Method and apparatus for synthesizing characterizing and assaying combinatorial libraries

• US 6,500,609 B1
• Filed: 02/11/1999
• Issued: 12/31/2002
• Est. Priority Date: 02/11/1999
• Status: Expired due to Fees

• Current Assignee: Scynexis Incorporated
• Original Assignee: SCYNEXIS Chemistry & Automation, Inc.
• Inventors: McComb, Susan Marie, Smith, Henry David III, Abedi, Jaleh Azmi, Monnet, Pierre, Ribeill, Yves
• Primary Examiner(s): CELSA, BENNETT M
• Application Number:
  US09/248,541
• Time in Patent Office: 1,419 Days
• Field of Search: 435/4, 435/6, 435/DIG.2, 435/DIG.44, 435/DIG.45, 436/43, 436/161, 422/68.1, 364/516, 210/656
• US Class Current: 506/3
• 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 2219/00283 Reactor vessels with top opening
• CPC Class Codes: B01J 2219/00308 interchangeably mounted in racks or blocks
• CPC Class Codes: B01J 2219/00452 Means for the recovery of reactants or products
• CPC Class Codes: B01J 2219/0054 Means for coding or tagging the apparatus or the reagents
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/00599 Solution-phase processes
• CPC Class Codes: B01J 2219/00689 using computers
• CPC Class Codes: B01J 2219/00691 using robots
• CPC Class Codes: B01J 2219/00693 Means for quality control
• CPC Class Codes: B01J 2219/00698 Measurement and control of process parameters
• CPC Class Codes: B01J 2219/00704 integrated with the reactor apparatus
• CPC Class Codes: B01J 2219/00707 separated from the reactor apparatus
• 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 2219/00745 Inorganic compounds
• CPC Class Codes: B01J 2219/00754 Metal oxides
• CPC Class Codes: C40B 40/10 Libraries containing peptides or polypeptides, or derivatives thereof
• CPC Class Codes: C40B 40/14 Libraries containing macromolecular compounds and not covered by groups C40B40/06 - C40B40/12
• CPC Class Codes: C40B 40/18 : Libraries containing only inorganic compounds or inorganic materials
• CPC Class Codes: C40B 50/08 : Liquid phase synthesis, i.e. wherein all library building blocks are in liquid phase or in solution during library creation; Particular methods of cleavage from the liquid support
• 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 2035/00217 : involving measurement of weight
• CPC Class Codes: G01N 35/028 : having reaction cells in the form of microtitration plates
• CPC Class Codes: Y10T 436/11 : Automated chemical analysis

Abstract

Devices and processes for synthesizing, purifying and analyzing large numbers of compounds for use in combinatorial libraries, are disclosed. The processes involve generating a series of compounds in multi-well plates or multi-tube racks, purifying the reaction mixtures, analyzing the purified compounds, and optionally performing bioassays on the compounds. The information regarding the compounds is stored in a central database. The devices include one or more multi-tube arrays, a purification device, means for transferring the contents of the tubes, a solvent evaporator, analytical instrumentation, and, optionally, a weighing instrument. The multi-tube array(s) optionally include a cover, which can be placed on or removed from the array by computer control. By correlating the orientation of tubes from one stage to the next, it is possible to use a single bar code or other identifying mark for each multi-tube array rather than for each individual tube. This simplifies data collection for large numbers of compounds.

Claims

1. A process for synthesizing, purifying, and analyzing a plurality of compounds while tracking the compounds by position alone using a relational database comprising:

a) synthesizing a series of reaction mixtures in a first multi-well plate or multi-tube array;

b) storing information regarding each synthesis in the relational database according to the position of each reaction mixture in the first plate or array;

c) transferring the reaction mixtures in the first wells or tubes to a liquid chromatography purification device selected from the group consisting of preparative scale HPLC and column chromatography;

d) submitting the reaction mixtures to a purification process which produces one or more eluent fractions comprising individual compounds;

e) transferring the eluent fraction(s) comprising individual compounds to one or more wells or tubes in a second multi-well plate or multi-tube array;

f) correlating the compounds to the reaction mixtures using the position of the wells or tubes in the multi-well plates or multi-tube arrays using the relational database;

g) analyzing the individual compounds in the wells or tubes of the second multi-well plate or multi-tube array;

h) storing information regarding the analysis of the compounds in the relational database according to the position of each compound in the second multi-well plate or multi-tube array; and

i) correlating the information regarding the analysis of each compound to the reaction mixtures using the position of the wells or tubes in the multi-well plates or multi-tube arrays using the relational database;

wherein the wells or tubes are not individually labeled and

the information regarding the compounds including the analysis of the compounds and the synthesis of the compounds is tracked and correlated by only the position of each tube or well in the various multi-well plates or multi-tube arrays.

2. The process of claim 1, wherein solvent is removed from the tubes following purification and transfer of the eluent fraction or fractions of the tubes in the second multi-tube array.

3. The process of claim 2, wherein the tubes in the second multi-tube array are weighed prior to receiving the eluent fraction and after the solvent has been removed.

4. The process of claim 3, wherein the weight of each purified compound is obtained by subtracting the weight of the empty tube from that of the solvent-evaporated tube in the second multi-tube array, and that information is stored in the database.

5. The process of claim 1, wherein the first and second multi-tube arrays are arranged in abcissa and ordinate configurations.

6. The process of claim 1, wherein the synthesized, purified and analyzed compounds are further subjected to one or more bioassays.

7. The process of claim 6, wherein results of the bioassay of the compounds are correlated with the stored information regarding the compounds using the position of the tubes in the multi-tube array using the relational database.

8. A method of automated chemical synthesis of a chemical library which comprises:

a) disposing an array of tubes, each of which contains at least one core compound, on a rigid support, wherein each tube is in a fixed location in the array;

b) storing information regarding the core compound in a relational database according to the location of each core compound on the rigid support;

c) performing a chemical reaction on the core compounds to form an array of reaction mixtures containing an array of reaction products;

d) storing information regarding the chemical reaction and the reaction mixtures in the relational database according to the location of each reaction mixture on the rigid support;

e) purifying the reaction mixtures using preparative scale HPLC or column chromatography and isolating the reaction products,

f) storing information regarding the reaction product in the relational database according to the location of each reaction product on the rigid support;

g) characterizing the reaction products with one or more analytical instruments;

h) storing information regarding the characterization of each reaction product in the relational database according to the location of each reaction product on the rigid support; and

i) optionally repeating one or more of steps a-d,

wherein the tubes are not individually labeled;

at least one or more of the steps is effected globally on the array and at least one of the steps is effected on each tube individually; and

the information stored in the relational database is tracked and correlated by only the location of each tube on the rigid support.

9. The method of claim 8 wherein the amount of isolated reaction product in each tube is calculated by obtaining a tare weight of the tubes, obtaining the weight of the previously tared tubes after the reaction products are isolated in the tubes and all solvent is removed, and subtracting the tare weight of the tubes from the weight of the tubes containing the reaction products.

10. A process for synthesizing, purifying, and analyzing a plurality of compounds while tracking the compounds by position alone using a relational database comprising:

a) synthesizing a series of reaction mixtures in a first multi-well plate or multi-tube array comprising individual wells or tubes;

b) purifying the reaction mixtures producing one or more eluent fractions comprising individual compounds; and

c) analyzing the individual compounds;

wherein the wells or tubes are not individually labeled and

information regarding the compounds including the analysis and the synthesis is tracked and correlated by only the position of each tube or well in the multi-well plates or multi-tube arrays using the relational database.