Tractable synthesis of multipurpose screening compounds with under-represented molecular features for an open access screening platform.

The layout of multipurpose screening libraries must address criteria for the compounds such as novelty, diversity potential, innovative design, and last but not least synthetic tractability. While academic compound collections are often innovative, novel, and highly divers, synthesis of analogs or larger substance quantities is often hampered by complex multistep syntheses with low overall yields. In addition, covalently binding compounds and interaction motifs designed to bind metal ions were discriminated against by the paradigm that these interaction types must almost inevitably lead to toxic effects. We would like to challenge this hypothesis. The lack of such interactions could be a reason for frequent failure in the disclosure of hits for hitherto undruggable target proteins using commercially available screening collections. Thus, easily synthesizable screening candidates equipped to bind covalently to nucleophiles or to metalloenzymes by chelation are under-represented in public access screening libraries. Within this work, we present the synthesis and deposition of 88 compounds with five distinct functional classes, each of which features under-represented screening motifs, for example, metal ion complexation, reversible covalent binding, or halogen bonding. The collection includes acetohydrazides, acylhydrazones, propylene glycol ethers, 2-cyanoacetamides, and 2-cyanoacrylamides. The rational for the synthesis of most of the compounds was recently published by our group and is now supplemented by additional compounds reported here for the first time. The public access disposition enables academic research groups to collectively expand the druggable space and interdisciplinary collaborate within the scientific field.

Microwave-assisted synthesis and evaluation of acylhydrazones as potential inhibitors of bovine glutathione peroxidase.

Glutathione peroxidases (GPx) were the first selenocysteine enzymes identified. They play critical roles in cellular defense to excessH(2)O(2) and lipid peroxides, with GPx1 contributing the most cellular activity. In the treatment of cancer, for example, in lymphomas and leukaemias, evidence has been accumulating that up-regulation of the GPx system may serve to protect cancer cells from oxidative stress caused by anticancer drugs. We hypothesize that small molecules which block GPx1 could help overcome acquired resistance to anticancer drugs by raising the level of oxidative stress in cancer cells. Our previous efforts identified an acylhydrazone as a lead structure for the inhibition of GPx1. Now we report the microwave-supported synthesis and inhibitory screening of a series of 78 analogs. The special conformational isomerism resulting of the acylhydrazone functionality was investigated by the analysis of distinct NMR data and crystal structures, indicating that conformers at the C(O)-N hydrazide bond are responsible for this phenomena. Though some of the analogs showed poor aqueous solubility and could not be tested in the enzyme assay, the combinatorial approach led to the identification of a closely related isomer of the lead compound with increased inhibitory activity: N'-[1-(4-hydroxyphenyl)ethylidene]-2-(1H-imidazol-1-yl)acetohydrazide. This success supports the idea that novel GPx1 inhibitors can be developed by drug-design methods and paves the way for a new class of GPx1 inhibitors.

Evaluation of (S)- and (R)-misonidazole as GPX inhibitors: synthesis, characterization including circular dichroism and in vitro testing on bovine GPx-1.

Racemic misonidazole, a radiosensitizer formally used in radiation therapy of cancer and to date still applied, was once reported to exhibit strong inhibitory effects on mouse glutathione peroxidases (GPX). This appeared to qualify misonidazole as a lead structure for the development of novel GPX inhibitors to cause oxidative stress in chemotherapy-resistant tumors. A unique feature of misonidazole as an inhibitor of GPX is the absence of a thiol functionality. Therefore, it was expected to selectively target inhibition devoid of promiscuous interactions with cations and sulfhydryl groups. We synthesized the isomers of misonidazole and analyzed the ability of chiroptical high-performance liquid chromatography (HPLC) to identify the particular enantiomers. Due to the chiral pool synthesis, the assignment of the correct configuration could be verified. Finally, we evaluated both isomers for their inhibitory activities on bovine erythrocyte GPx-1, which is 87% homologous to the human enzyme. Despite the previously reported inhibition of racemic misonidazole on the less homologous mouse GPx-1, we did not find any significant inhibitory activity on the bovine enzyme for either isomer. Though misonidazole appears unlikely to be an inhibitor of human GPx-1 activity, we still spotlight misonidazole as a promising fragment-like lead structure in general.

Advances in the design of a multipurpose fragment screening library.

INTRODUCTION: Fragment-based lead discovery (FBLD) has evolved from an emerging technology to a state-of-the-art approach in drug research. The efficacious use of fragment libraries for the discovery of hits and generation of lead structures has to an increasing extent become implemented both within academia and the pharmaceutical industry but the careful or optimal selection of appropriate fragments remains a demanding task, especially when fragments are intended for the lead generation in more than one or even diverse and difficult targets. AREAS COVERED: Progress in non-commercial screening collections of fragment-like compounds for multiple screening purposes deposited at academic institutions is reviewed as well as approaches for the generation of slim and shapely novel platforms for diversity. Recent literature on multipurpose fragment screening libraries and the papers presented at the EFMC-ISMC meeting in Berlin in August 2012 have been taken into account. EXPERT OPINION: Existing fragment libraries tend to focus on sp (2)-rich compounds covering well-explored areas of chemical space. In order to improve the quality of the hits and to be able to tackle seemingly undruggable targets, flat scaffolds should be replaced by shapely molecular cores dominated by sp (3) hybridization. Structurally novel fragments are needed and in this respect, the role of halogen bonds has been underestimated. Pooling strategies for fragment cocktails must be designed to detect simultaneous binding of weak ligands in close proximity: cooperative binding is too important to rely on chance discoveries.