Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or...
Utility Patent
1996-01-23
2001-01-02
Venkat, Jyothsna (Department: 1627)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
C435S007100, C435S007200, C435S091500, C436S501000, C436S518000, C436S536000
Utility Patent
active
06168912
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The invention relates to the field of drug research. In particular, it relates to new methods for generating chemical libraries using combinatorial methods, for development and screening of new drugs.
BACKGROUND OF THE INVENTION
Conventional drug discovery involves mailing thousands of compounds and testing them for biological activities to find a “lead” compound. The success rate of finding a drug is <1/10,000 compounds tested. The time required is about seven to ten years. The cost is in the millions of dollars.
Recent developments in drug discovery via the combinatorial approach have had an impact on the pharmaceutical industry. (See Bibliography.) The cost of finding a drug may be lowered because the new approach is capable of supplying compounds readily and cheaply. Some compounds developed using this approach are oligomeric molecules (peptides, nucleotides, oligosaccharides) and others are non-oligomeric molecules (“small molecules”, i.e., less than ~m.w. 600). The size of a linear oligomeric library depends on the number of monomeric units and the length of the oligomers assembled. For instance, using a two substrate matrix (A and B) there are four possible compounds (AA, AB, BA, and BB) in the library of dimers. Non-linear libraries are made by simultaneously transforming a large group of chemical substrates under a given set of conditions to afford a group of compounds that are different from the starting materials. The latter type of library may not greatly expand the number of compounds, nevertheless, this operation leads to the formation of a new collection of compounds efficiently.
Combinatorial chemistry was born of the marriage between mass screening and medicinal chemistry. It was developed in response to the statistical evidence that drug discovery is a “numbers game”. Classical mass screening involves testing tens of thousands of compounds and natural extracts looking for a lead compound with a desired biological activity. Classical medicinal chemistry, based on the lead compound identified, modifies the lead compound, atom by atom, group by group making structural analogues, with the goal of improving activity that may advance the lead compound to a clinically useful drug. Combinatorial chemistry combines the two classical approaches. By allowing a given set of starting materials to react with each other under a given set of conditions, the combinatorial approach generates a large number of compounds that are defined by the combinatorial probability. If enough compounds are made, one of them will be a lead compound or may even be a clinically useful drug. Furthermore, this approach can make structural analogues simultaneously. A stringent screening process can select the best drug candidate among structural analogues. The combinatorial approach combines lengthy initial mass screenings and medicinal chemical optimizations into a single process. Thus this approach is favorable with respect to both efficiency and speed.
However, problems have arisen in using both linear oligomeric libraries and small molecule libraries for drug discovery. First, the number of compounds generated by the conventional combinatorial libraries is relatively small. For instance, with 20 common amino acids, a hexapeptide (linear oligomeric) library contains only 64 million compounds. For small molecule libraries, the number of compounds generated is even smaller. Second, the compounds present in conventional combinatorial libraries lack chemical diverstiy. For the linear oligomeric library, a major contributor to the lack of diversity is the monotonous chemical linkages; for small molecule libraries, the lack of diversity is caused by the limited chemical transformations possible with the chemical substrates used.
Thus there is a need in the art for additional methods of generating large numbers of diverse chemicals for testing for biological activities.
SUMMARY OF THE INVENTION
It is an object of the invention to provide a method of making “building blocks” and using them to build a combinatorial library.
It is an object of the invention to provide a method of making a chemical library.
It is another object of the invention to provide a kit for creating a combinatorial chemical library.
It is another object of the invention to provide combinatorial chemical libraries.
These and other objects of the invention are provided by one or more of the embodiments described below. In one embodiment of the invention a method is provided of making a chemical library. The method comprises the step of:
converting in parallel a set of at least two carboxylates having a structure R
1
R
2
CHCOR
3
to &agr;-allyl carboxylate monomers having a structure
R
1
R
2
C(CR
4
R
5
—CR
6
═CR
7
R
8
)—COR
3
,
wherein R
1-2
are independently H, alkyl, aryl, carbocyclic, heterocyclic, or chemical moieties containing heteroatoms O, N, S, X, or P;
COR
3
is an amide, an ester, or a carboxyl group; and
R
4-8
are independently H, aryl, or alkyl.
In another embodiment of the invention a method of making a chemical library is provided. The method comprises the step of:
converting in parallel a set of at least two &agr;-allyl carboxylate monomers to form monomer derivatives, said monomers having a structure
R
1
R
2
C(CR
4
R
5
—CR
6
═CR
7
R
8
)—COR
3
wherein R
1-2
are independently H, alkyl, aryl, carbocyclic, heterocyclic, or chemical moieties containing heteroatoms O, N, S, X, or P, wherein X is a halogen;
COR
3
is an amide, an ester, or a carboxyl group; and
R
4-8
are independently H, aryl, or alkyl; and
wherein said step of converting comprises converting any of R
4
-R
8
of said monomers to other chemical moieties.
In another embodiment of the invention a kit for creating a combinatorial chemical library is provided. The kit comprises:
a set of monomers consisting of at least two &agr;-allyl carboxylic acids, said acids having a structure
R
1
R
2
C(CR
4
R
5
—CR
6
═CR
7
R
8
)—COR
3
wherein R
1-2
are independently H, alkyl, aryl, carbocyclic, heterocyclic, or chemical moieties containing heteroatoms O, N, S, X, or P;
COR
3
is an amide, an ester, or a carboxyl group; and
R
4-8
are independently H, aryl, or alkyl;
and wherein said monomers are in separate compartments of said kit.
According to yet another embodiment of the invention another method is provided for making a combinatorial library. The method comprises the steps of:
converting in parallel a set of at least two &agr;-allyl carboxylate monomers to form monomer derivatives, the monomers having a structure
R
1
R
2
C(CR
4
R
5
—CR
6
═CR
7
R
8
)—COR
3
wherein R
1-2
are independently H, alkyl, aryl, carbocyclic, heterocyclic, or chemical moieties containing heteroatoms O, N, S, X, or P;
COR
3
is an amide, an ester, or a carboxyl group; and
R
4-8
are independently H, aryl, or alkyl;
wherein the step of converting comprises converting any of R
4
-R
8
of the monomers to other chemical moieties;
covalently linking at least two monomers to form oligomers, wherein the monomers are selected from the group consisting of: the &agr;-allyl carboxylate monomers and the monomer derivatives; and
testing the oligomers for a biological activity.
In still another embodiment of the invention combinatorial libraries are provided. Such libraries are made by the processes described here. Members of the libraries which demonstrate biological activities are identified and provided.
Thus the present invention provides the art with the tools and methods for creating diverse chemical libraries which themselves have great chemical diversity. This is a great boon to the art of drug screening and development.
REFERENCES:
patent: 5306718 (1994-04-01), Lauffer et al.
patent: 5393669 (1995-02-01), Brown
patent: 5565324 (1996-10-01), Still et al.
Meyers, et al., “Multiple Simultaneous Synthesis of Phenolic Libraries”,Molecular Diversity 1:13-20 (1995).
DeWitt et al., “‘Diversomers’: An Approach to Nonpeptide, Nonoligomeric Chemical Diversity”,Proc. Natl. Acad. Sci., USA 90:6909-6913 (1993).
Pavia et al., “The Generation of Molecul
Brobeck Phleger & Harrison LLP
Garcia Maurie E.
Martek Biosciences Corporation
Venkat Jyothsna
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