Methods and apparatus for synthesizing labeled combinatorial chemistry libraries

• US 6,087,186 A
• Filed: 02/02/1995
• Issued: 07/11/2000
• Est. Priority Date: 07/16/1993
• Status: Expired

• Current Assignee: NEXUS Biosystems, Inc. (Azenta, Inc.)
• Original Assignee: Irori
• Inventors: Cargill, John, Armstrong, Robert W.
• Primary Examiner(s): ZITOMER, STEPHANIE W
• Application Number:
  US08/383,766
• Time in Patent Office: 1,986 Days
• Field of Search: 436/518, 436/523, 436/524, 436/525, 436/526, 436/527, 436/528, 530/334, 530/335
• US Class Current: 506/15
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 2219/00281 Individual reactor vessels
• CPC Class Codes: B01J 2219/00308 interchangeably mounted in racks or blocks
• CPC Class Codes: B01J 2219/00351 Means for dispensing and evacuation of reagents
• CPC Class Codes: B01J 2219/00463 Directed sorting
• CPC Class Codes: B01J 2219/00497 Features relating to the solid phase supports
• CPC Class Codes: B01J 2219/005 Beads
• CPC Class Codes: B01J 2219/00502 Particles of irregular geometry
• CPC Class Codes: B01J 2219/00504 Pins
• CPC Class Codes: B01J 2219/0054 Means for coding or tagging the apparatus or the reagents
• CPC Class Codes: B01J 2219/00545 Colours
• CPC Class Codes: B01J 2219/00547 Bar codes
• CPC Class Codes: B01J 2219/00549 2-dimensional
• CPC Class Codes: B01J 2219/00554 Physical means
• CPC Class Codes: B01J 2219/00563 Magnetic means
• CPC Class Codes: B01J 2219/00565 Electromagnetic means
• CPC Class Codes: B01J 2219/00567 Transponder chips
• CPC Class Codes: B01J 2219/00572 Chemical means
• CPC Class Codes: B01J 2219/00585 : Parallel processes
• CPC Class Codes: B01J 2219/0059 : Sequential processes
• CPC Class Codes: B01J 2219/00592 : Split-and-pool, mix-and-divide processes
• CPC Class Codes: B01J 2219/00596 : Solid-phase processes
• CPC Class Codes: B01J 2219/00659 : Two-dimensional arrays
• CPC Class Codes: B01J 2219/00686 : Automatic
• CPC Class Codes: B01J 2219/00689 : using computers
• CPC Class Codes: B01J 2219/0072 : Organic compounds
• CPC Class Codes: B01J 2219/00722 : Nucleotides
• CPC Class Codes: B01J 2219/00725 : Peptides
• CPC Class Codes: B01J 2219/00731 : Saccharides
• CPC Class Codes: C07B 43/06 : of amide groups
• CPC Class Codes: C07K 1/047 : Simultaneous synthesis of different peptide species; Peptide libraries
• CPC Class Codes: C40B 40/06 : Libraries containing nucleotides or polynucleotides, or derivatives thereof
• CPC Class Codes: C40B 40/10 : Libraries containing peptides or polypeptides, or derivatives thereof
• CPC Class Codes: C40B 40/12 : Libraries containing saccharides or polysaccharides, or derivatives thereof
• CPC Class Codes: C40B 60/14 : for creating libraries
• CPC Class Codes: C40B 70/00 : Tags or labels specially adapted for combinatorial chemistry or libraries, e.g. fluorescent tags or bar codes
• CPC Class Codes: G01N 33/532 : Production of labelled immunochemicals
• CPC Class Codes: G01N 33/54373 : involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
• CPC Class Codes: G01N 33/552 : Glass or silica
• CPC Class Codes: G01N 33/553 : Metal or metal coated

Abstract

The present invention provides labeled synthetic libraries of random oligomers and methods and apparatus for generating labeled synthetic oligomer libraries. Each member of such a library is labeled with a unique identifier tag that specifies the structure or sequence of the oligomer. In a preferred embodiment of the present invention the identifier tag is a microchip that is pre-encoded or encodable with information that is related back to a detector when the identifier tag is pulsed with electromagnetic radiation.

