Methods for hard-tagging an encoded synthetic library

Details Methods for hard-tagging an encoded synthetic library Methods for hard-tagging an encoded synthetic library

1999-11-17

2002-04-09

Ponnaluri, Padmashri (Department: 1618)

Chemistry: analytical and immunological testing

Involving an insoluble carrier for immobilizing immunochemicals

C436S501000, C436S528000, C436S085000, C435S007100, C435S091500, C435S091500, C435S091500, C435S091500, C435S091500, C435S091500, C435S091500, C435S091500, C435S091500, C536S023100

Reexamination Certificate

active

06368874

ABSTRACT:

BACKGROUND OF THE INVENTION
Field of the Invention
This invention relates to the chemical encryption of the structure of compounds formed in situ on solid supports by the use of specific amine tags which, after compound synthesis, can be deencrypted to provide the structure of the compound found on the support.
The solid supports of this invention find particular utility in preparing encoded synthetic libraries of compounds on the support for facilitating screening of these compounds for biological activity.
REFERENCES
The following publications and patent applications are cited in this application as superscript numbers:
1 M. A. Gallop, R. W. Barrett, W. J. Dower, S. P. A. Fodor and E. M. Gordon,
J. Med. Chem
., 37:1233 (1994)
2 E. M. Gordon, R. W. Barrett, W. J. Dower, S. P. A. Fodor and M. A. Gallop,
J. Med. Chem
., 37:1385 (1994)
3 A. Furka, F. Sebestyen, M. Asgedom and G. Dibo,
Int. J. Peptide Protein Res
., 37:487 (1991)
4 W. J. Dower, R. W. Barrett and M. A. Gallop, International Patent Application Publication No. WO 93/06121 (1993)
5 S. Brenner and R. A. Lerner,
Proc. Natl. Acad. Sci., USA
, 89:5181 (1992)
6 J. M. Kerr, S. C. Banville and R. N. Zuckermann,
J. Am. Chem. Soc
., 115:2529 (1993).
7 V. Nikolaiev, A. Stierandova, V. Krchnak, B. Seligmann, K. S. Lam, S. E. Salmon and M. Lebl,
Pept. Res
., 6:161 (1993)
8 M. C. Needels, D. G. Jones, E. M. Tate, G. L. Heinkel, L. M. Kochersperger, W. J. Dower, R. W. Barrett and M. A. Gallop,
Proc. Natl. Acad. Sci., USA
, 90: 10700 (1993)
9 M. H. J. Ohlmeyer, R. N. Swanson, L. W. Dillard, J. C. Reader, G. Asouline, R. Kobayashi, M. Wigler and W. C. Still,
Proc. Natl. Acad. Sci. USA
, 90:10922 (1993)
10 C. P. Holmes, International Patent Application Serial No. PCT/US95/07988 for “Methods for the Solid Phase Synthesis of Thiazolidinones, Metathiazanones, and Derivatives Thereof”, filed Jun. 23, 1995
11 Lebl, et al.,
Peptide Science
, February 1995
12 Campbell, et al., International Patent Application Serial No. PCT/US95/07964, for “Methods for the Synthesis of Diketopiperazines”, filed Jun. 23, 1995
13 Gallop, et al., International Patent Application Serial No. PCT/US95/07878, for “Methods for Synthesizing Diverse Collections of Pyrrolidine Compounds”, filed Jun. 22, 1995
14 Gallop, et al., U.S. patent application Ser. No. 08/264,136 for: “Methods for Synthesizing Diverse Collections of &bgr;-Lactam Compounds”, filed Nov. 21, 1995
15 Farina, et al.,
J. Med. Chem
., 3:877 (1991)
16 Stills, et al., International Patent Application Serial No. PCT/US93/09345 for “Complex Combinatorial Chemical Libraries Encoded with Tags”, filed Oct. 1, 1993
All of the above publications and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
STATE OF THE ART
Synthetic chemical libraries produced by combinatorial synthesis have rapidly become important tools for pharmaceutical lead discovery and compound optimization.
1,2
Typically, combinatorial synthesis is conducted via a multi-step synthesis to provide a library of target compounds. Each step in this synthesis involves a chemical modification of the then existing molecule formed from the previous step wherein one can vary the choice of reagents and/or reaction conditions to provide for a variety of different target compounds. For example, such steps could include the use of different building blocks to form different compounds, the use of different inorganic or organic reagents which alter where the building blocks are added or the stereochemistry of the addition, etc.
Many of the combinatorial approaches devised to prepare such libraries rely on solid-phase synthetic techniques and exploit the efficient “split/pool” method to assemble all possible combinations of a set of chemical building blocks.
