当前位置： SCI文献检索 > MOLECULAR PHARMACEUTICS期刊下所有文献 > Toward the Optimization of Dinitrosyl Iron Complexes as Therapeutics for Smooth Muscle Cells.

Toward the Optimization of Dinitrosyl Iron Complexes as Therapeutics for Smooth Muscle Cells.

Abstract：

:In this study, dinitrosyl iron complexes (DNICs) are shown to deliver nitric oxide (NO) into the cytosol of vascular smooth muscle cells (SMCs), which play a major role in vascular relaxation and contraction. Malfunction of SMCs can lead to hypertension, asthma, and erectile dysfunction, among other disorders. For comparison of the five DNIC derivatives, the following protocols were examined: (a) the Griess assay to detect nitrite (derived from NO conversion) in the absence and presence of SMCs; (b) the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium (MTS) assay for cell viability; (c) an immunotoxicity assay to establish if DNICs stimulate immune response; and (d) a fluorometric assay to detect intracellular NO from treatment with DNICs. Dimeric Roussin's red ester (RRE)-type {Fe(NO)2}9 complexes containing phenylthiolate bridges, [(μ-SPh)Fe(NO)2]2 or SPhRRE, were found to deliver NO with the lowest effect on cell toxicity (i.e., highest IC50). In contrast, the RRE-DNIC with the biocompatible thioglucose moiety, [(μ-SGlu)Fe(NO)2]2 (SGlu = 1-thio-β-d-glucose tetraacetate) or SGluRRE, delivered a higher concentration of NO to the cytosol of SMCs with a 10-fold decrease in IC50. Additionally, monomeric DNICs stabilized by a bulky N-heterocyclic carbene (NHC), namely, 1,3-bis(2,4,6-trimethylphenyl)imidazolidene (IMes), were synthesized and yielded the DNIC complexes SGluNHC, [IMes(SGlu)Fe(NO)2], and SPhNHC, [IMes(SPh)Fe(NO)2]. These oxidized {Fe(NO)2}9 NHC DNICs have an IC50 of ∼7 μM; however, the NHC-based complexes did not transfer NO into the SMC. Per contra, the reduced, mononuclear {Fe(NO)2}10 neocuproine-based DNIC, neoDNIC, depressed the viability of the SMCs, as well as generated an increase of intracellular NO. Regardless of the coordination environment or oxidation state, all DNICs showed a dinitrosyl iron unit (DNIU)-dependent increase in viability. This study demonstrates a structure-function relationship between the DNIU coordination environment and the efficacy of the DNIC treatments.

journal_name

Mol Pharm

journal_title

Molecular pharmaceutics

authors

Pectol DC,Khan S,Chupik RB,Elsabahy M,Wooley KL,Darensbourg MY,Lim SM

doi

10.1021/acs.molpharmaceut.9b00389

subject

Has Abstract

pub_date

2019-07-01 00:00:00

pages

3178-3187

issue

eissn

1543-8384

issn

1543-8392

journal_volume

pub_type

杂志文章

在线工具

Toward the Optimization of Dinitrosyl Iron Complexes as Therapeutics for Smooth Muscle Cells.