Antitubercular Triazines: Optimization and Intrabacterial Metabolism.

The triazine antitubercular JSF-2019 was of interest due to its in vitro efficacy and the nitro group shared with the clinically relevant delamanid and pretomanid. JSF-2019 undergoes activation requiring FH and one or more nitroreductases in addition to Ddn. An intrabacterial drug metabolism (IBDM) platform was leveraged to demonstrate the system kinetics, evidencing formation of NO and a des-nitro metabolite.

Discovery and clinical introduction of first-in-class imipridone ONC201.

ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL.

The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity.

We previously identified TRAIL-inducing compound 10 (TIC10), also known as NSC350625 or ONC201, from a NCI chemical library screen as a small molecule that has potent anti-tumor efficacy and a benign safety profile in preclinical cancer models. The chemical structure that was originally published by Stahle, et. al.

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.

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.

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.

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.

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.

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.