3
The “split/pool” method employs a pool of solid supports which contains or can be derivatized to contain reactive moieties for forming the molecules of interest tethered to the solid support. This pool is initially split and each split pool is then subjected to a first reaction which reaction results in different modifications to each of the pools. After reaction, the pools of solid supports are combined and the pooled supports are then again split. Each split pool is subjected to a second reaction which is different for each of the pools. The process is continued until a library of target compounds are formed on the solid supports.
The reactions employed at each stage of this synthesis can include the addition of different building blocks to the solid support, the use of different reagents and/or reaction conditions to differentially alter the existing chemical entity on the solid support, etc. Also combinations of different building blocks with different reagents and/or reaction conditions can also be employed.
The “split/pool” protocol is particularly well-suited to the generation of large libraries, and the synthetic target compounds may be screened for interaction with macromolecular receptors either in binding assays where the compounds remain tethered to their synthetic supports, or in soluble assays after cleavage of the compounds from the resin. Elucidation of the chemical structure of biologically active library members has represented a major challenge because the quantity of material available for chemical analysis from a complex library is frequently minuscule.
A general solution to this structure eludication problem has been proposed that exploits a set of surrogate analytes, or identifier tags, which can be detected with either greater ease and/or sensitivity than the chemical entities which they represent.
4
Through their concurrent appendage to the synthesis supports, these tags provide an unambiguous record of chemical reaction history and/or chronology of monomer (building block). additions to each support in the library. This method, which has become known as encoded combinatorial synthesis
5
, has broad scope and utility, and conceptually may be applied to the construction of any collection of compounds that can be produced through a multi-step scheme of synthesis on solid supports.
Two conceptually different approaches to encoding a combinatorial synthesis have been described. In the first mode, the sequence of monomer addition steps is recorded by the parallel and alternating assembly of a polymeric molecule that is itself amenable to chemical sequence analysis. Here the structure of any combinatorial product is reflected by the sequence of a single cognate identifier tag on the solid support. Both peptides
6,7
and oligonucleotides
8
have been sucessfuly used in this manner to encode the synthesis of polyamide combinatorial libraries, the tags being analyzed by, for example, Edman or dideoxy Sanger sequencing respectively.
In the second encoding method, a set of readily identifiable unique markers employed for each reaction step is attached to the solid support to identify which reaction was visited in which step of the target compound synthesis on that particular support.
4,9
The set of identifiable markers is employed in binary code format with each set identifying a different monomer and/or reaction conditions. For example, each marker can be represented in binary code format by either a “0” for its absence or a “1” for its presence. Accordingly, if 3 different identifiable markers are employed in a first set, this set contains 7 unique binary code combinations (the binary code represented by 000 is not used). Specifically, the binary codes for these combinations employing markers A, B and C would read as follows:
SUBCOMBINATIONS FOR
BINARY CODE FOR THIS
MARKERS A, B AND C
SUBCOMBINATION
A
001
B
010
C
100
A, B
011
A, C
101
B, C
110
A, B, C
111
In this example, the use of 7 different building blocks for a given step in the “split/pool” synthesis could be encoded by the above set of 3 markers using the 7 different combination of these markers. Each different combinat

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