Over the years, researchers
in drug discovery have taken advantage
of the use of privileged structures to design innovative hit/lead
molecules. The α-ketoamide motif is found in many natural products,
and it has been widely exploited by medicinal chemists to develop
compounds tailored to a vast range of biological targets, thus presenting
clinical potential for a plethora of pathological conditions. The
purpose of this perspective is to provide insights into the versatility
of this chemical moiety as a privileged structure in drug discovery.
After a brief analysis of its physical–chemical features and
synthetic procedures to obtain it, α-ketoamide-based classes
of compounds are reported according to the application of this motif
as either a nonreactive or reactive moiety. The goal is to highlight
those aspects that may be useful to understanding the perspectives
of employing the α-ketoamide moiety in the rational design of
compounds able to interact with a specific target.
In glioblastoma multiforme (GBM), translocator protein (TSPO) and murine double minute (MDM)2/p53 complex represent two druggable targets. We recently reported the first dual binder 3 possessing a higher anticancer effect in GBM cells than the standards PK11195 1 or Nutlin-3 2 singularly applied. Herein, through a structure-activity relationship study, we developed derivatives 4-10 with improved potencies toward both TSPO and MDM2. As a result, compound 9: (i) reactivated the p53 functionality; (ii) inhibited the viability of two human GBM cells; (iii) impaired the proliferation of glioma cancer stem cells (CSCs), more resistant to chemotherapeutics and responsible of GBM recurrence; (iv) sensitized GBM cells and CSCs to the activity of temozolomide; (v) directed its effects preferentially toward tumor cells with respect to healthy ones. Thus, 9 may represent a promising cytotoxic agent, which is worthy of being further developed for a therapeutic approach against GBM, where the downstream p53 signaling is intact and TSPO is overexpressed.
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