Claims

1. A labeled synthetic oligomer library comprising a plurality of different members each member comprising an oligomer linked to an identifier which is a microchip encoded with information identifying the structure of said oligomer.

2. The library of claim 1 wherein said identifier tag is retained within a frame or housing and said oligomer is attached to a synthesis support, which synthesis support is also retained within said frame or housing.

3. The library of claim 1 that has from about 100 to about 250,000 members.

4. The library of claim 1, wherein said oligomers are structurally related analogues having a common core structure.

5. The library of claim 1 wherein said oligomers are selected from the group consisting of:

benzodiazepine, β

-lactam, hydantoin, quinone, hydroquinone, terpene, carbohydrate, polypeptide and polynucleotide.

6. The library of claim 1 wherein said identifier tag relates information back to a detector when pulsed with electromagnetic radiation.

7. The library of claim 6 wherein said identifier tag is selected from the group consisting of:

encodable microchip and pre-encoded microchip.

8. The library of claim 7 wherein said encodable microchip is a TIRIS™

and said pre-encoded microchip is an ELAM™

.

9. The library of claim 1 wherein:

i. the library has from about 100 to about 250,000 members;

ii. said oligomers are structurally related analogues having a common core structure; and

iii. the identifier tag is selected from the group consisting of;

pre-encoded microchip and encodable microchip.

10. A labeled synthetic oligomer library produced by synthesizing on each of a plurality of pre-encoded substrates, each of which has a unique identifier tag, which is a microchip encoded with information, a single oligomer structure obtained by a method comprising the steps of:

a) apportioning said pre-encoded substrates among a plurality of reaction vessels;

b) exposing said pre-encoded substrates in each reaction vessel to one or a plurality of transformation events;

c) detecting and recording identifier information for each of said identifier tags in each of said reaction vessels;

d) apportioning said pre-encoded substrates among a plurality of reaction vessels; and

e) repeating steps a) through c) from at least one to about twenty times.

11. The library of claim 10, wherein said oligomer is attached to a synthesis support and said pre-encoded substrate comprises a frame or housing retaining said identifier tag which is a microchip encoded with information and said oligomer.

12. The library of claim 10, wherein at least one transformation event is a stepwise or concerted enzymatic or chemical addition of one or a plurality of monomers.

13. The library of claim 10, wherein said oligomers are structurally related analogues having a common core structure.

14. The library of claim 10, wherein said oligomers are selected from the group consisting of:

benzodiazepine, β

-lactam, hydantoin, quinone, hydroquinone, terpene, carbohydrate, polypeptide and polynucleotide.

15. The library of claim 10, wherein said oligomer is cleaved from said pre-encoded substrate after completion of oligomer synthesis.

16. A labeled synthetic oligomer library produced by synthesizing on each of a plurality of encodable substrates each of which contains a microchip encoded with information, a single oligomer structure obtained by a method comprising the steps of:

a) apportioning said encodable substrates among a plurality of reaction vessels;

b) exposing said encodable substrates in each reaction vessel to one or a plurality of transformation events;

c) adding identifier information to said encodable substrates;

d) apportioning said encodable substrates among a plurality of reaction vessels; and

d) repeating steps a) through c) from at least one to about twenty times.

17. The library of claim 16, wherein said oligomer is attached to a synthesis support and said pre-encoded substrate comprises a frame or housing retaining said identifier tag and said oligomer.

18. The library of claim 16, wherein at least one transformation event is a stepwise or concerted enzymatic or chemical addition of one or a plurality of monomers.

