Synthesis and Evaluation of O²-Derived Diazeniumdiolates Activatable via Bioorthogonal Chemistry Reactions in Living Cells

Abstract

A class of O-alkyl derived diazeniumdiolates 3a-f and 4a-c were designed and synthesized as new bioorthogonal NO precursors, which can be effectively uncaged in the presence of a palladium catalyst via bioorthogonal bond cleavage reactions to generate NO in living cancer cells, eliciting potent antiproliferative activity.

Catalysis Concepts in Medicinal Inorganic Chemistry

“…This masked pyrrolidinyl diazeniumdiolate was stable in plasma and exhibited potent antiproliferativea ctivity against human colon carcinoma HCT116 cells, only when cells were pretreated witht he [Pd(dba) 2 ]c atalyst (dba = dibenzylideneacetone). [58] PanØ and collaborators designed hybrid FePd magnetic nanowires responding to magnetic fields and capable of performing the deprotection of propargyl-caged 5FU ( Figure 5). By placing am agnet under specific regions of aP etri dish, they could attract the magnetic catalysts in defined areas where they triggeredt he activation of the prodrug and induced cell death with spatial control.F ePd nanowires injected in tumors and intraperitoneal administration of 5FU significantly reduced tumor growth in mice models.…”

“…to activate a newly designed propargyl‐masked NO‐releasing agent (Figure ). This masked pyrrolidinyl diazeniumdiolate was stable in plasma and exhibited potent antiproliferative activity against human colon carcinoma HCT116 cells, only when cells were pretreated with the [Pd(dba) 2 ] catalyst (dba=dibenzylideneacetone) …”

Dissociative Bioorthogonal Reactions

“…Researchers have adapted these reactions to developingg asotransmitters that allow the controlled release of bioactive gases such as H 2 S, NO, SO 2 ,a nd CO so as to study the biological or therapeutic roles of these short-lived messengers. [109] Dissociative bioorthogonal chemistry is an important component of DNA sequencing based on the sequencing-by-synthesis approach. Phosphine-responsive azidomethoxyt ermini and a-azidoether linkersa re the basis of the chemistry used for Illuminas equencing.…”

Bioorthogonal Uncaging of the Active Metabolite of Irinotecan by Palladium‐Functionalized Microdevices

“…Palladium (Pd) catalysts are one of the tools of choice currently under investigation to release caged drugs in vitro and in vivo . The selection of this metal is based on its high bio‐compatibility, its versatility to adopt different shapes and sizes and its remarkable capabilities to catalyze N ‐ and O ‐dealkylation reactions on manifold types of substrates under physiological conditions .…”