The bioregulatory molecule NO plays key roles in cancer biology and has been implicated in both tumor growth and suppression. Furthermore, it is a γ-radiation sensitizer that may enhance selective killing of neoplastic tissues. For these reasons, there is considerable interest in developing methods for NO delivery to specific physiological targets. In this Perspective, we describe ongoing investigations focused on photochemical methodologies to deliver therapeutic doses of NO to such targets utilizing transition metal complexes that are nitric oxide precursors. The photochemical strategy has the advantages that it allows for precise control of the timing, location, and dosage for the targeted delivery of a bioactive agent.

Metal complexes as photochemical nitric oxide precursors: Potential applications in the treatment of tumors

Biological activity of ruthenium nitrosyl complexes.

Presented is an overview of the fundamental chemical properties of nitric oxide and nitrite ion in relation to the reactions with ferri- and ferroheme models and proteins potentially relevant to the roles of these species in mammalian biology.

Reactions of NO and nitrite with heme models and proteins.

Immobilized ruthenium complexes and aspects of their reactivity

Iron, the most abundant transition metal ion in humans, participates in the biosynthesis, translocation, signal transduction, and transformation of nitric oxide through its encapsulation in the form of heme, [Fe-S], and [Fe(NO)2] cofactors within a variety of enzymes and proteins. After the review on nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC) for the biosynthesis and detection of NO, in this report, we discuss the natural utilization of the [Fe(NO)2] motif for translocation of endogenous NO and the translational development of synthetic dinitrosyl iron complexes (DNICs) for biomedical applications. A mechanistic study of NO-release and NO-transfer reactivity of structure-characterized DNICs promoted the discovery of cell-penetrating and in vivo NO-delivery reactivity for treatment of cancer and wound healing in diabetes. Beyond activation of sGC and vasodilation, phase I/II clinical trials of glutathione-bound DNICs (Oxacom®) against hypertension encourage bioinorganic engineering of DNICs into scaffolds for tissue regeneration and repair relying on anti-bacterial, anti-inflammation, cytoprotective, and proliferative effects of NO.

Fe in biosynthesis, translocation, and signal transduction of NO: toward bioinorganic engineering of dinitrosyl iron complexes into NO-delivery scaffolds for tissue engineering.

I.E. Borissevitch

Papers

Acidity and photolability of ruthenium salen nitrosyl and aquo complexes in aqueous solutions