

• Current Assignee: Smithkline Beecham Corporation (Smithkline Beecham PLC)
• Original Assignee: Glaxo Wellcome Incorporated (GlaxoSmithKline PLC)
• Inventors: Campbell, David A., Ida, Satoru, Antonenko, Valery V., Gavin, Robert M., Selick, Harold E., Muir, Arthur H.
• Primary Examiner(s): Venkat, Jyothsan
• Assistant Examiner(s): Ricigliano, Joseph W.
• Application Number:
  US09/216,093
• Time in Patent Office: 746 Days
• Field of Search: 422/130, 422/131, 422/132, 422/134, 422/187, 422/188, 422/193, 422/196, 435/4, 435/6, 435/7.1, 435/DIG.44, 435/DIG.49, 436/174
• US Class Current: 506/30
• 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 a combinatorial library of compounds, the system comprising:

(X×

Y×

Z) reaction zones arranged in a free dimensional array having x, y and z axes and forming X (y,z), Y (x,z) and Z (x,y) reaction planes, such that there are a plurality of Z(x,y) reaction planes wherein

(i) the location of each zone in the array is defined by its (x,y,z) coordinates,

(ii) each of said zones comprises a solid support formed of a portion of a sheet of membrane disposed in a Z(x,y) reaction plane such that said portion of a sheet of membrane provides support for a plurality of (x,y) reaction zones,

(iii) each sheet of membrane provides supports for a plurality of (x,y) reaction zones which have a common z coordinate and which are isolated from one another by fluid-tight seals, and

(iv) reaction zones having common (x,y) coordinates are in fluid communication with one another;

a reagent source,

a transfer means connecting said reaction zones with said reagent source, and

a delivery means for delivering fluid from said reagent source to said reaction zones by way of said transfer means.

2. A system as in claim 1, wherein each solid support has a first building block, derivatized thereto.

3. A system as in claim 1, further comprising a plurality of manifolds, each of which is selectively alignable with one of the (x,z) or (y,z) planes of reaction zones, to allow building blocks from a single reagent source to pass through a selected one of said planes of reaction zones.

4. A system as in claim 1, further comprising a pair of end plates in a (x,y) plane flanking the three dimensional array of reaction zones along the z axis, wherein the end plates each include plumbing to circulate the chemicals through each (x,z) array or each (y,z) array of reaction vessels.

5. A system as in claim 4, wherein

the end plates are rotatable about a z axis relative to the reaction zones to align the plumbing with selected (x,z) or (y,z) planes of Z(x,y) reaction planes, and

the plumbing comprises channels in the end plates to circulate the same building block through reaction zones having a common x coordinate value when the end plates are in a first orientation, and to circulate the same building block through zones having a common y coordinate value when the end plates are in a second orientation.

6. A system as in claim 1, wherein said delivery means comprises a pump, said reagent source comprises a reagent vessel, and said transfer means comprising tubing and manifolds.

7. A system as in claim 1, wherein said transfer means forms a closed loop to re-circulate reagent through the reaction zones.

8. A system as in claim 1, wherein said reagent source comprises a number of reagent vessels that is equal to the number of X or Y reaction planes, whichever is greater.

15. The method of claim 1, wherein the contacting steps comprise flowing the building blocks through one or more (x,y) reaction zones, and the three dimensional array of reaction zones is flanked along the z axis by a pair of end plates, each in an (x,y) plane and each of which includes plumbing to flow the building blocks through the reaction zones.

16. The method of claim 15, wherein the plumbing comprises channels in the plates effective to

(i) circulate the same first building block through each zone having a common x coordinate value when the end plates are in a first orientation, and

(ii) circulate the same second building block through each zone having a common y coordinate value when the end plates are in a second orientation.

17. The method of claim 16, wherein each of said reaction zones formed on said portion of a sheet of membrane further comprises a hole in said sheet of membrane to facilitate circulation of building blocks.

9. A method for preparing a combinatorial library of compounds, comprising:

(1) providing (X×

Y×

Z) reaction zones arranged in a three dimensional array having x, y and z axes and forming X(y,z), Y(x,z) and Z(x,y) reaction planes, such that there are a plurality of Z(x,y) reaction planes, where

the location of each zone in the array is defined by its (x,y,z) coordinates in the array,

each of said zones comprises a solid support formed of a portion of a sheet of membrane disposed in a Z(x,y) reaction plane such that said portion of a sheet of membrane provides support for a plurality of (x,y) reaction zones,

each sheet of membrane provides support for a plurality of (x,y) reaction zones which are isolated from one another by fluid-tight seals, and

each solid support has a first building block derivatized thereto;

(2) contacting a second building block with the support in each of the zones such that supports in all zones having a common x coordinate value are contacted with the same second building block, under conditions effective to form an intermediate product; and

(3) contacting a third building block with the support in each of the zones such that supports in all zones having a common y coordinate value are contacted with the same third building block, under conditions effective to form a plurality of different compounds in different reaction zones;

wherein said different compounds in different reactions zones together form said combinatorial library of compounds.

10. The method of claim 9, wherein all zones having a common z coordinate value contain supports with the same first building block.

11. The method of claim 9, utilizing X different second building blocks and Y different third building blocks, where X is defined as the number of reaction planes having different x coordinate values and Y is defined as the number of reaction planes having different y coordinate values and wherein:

supports in all zones having a particular x coordinate value are contacted with a second building block that is different from the second building block contacted with supports in zones having a different x coordinate value; and

supports in all zones having a particular y coordinate value are contacted with a third building block that is different from the third building block contacted with supports in zones having a different y coordinate value.

12. The method of claim 11, wherein the X different second building blocks are stored in X different reagent vessels, respectively, and are introduced to the zones through X different manifolds operably connected to said X reagent vessels, respectively;

and

the Y different third building blocks are stored in Y different reagents vessels, respectively, and are introduced to the zones through Y different manifolds operably connected to said Y reagent vessels, respectively.

13. The method of claim 9, wherein the second and third building blocks are introduced to the zones through an array of manifolds, and wherein each manifold of said array is:

(i) aligned with zones having a common x coordinate value when in a first orientation; and

(ii) aligned with zones having a common y coordinate value when in a second orientation.

14. The method of claim 13, further comprising rotating the array of manifolds relative to the reaction zones to move the array of manifolds from the first orientation to the second orientation.

18. The method of claim 9, wherein the membrane is 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.

19. The method of claim 18, wherein said membrane is a polyacrylate terpolymer or polyvinlylidine difluoride membrane.

20. The method of claim 9, wherein the supports for zones having a common z coordinate value are all on a sheet of membrane.

21. The method of claim 9, wherein supports for zones having different z coordinate values are isolated from one another and from the end plates by middle plates, each of said middle plates having an array of holes corresponding to the (x,y) reaction zones.

22. The method of claim 21, where the fluid-tight seal is achieved by applying pressure to the end plates, thereby compressing the membrane between the middle plates,

wherein said reaction zones are defined by the portions of membrane aligned with the holes of the middle plate.

23. The method of claim 9, wherein the supports for zones having a common z coordinate value are on a plurality of sheets of membrane.