Logically ordered arrays of compounds and methods of making and using the same

• US 6,878,557 B1
• Filed: 01/20/1998
• Issued: 04/12/2005
• Est. Priority Date: 01/20/1995
• Status: Expired due to Fees

• Current Assignee: ArQule, Inc. (Merck & Co., Inc.)
• Original Assignee: ArQule, Inc. (Merck & Co., Inc.)
• Inventors: Tu, Cheng, Furth, Paul, Casebier, David, Hogan, Joseph C., Bolten, David A., Zambias, Robert
• Primary Examiner(s): Ponnaluri, Padmashri
• Application Number:
  US09/009,846
• Time in Patent Office: 2,639 Days
• Field of Search: 436/518, 530/338, 536/25.3, 435/DIG.1, 435/DIG.48, 435/6
• US Class Current: 506/25
• CPC Class Codes: C40B 30/04 by measuring the ability to specifically bind a target molecule, e.g. antibody-antigen binding, receptor-ligand binding
• 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: Y10S 977/774 Exhibiting three-dimensional carrier confinement, e.g. quantum dots
• CPC Class Codes: Y10S 977/779 Possessing nanosized particles, powders, flakes, or clusters other than simple atomic impurity doping
• CPC Class Codes: Y10S 977/789 in array format
• CPC Class Codes: Y10S 977/791 Molecular array

Abstract

A method for constructing an array of synthetic molecular constructs, by forming a plurality of molecular constructs having a scaffold backbone of a chemical molecule comprising a linear, branched or cyclic organic compound having at least atoms of carbon, nitrogen, sulfur, phosphorus, or combinations thereof, and at least one location on the molecule capable of undergoing reaction with other molecules for attachment of at least one structural diversity element; laying out an array possessing a logical ordering of sub-arrays of the molecular constructs; providing each sub-array with molecular constructs having the scaffold backbone and at least one structural diversity element which is different from the others; and relating each sub-array within the array to all other sub arrays by the difference in the structural diversity elements.

Claims

1. A method of making a logically-ordered, spatially-addressable array of compounds having a same common linear, branched or cyclic molecular core structure comprising at least three atoms of carbon, nitrogen, oxygen, phosphorus or sulfur and at least two structural diversity elements, wherein the molecular cores have attachment points for the structural diversity elements, an ability to present the structural diversity elements in controlled varying arrangements, and an ability to be constructed in a rapid concerted fashion, said array comprising at least a first sub-array and a second sub-array, wherein the compounds composing the first sub-array each have at least one common structural diversity element and the compounds composing the second sub-array each have at least one common structural diversity element, said method comprising the steps of:

(a) providing a plurality of reaction vessels organized into the first and second sub-arrays;

(b) adding reactants to each of the reaction vessels in a manner such that when reacted, the reactants form the compounds of the array, and such that the compounds composing each sub-array differ from one another by one change in a structural diversity element; and

(c) reacting the contents of each reaction vessel under appropriate conditions to form the compounds of the sub-arrays in the logically-ordered array.

4. The method of claim 1, 2 or 3, wherein each base module compound in the array is unique.

5. The method of claim 1, wherein the combinatorial array comprises at least 1000 compounds.

2. A method of making a spatially-addressable combinatorial array of at least 500 compounds in solution in multiple cycles, said method comprising the steps of:

(a) apportioning into a plurality of reaction vessels that are identifiable by their spatial addresses (i) a first plurality of reactants, each reactant comprising a same first reactive group and a different first structural diversity element such that the reactants composing the first plurality differ from one another, with one first reactant per reaction vessel; and

(ii) a second reactant comprising a second reactive group and a second structural diversity element, with one second reactant per reaction vessel; and

(b) concurrently reacting said first and second reactants in each of the plurality of reaction vessels under solution phase conditions wherein the first and second reactive groups react with one another by an addition reaction to form a compound; and

(c) repeating steps (a) and (b), thus forming the combinatorial array of at least 500 different compounds in solution;

wherein each reaction vessel contains substantially only one compound,

wherein each compound composing the combinatorial array comprises a same common linear, branched, or cyclic molecular core comprising at least three atoms of carbon, nitrogen, oxygen, phosphorus or sulfur having the first and second structural diversity elements attached thereto, and further wherein the compounds composing the array differ from one another by at least one change in a structural diversity element.

3. The method of claim 2 further including the step of formatting the contents of the reaction vessels into a spatially-addressable array.

6. The method of claim 2, wherein the combinatorial array comprises at least 1000 compounds.

7. A method for making a spatially-addressable combinatorial array of compounds in solution, the compounds having a common molecular core structure and at least two structural diversity elements, wherein the array comprises at least 500 different compounds, the method comprising:

(a) selecting reagents suitable for preparing the compounds of the array;

(b) providing at least 500 spatially-addressable reaction vessels;

(c) apportioning the reagents into the reaction vessels; and

(d) concurrently reacting the reagents in the reaction vessels in one of more cycles under solution phase conditions such that all the compounds of the array are formed in solution;

wherein each reaction vessel contains substantially only one compound,

wherein each compound composing the combinatorial array comprises a same common linear, branched, or cyclic molecular core comprising at least three atoms of carbon, nitrogen, oxygen, phosphorus or sulfur, said core having at least two structural diversity elements attached thereto, and further wherein the compounds composing the array differ from one another by one at least one change in a structural diversity element.

8. The method of claim 7, further including, after step b) or step c), the step of formatting the contents of the reaction vessels into a spatially-addressable array.

9. The method of claim 7 wherein for each cycle the reagents in at least 80 different reaction vessels are concurrently reacted.

10. A method of making a spatially-addressable array of at least 500 different compounds, each of which is in solution, said compounds having a same common linear, branched, or cyclic molecular core comprising at least three atoms of carbon, nitrogen, oxygen, phosphorus or sulfur and at least two structural diversity elements attached thereto, said array comprising at least a first sub-array and a second sub-array, wherein the compounds composing the first sub-array each have at least one common structural diversity element, and the compounds composing the second sub-array each have at least one common structural diversity element, said method comprising the steps of:

(a) providing at least 500 wells organized into at least first and second sub-arrays;

(b) adding reactants to each of the wells in a manner such that, when reacted, the reactants form the compounds of the sub-arrays in the array, and such that the compounds composing each sub-array differ from one another by one change in a structural diversity element; and

(c) concurrently reacting the contents of the wells under appropriate solution-phase conditions in one or more cycles to form all compounds of the sub-arrays in the array.