Biomedical subjects

Richard S Pottorf

Publications and source records attributed to Richard S Pottorf.

6 recordsLinked to original sources

PubMed2004

Process technologies for purity enhancement of large discovery libraries.

The design, synthesis and characterization of structurally diverse compound libraries are key first steps in drug discovery. High-throughput screening of these libraries against protein targets is a useful procedure for identifying hits, which can then be optimized to produce compound leads against these protein targets. For this process to be most successful the initial compounds screened must be of high quality, necessitating high-throughput characterization and purification. This review summarizes recent advances in purification processes for combinatorial chemistry.

Chromatography↗

PubMedDate not supplied

Solid-phase synthesis of a tyrphostin ether library.

The solid-phase synthesis of a 4500-member (30 x 15 x 10) tyrphostin library is demonstrated utilizing the Irori-directed sorting system. Fmoc-protected PL-Rink resin was used as the solid support. After Fmoc-deprotection, aryl aldehydes were attached to the resin through reductive amination. Acylation of the resulting secondary amines with cyanoacetic acid was followed by a Knoevenagel condensation with phenolic aldehydes. Mitsunobu coupling of primary alcohols to the resin-bound phenols yielded the final library of compounds 1.

Acetates↗

PubMedDate not supplied

Solid-phase synthesis of a library of hydroxyproline derivatives.

The synthesis of a library of N-alkylated O-arylated hydroxyproline derivatives has been achieved on solid phase. The choice of O-protection and the optimization of the Mitsunobu reaction involving a secondary alcohol were key to the success of this synthesis. First, acylation of resin-bound amines with N-Fmoc-O-THP-hydroxyproline was accomplished readily. Subsequent deprotection of the Fmoc and reductive amination with different aldehydes resulted in the tertiary amine intermediate. The deprotection of the THP group by p-toluenesulfonic acid was followed by a Mitsunobu reaction with a series of phenols. Finally, the products were cleaved from the resin using trifluoroacetic acid to produce a 10 200 member library.

Acylation↗

PubMedDate not supplied

Solid-phase synthesis of a 4-substituted gamma-lactam library.

Pyrrolidin-2-one (gamma-lactam) derivatives have shown a wide range of activities as ligands to diverse receptors, e.g., integrin, CCR5, and CCK. Therefore, we have prepared a large library of these derivatives for high-throughput screening against various protein targets, after developing a synthesis of pyrrolidin-2-ones on solid phase. Exploration of the ring formation was key to the success of this synthesis. First, acylation of resin-bound amines with N-Fmoc-protected amino acids and subsequent deprotection of the Fmoc group were accomplished readily. The resulting resin-bound primary amines were treated with beta-monomethyl itaconate under gentle heat in a mixture of methanol and toluene to yield the desired intermediates. Finally, saponification, amide formation, and cleavage from the resin led to the production of a library of 12,000 pyrrolidin-2-one derivatives. These products were isolated as diastereomeric mixtures of high purity and were obtained in good yields.

Journal Article↗

PubMedDate not supplied

Solid-phase synthesis of an alkylaminobenzanilide library.

The synthesis of a library of 2- and 3-substituted benzanilides has been achieved on solid phase. Attachment of anilines to formyldimethoxyphenyl (FDMP) resin via reductive amination was optimized to allow a wide range of anilines to be used. Acylation of this resin-bound aniline was accomplished with 2- or 3-nitrobenzoyl chloride to yield nitrobenzanilides. Following reduction of the nitro group, the resulting amine was alkylated using aromatic and heteroaromatic aldehydes in the presence of NaBH(OAc)(3) under controlled conditions. Finally, the products were cleaved from the resin using trifluoroacetic acid to produce a 10 800-member library.

Journal Article↗

PubMedDate not supplied

Solid-Phase Synthesis of 2,4-diaminopyrimidines via Lewis acid-mediated aromatic nucleophilic substitution.

Primary amines were immobilized on (4-formyl-3,5-dimethoxyphenoxy)methylpolystyrene resin via reductive amination. Attachment of two different 4-chloro-2-methylthiopyrimidines, followed by sulfide oxidation, led to their corresponding sulfone intermediates. Aromatic nucleophilic substitution with various anilines or heteroaromatic amines in the presence of trimethyl aluminum afforded the desired 2,4-diaminopyrimidines after acidic cleavage from the resin. The synthetic methodology described herein was validated with the synthesis of a small 162-member library.

Amination↗