19. The library of claim 16, wherein said oligomers are structurally related analogues having a common core structure.

20. The library of claim 16, wherein said oligomers are selected from the group consisting of:

benzodiazepine, β

-lactam, hydantoin, quinone, hydroquinone, terpene, carbohydrate, polypeptide and polynucleotide.

21. The library of claim 16, wherein said oligomer is cleaved from said pre-encoded substrate after completion of oligomer synthesis.

22. The library of claim 16, wherein said encodable substrate is blank prior to synthesis of a labeled oligomer library, and wherein each transformation event in a series of transformation events in the synthesis of a labeled oligomer library is recorded by adding identifier information to said encodable substrate in conjunction with each transformation event.

23. The library of claim 16, wherein said encodable substrate is encoded with a partial identifier information prior to synthesis, and wherein each transformation event in a series of transformation events in the synthesis of a labeled oligomer library is recorded by adding identifier information to said encodable substrate in conjunction with each transformation event.

24. A method of preparing a labelled synthetic oligomer library comprising a plurality of different members, each member comprising a pre-encoded substrate linked to a single oligomer structure and bearing a unique identifier tag which is a microchip encoded with information identifying said oligomer structure, said method comprising the steps of:

a) apportioning said pre-encoded substrates among a plurality of reaction vessels;

b) exposing said pre-encoded substrates in each reaction vessel to one or a plurality of transformation events;

c) detecting and recording identifier information for each of said identifier tags in each of said reaction vessels;

d) apportioning said pre-encoded substrates among a plurality of reaction vessels; and

e) repeating steps a) through c) from at least one to about twenty times.

26. The method of claim 24 wherein said encodable substrate is blank prior to synthesis of a labeled oligomer library, and wherein each transformation event in a series of transformation events in the synthesis of a labeled oligomer library is recorded by adding identifier information to said encodable substrate in conjunction with each transformation event.

29. The method of claim 24, wherein said pre-encoded substrate is a pre-encoded microchip.

25. A method of preparing a labeled synthetic oligomer library comprising a plurality of different members, each member comprising an encodable substrate linked to a single oligomer structure and having a unique identifier tag which is a microchip encoded with information identifying said oligomer structure, said method comprising the steps of:

a) apportioning said encodable substrates among a plurality of reaction vessels;

b) exposing said encodable substrates in each reaction vessels to one or a plurality of transformation events;

c) adding first identifier information to said encodable substrates;

d) apportioning said encodable substrates among a plurality of reaction vessels; and

e) repeating steps a) through c) from at least one to about twenty times.

27. The method of claim 25, wherein said encodable substrate is encoded with a partial identifier information prior to synthesis, and wherein each transformation event in a series of transformation events in the synthesis of a labeled oligomer library is recorded by adding identifier information to said encodable substrate in conjunction with each transformation event.

28. The method of claim 25, wherein said encodable substrate is an encodable microchip.

30. A labeled synthetic oligomer library produced by synthesizing on each of a plurality of pre-encoded substrates, each of which has a unique identifier tag which is a microchip encoded with information, a single oligomer structure obtained by a method comprising the steps of:

a) apportioning said pre-encoded substrates among a plurality of reaction vessels;

b) exposing said pre-encoded substrates in each reaction vessel to one or a plurality of monomers;

c) detecting and recording identifier information for each of said identifier tags in each of said reaction vessels;

d) apportioning said pre-encoded substrates among a plurality of reaction vessels; and

d) repeating steps a) through c) from at least one to about twenty times.

31. The library of claim 30, wherein said oligomer is attached to a synthesis support and said pre-encoded substrate comprises a frame or housing retaining said identifier tag and said oligomer.

32. The library of claim 30, wherein said oligomers are formed by the concerted addition of one or a plurality of monomers.

33. The library of claim 30, wherein said oligomers are structurally related analogues having a common core structure.

34. The library of claim 30, wherein said oligomers are selected from the group consisting of:

benzodiazepine, β

-lactam, hydantoin, quinone, hydroquinone, terpene, carbohydrate, polypeptide and polynucleotide.

