1,2-Diamines as inhibitors of co-activator associated arginine methyltransferase 1 (CARM1).

We have identified the N(1)-benzyl-N(2)-methylethane-1,2-diamine unit as a substitute for the (S)-alanine benzylamide moiety for the design of co-activator associated arginine methyltransferase 1 (CARM1) inhibitors. The potency of these inhibitors is in the same order of magnitude as their predecessors and their clearance, volume of distribution, and half lives were greatly improved.

Synthesis and evaluation of lysine derived sulfamides as histone deacetylase inhibitors.

We have recently reported on a novel class of histone deacetylase (HDAC) inhibitors bearing a sulfamide group as the zinc-binding unit. Herein, we report on the synthesis of sulfamide based inhibitors designed around a lysine scaffold and their structure-activity relationships against HDAC1 and HDAC6 isotypes as well as 293T cells. Our efforts led us to an improvement of the originally disclosed lysine-based sulfamide, 2a to compound 12h which has equal potency in enzyme and cell-based assays as well as enhanced metabolic stability and PK profile.

N-Benzyl-1-heteroaryl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamides as inhibitors of co-activator associated arginine methyltransferase 1 (CARM1).

A series of N-benzyl-1-heteroaryl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamides targeting co-activator associated arginine methyltransferase 1 (CARM1) have been designed and synthesized. The potency of these inhibitors was influenced by the nature of the heteroaryl fragment with the thiophene analogues being superior to thiazole, pyridine, isoindoline and benzofuran based inhibitors.

Novel HDAC6 isoform selective chiral small molecule histone deacetylase inhibitors.

In an effort to identify HDAC isoform selective inhibitors, we designed and synthesized novel, chiral 3,4-dihydroquinoxalin-2(1H)-one and piperazine-2,5-dione aryl hydroxamates showing selectivity (up to 40-fold) for human HDAC6 over other class I/IIa HDACs. The observed selectivity and potency (IC(50) values 10-200 nM against HDAC6) is markedly dependent on the absolute configuration of the chiral moiety, and suggests new possibilities for use of chiral compounds in selective HDAC isoform inhibition.

Sulfamides as novel histone deacetylase inhibitors.

The sulfamide moiety has been utilized to design novel HDAC inhibitors. The potency and selectivity of these inhibitors were influenced both by the nature of the scaffold, and the capping group. Linear long-chain-based analogs were primarily HDAC6-selective, while analogs based on the lysine scaffold resulted in potent HDAC1 and HDAC6 inhibitors.

Screening of a combinatorial library of synthetic polyamines displaying selectivity in multiple ion-pairing interactions with model polyanionic compounds in aqueous organic solutions.

The biological activity of natural polyamines is due in large part to their ability to form ion-pairing interactions with polyanionic biomolecules, such as proteins, oligonucleotides, and sulfated oligosaccharides. Unfortunately, the diversity of biogenic polyamines is compromised by their limitation to only just a few internitrogen spacers. As a proof-of-principle study, a synthetic split-pool library of linear triamines was screened in an on-bead assay against a selection of model trisulfonated azo dyes (1, 2, and 3) and a short glutamate-rich nonameric peptide (4) to demonstrate its use in the discovery of selective ligands via multivalent ion pairing.

Fluorous mixture synthesis of fused-tricyclic hydantoins. Use of a redundant tagging strategy on fluorinated substrates.

Simple HPLC experiments were used to identify a redundant tagging scheme wherein six different amino acids were tagged with only four fluorous tags. The tagged amino acids were converted to regiosiomeric mixtures of tricyclic hydantoins. Despite the lack of selectivity, the mixtures were demixed and detagged to give 11 individual pure products in just 25 steps.

Fluorous mixture synthesis of 4-alkylidene cyclopentenones via a rhodium-catalyzed [2+2+1] cycloaddition of alkynyl allenes.

Fluorous mixture synthesis was used to prepare a library of 4-alkylidene cyclopentenones starting from a mixture of four alpha-amino acid derivatives tagged with different fluorous benzyl carbamates ((F)CBz) of varying fluorine content. The amino acids were converted to the corresponding propargyl esters and then subjected to an ester-enolate Claisen rearrangement to give a mixture of allenic amino esters. The allenes were then split four ways and propargylated with different propargyl bromides to give four mixtures of alkynyl allenes.

Modular solid-phase synthetic approach to optimize structural and electronic properties of oligoboronic acid receptors and sensors for the aqueous recognition of oligosaccharides.

This article describes the design and optimization of the first entirely modular, parallel solid-phase synthetic approach for the generation of well-defined polyamine oligoboronic acid receptors and fluorescence sensors for complex oligosaccharides. The synthetic approach allows an effective building of the receptor polyamine backbone, followed by the controlled diversification of the amine benzylic side chains. This approach enabled the testing, in a modular fashion, of the effect of different arylboronic acid units substituted with unencumbering para electron-withdrawing or electron-donating groups.

Synthesis and high performance liquid chromatography/electrospray mass spectrometry single-bead decoding of split-pool structural libraries of polyamines supported on polystyrene and polystyrene/ethylene glycol resins.

Natural polyamines are ubiquitous biomolecules present in all living cells. These cationic compounds play essential roles in both cell growth and differentiation and are known to interact in complex ways with polyanionic biomolecules. Consequently, there is significant interest in expanding nature's polyamine diversity using combinatorial synthesis and screening strategies.

Combinatorial approach to selective multivalent ion pairing in mixed aqueous-organic media using bead-supported libraries of unnatural polyamines.

[structure: see text] Screening of a bead-supported encoded library of unnatural polyamines against model polyanionic targets (1 and 2) demonstrated that a combinatorial approach can highlight structural selectivity in multivalent ion pairing in aqueous solutions. This approach even provided -NH-2Acc(R)-6Ahx(R)-Et, a highly target-selective triamine sequence that can discriminate between two trisulfonated dyes displaying subtle structural differences.