Abstract
The burden of neoplastic diseases is widely recognized as a severe cause of mortality. The clinical inadequacy of most anticancer therapeutics urgently prompted intense drug discovery efforts toward the identification of new chemical entities endowed with a potent and safe antitumor profile. In this scenario, targeting cancer cells apoptosis machinery has emerged as a relevant strategy, useful for tackling the emergence of drug resistance. On this basis, a small library of naturally inspired hybrid molecules was obtained by combining, through a click chemistry approach, “privileged” synthons such as curcumin scaffold and 1,2,3-triazole building block. Compound 1, bearing a para-fluoro phenyl moiety, showed low-micromolar potency against T acute lymphoblastic leukemia cell growth. More in-depth biologic studies demonstrated, for this analog, cell death-inducing properties associated with its capability to simultaneously activate both the receptor and the mitochondrial apoptosis cascades. This peculiar behavior offers promises for achieving an expanded anticancer effect, namely intense cytotoxic response coupled with reduced predisposition of chemoresistance insurgence. Altogether, this study allowed the identification of compound 1 as a lead compound worth to be progressed as an anticancer drug candidate.
Highlights
Cancer is expected to become, in every country of the world in the 21st century, the leading cause of death along with a remarkable obstacle for the life expectancy increasing [1]
The curcumin-based analogs 1–6 were synthetized by exploiting the classical Pabon reaction [29], while, to attain synthons conjugation, the copper-catalyzed azide–alkyne cycloaddition (CuAAC), between the suitable azide (9 and 10) and alkyne (8 and 12) derivatives was performed (Schemes 1–3)
Azide intermediates (9 and 10) were prepared by a nucleophilic substitution reaction of the appropriate benzyl halides with NaN3
Summary
Cancer is expected to become, in every country of the world in the 21st century, the leading cause of death along with a remarkable obstacle for the life expectancy increasing [1]. It ranks as one of the principal life-threatening maladies. The induction of apoptosis represents a common mechanism through which several therapeutics influence cancer cell death. Apoptosis is a very complex cellular phenomenon that can be triggered by caspases activation by two diverse, but overlapping pathways, the intrinsic and the extrinsic one [2]
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