35. The library of claim 30, wherein said oligomer is cleaved from said pre-encoded substrate after completion of oligomer synthesis.

36. A labeled synthetic oligomer library produced by synthesizing on each of a plurality of encodable substrates each of which has a unique identifier tag which is a microchip encodable with information, a single oligomer structure obtained by a method comprising the steps of:

a) apportioning said encodable substrates among a plurality of reaction vessels;

b) exposing said encodable substrates in each reaction vessel to one or a plurality of monomers;

c) adding identifier information to said encodable substrates;

d) apportioning said encodable substrates among a plurality of reaction vessels; and

d) repeating steps a) through c) from at least one to about twenty times.

37. The library of claim 36, wherein said oligomer is attached to a synthesis support and said pre-encoded substrate comprises a frame or housing retaining said identifier tag and said oligomer.

38. The library of claim 36, wherein said oligomers are formed by the concerted addition of one or a plurality of monomers.

39. The library of claim 36, wherein said oligomers are structurally related analogues having a common core structure.

40. The library of claim 36, wherein said oligomers are selected from the group consisting of:

benzodiazepine, β

-lactam, hydantoin, quinone, hydroquinone, terpene, carbohydrate, polypeptide and polynucleotide.

41. The library of claim 36, wherein said oligomer is cleaved from said pre-encoded substrate after completion of oligomer synthesis.

42. The library of claim 36, wherein said encodable substrate is blank prior to synthesis of a labeled oligomer library, and wherein each step in a series of oligomer monomer additions in the synthesis of a labeled oligomer library is recorded by adding identifier information to said encodable substrate in conjunction with the addition of monomers.

43. The library of claim 36, wherein said encodable substrate is encoded with a partial identifier information prior to synthesis, and wherein each step in a series of oligomer monomer additions in the synthesis of a labeled oligomer library is recorded by adding identifier information to said encodable substrate in conjunction with the addition monomers.

44. A method of preparing a labelled synthetic oligomer library comprising a plurality of different members, each member comprising a pre-encoded substrate linked to a single oligomer structure and bearing a unique identifier tag identifying said oligomer structure, said method comprising the steps of:

a) apportioning said pre-encoded substrates among a plurality of reaction vessels;

b) exposing said pre-encoded substrates in each reaction vessel to one or a plurality of monomers;

c) detecting and recording identifier information for each of said identifier tags in each of said reaction vessels;

d) apportioning said pre-encoded substrates among a plurality of reaction vessels; and

e) repeating steps a) through c) from at least one to about twenty times.

48. The method of claim 44, wherein said pre-encoded substrate is a pre-encoded microchip.

45. A method of preparing a labeled synthetic oligomer library comprising a plurality of different members, each member comprising an encodable substrate linked to a single oligomer structure and having a unique identifier tag which is a microchip encoded with information identifying said oligomer structure, said method comprising the steps of:

a) apportioning said encodable substrates among a plurality of reaction vessels;

b) exposing said encodable substrates in each reaction vessels to one or a plurality of monomers;

c) adding first identifier information to said encodable substrates;

d) apportioning said encodable substrates among a plurality of reaction vessels; and

e) repeating steps a) through c) from at least one to about twenty times.

46. The method of claim 45 wherein said encodable substrate is blank prior to synthesis of a labeled oligomer library, and wherein each step in a sequence of oligomer monomer additions in the synthesis of a labeled oligomer library is recorded by adding identifier information to said encodable substrate in conjunction with the addition of each monomer.

47. The method of claim 45, wherein said encodable substrate is encoded with a partial identifier information prior to synthesis, and wherein each step in a sequence of oligomer monomer additions in the synthesis of a labeled oligomer library is recorded by adding identifier information to said encodable substrate in conjunction with the addition of each monomer.

49. The method of claim 45, wherein said encodable substrate is an encodable microchip.