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.
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.
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.
Trisubstituted cyclopentanes have a discrete shapely curvature. While the central ring of these compounds is devoid of rotatable bonds, the pseudo rotation of the cyclopentane ring leads to a desirable disruption of planarity. This is favorable for aqueous solubility and enables addressing of wide-ranging conformational space. The sp 3 -rich framework of 4-aminocyclopentane-1,3-diols offers stereochemically defined attachment points for substituents and renders these fragment-like molecules good platforms for molecular diversity. By using an established N-selective polymer-assisted acylation protocol, these scaffolds with natural product-like properties were transformed into a screening library by attachment of substituents at defined positions. Here we describe the synthesis and characterization of these molecular platforms and their use as starting points for the construction of an 80-member library of 4-amidocyclopentane-1,3-diol monoethers. Five of the compounds displayed cytotoxicity in a tumor cell line assay with IC 50 values in the low micromolar range. Results and discussion SynthesisKey components for assessing structural diversity in diversityoriented synthesis (DOS) were recognized by Spring et al. as (1) appendage diversityvariation in structural moieties, around a common core scaffold, (2) functional group diversityvariation in the functional groups introduced into the periphery, (3) stereochemical diversityvariation in the orientation of potential macromolecule-interacting elements and (4) skeletal (scaffold) diversity. 12 With the intention to generate a set of platforms for molecular diversity and subsequently ornament
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