Potent and selective Aurora kinase inhibitors were identified from the combinatorial expansion of the 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole bi-cycle, a novel and versatile scaffold designed to target the ATP pocket of protein kinases. The most potent compound reported in this study had an IC(50) of 0.027 microM in the enzymatic assay for Aur-A inhibition and IC(50)s between 0.05 microM and 0.5 microM for the inhibition of proliferation of different tumor cell lines.
A series of new compounds containing a benzimidazole, benzothiazole, or benzoxazole nucleus linked to an arylpiperazine by different thioalkyl chains was prepared. They were tested in radioligand binding experiments to evaluate their affinity for 5-HT 1A and 5-HT 2A serotonergic, alpha 1 adrenergic, D1, and D2 dopaminergic receptors. Many of tested compounds showed an interesting binding profile; in particular, 36 displayed very high 5-HT 1A receptor affinity and selectivity over all the other investigated receptors. Selected compounds, evaluated in functional assays, showed antagonistic or partial agonistic activity at 5-HT 1A receptor. An extensive conformational research using both NMR and modeling techniques indicated that extended conformations predominated in vacuum, in solution and during interactions with 5-HT 1A receptor. Finally, the elaborated binding mode of selected compounds at 5-HT 1A receptor was used to explain the influence of spacer length on ligands affinity.
Since their discovery
as distinct receptor proteins, the specific
physiopathological role of sigma receptors (σRs) has been deeply
investigated. It has been reported that these proteins, classified
into two subtypes indicated as σ
1
and σ
2
, might play a pivotal role in cancer growth, cell proliferation,
and tumor aggressiveness. As a result, the development of selective
σR ligands with potential antitumor properties attracted significant
attention as an emerging theme in cancer research. This perspective
deals with the recent advances of σR ligands as novel cytotoxic
agents, covering articles published between 2010 and 2020. An up-to-date
description of the medicinal chemistry of selective σ
1
R and σ
2
R ligands with antiproliferative and cytotoxic
activities has been provided, including major pharmacophore models
and comprehensive structure–activity relationships for each
main class of σR ligands.
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