"Nitric Oxide Donors for Biomedical Applications: A Themed Issue Dedicated to Professor Alberto Gasco": Special Issue Editorial Overview.

The Guest Editors Federica Sodano, Elena Gazzano, and Roberta Fruttero are pleased to present this editorial overview of the Special Issue entitled "Nitric Oxide Donors for Biomedical Applications: A Themed Issue Dedicated to Professor Alberto Gasco" [...

Proteomics Studies Suggest That Nitric Oxide Donor Furoxans Inhibit In Vitro Vascular Smooth Muscle Cell Proliferation by Nitric Oxide-Independent Mechanisms.

Physiologically, smooth muscle cells (SMC) and nitric oxide (NO) produced by endothelial cells strictly cooperate to maintain vasal homeostasis. In atherosclerosis, where this equilibrium is altered, molecules providing exogenous NO and able to inhibit SMC proliferation may represent valuable antiatherosclerotic agents. Searching for dual antiproliferative and NO-donor molecules, we found that furoxans significantly decreased SMC proliferation in vitro, albeit with different potencies.

NO in Viral Infections: Role and Development of Antiviral Therapies.

Nitric oxide is a ubiquitous signaling radical that influences critical body functions. Its importance in the cardiovascular system and the innate immune response to bacterial and viral infections has been extensively investigated. The overproduction of NO is an early component of viral infections, including those affecting the respiratory tract.

A generator of peroxynitrite activatable with red light.

The generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) as "unconventional" therapeutics with precise spatiotemporal control by using light stimuli may open entirely new horizons for innovative therapeutic modalities. Among ROS and RNS, peroxynitrite (ONOO) plays a dominant role in chemistry and biology in view of its potent oxidizing power and cytotoxic action. We have designed and synthesized a molecular hybrid based on benzophenothiazine as a red light-harvesting antenna joined to an -nitroso appendage through a flexible spacer.

Tuning NO release of organelle-targeted furoxan derivatives and their cytotoxicity against lung cancer cells.

We herein report a study on a set of hybrid compounds in which 3-R-substituted furoxan moieties (R = CH, CONH, CN, SOCH), endowed with varying NO-releasing capacities, are joined to a mitochondrial probe, rhodamine B. Each product has been investigated for its ability to release NO both in physiological solution, in the presence of cysteine, and in A549 lung adenocarcinoma cancer cells. The cytotoxicity of all the products against the aforementioned cancer cells has been assessed, including the structurally related compounds with no mitochondrial targeting, which were taken as a reference.

One molecule two goals: A selective P-glycoprotein modulator increases drug transport across gastro-intestinal barrier and recovers doxorubicin toxicity in multidrug resistant cancer cells.

In the present study a series of tetrahydroisoquinoline derivatives were synthesized and evaluated for their activity towards three ABC transporters, P-gp, MRP1 and BCRP. The compounds proved to be selective against P-gp. One of them, 8b, displayed activity in the nanomolar range (EC = 94 nM).

MRP5 nitration by NO-releasing gemcitabine encapsulated in liposomes confers sensitivity in chemoresistant pancreatic adenocarcinoma cells.

Pancreatic ductal adenocarcinoma (PDAC) is a therapy recalcitrant disease characterized by the aberrations in multiple genes that drive pathogenesis and drug chemoresistance. In this study, we synthesize a library of seven novel nitric oxide-releasing gemcitabine pro-drugs (NO-GEMs) in order to improve the effectiveness of GEM by exploiting the therapeutic effects of NO. Among these NO-GEM pro-drugs we select 5b as the most effective compound in GEM-resistant PDAC cells.

DNA-Targeted NO Release Photoregulated by Green Light.

A novel molecular hybrid has been designed and synthesized in which acridine orange (AO) is covalently linked to an N-nitrosoaniline derivative through an alkyl spacer. Photoexcitation of the AO antenna with the highly biocompatible green light results in intense fluorescence emission and triggers NO detachment from the N-nitroso appendage via an intramolecular electron transfer. The presence of the AO moiety encourages the binding with DNA through both external and partially intercalative fashions, depending on the DNA:molecular hybrid molar ratio.

In vitro vascular toxicity assessment of NitDOX, a novel NO-releasing doxorubicin.

The conjugation of doxorubicin (DOX) with nitric oxide (NO)-releasing groups gave rise to novel anthracyclines, such as nitrooxy-DOX (NitDOX), capable to overcome multidrug resistance. The widely described anthracycline cardiovascular toxicity, however, might limit their clinical use. This study aimed to investigate NitDOX-induced effects, as potential hazard, on vascular smooth muscle A7r5 and endothelial EA.

NO release regulated by doxorubicin as the green light-harvesting antenna.

We report for the first time a NO photodonor (NOPD) operating with the widely used chemotherapeutic agent doxorubicin (DOX) as the light-harvesting antenna. This permits NO uncaging from an N-nitroso appendage upon selective excitation of DOX with highly biocompatible green light, without precluding its typical red emission. This NOPD effectively binds DNA and photodelivers NO nearby, representing an intriguing candidate for potential multimodal therapeutic applications based on the combination of DOX and NO.

Improvement of conventional anti-cancer drugs as new tools against multidrug resistant tumors.

Multidrug resistance (MDR) is the dominant cause of the failure of cancer chemotherapy. The design of antitumor drugs that are able to evade MDR is rapidly evolving, showing that this area of biomedical research attracts great interest in the scientific community. The current review explores promising recent approaches that have been developed with the aim of circumventing or overcoming MDR.

Combination of PDT and NOPDT with a Tailored BODIPY Derivative.

The engineering of photosensitizers (PS) for photodynamic therapy (PDT) with nitric oxide (NO) photodonors (NOPD) is broadening the horizons for new and yet to be fully explored unconventional anticancer treatment modalities that are entirely controlled by light stimuli. In this work, we report a tailored boron-dipyrromethene (BODIPY) derivative that acts as a PS and a NOPD simultaneously upon single photon excitation with highly biocompatible green light. The photogeneration of the two key species for PDT and NOPDT, singlet oxygen (O) and NO, has been demonstrated by their direct detection, while the formation of NO is shown not to be dependent on the presence of oxygen.

Molecular dynamics simulations reveal the determinants of cyclin-dependent kinase 2 inhibition by 5-nitrosopyrimidine derivatives.

Communicated by Ramaswamy H. Sarma.

A cooperation project between hospital pharmacists and general practitioners about drug interactions in clinical practice.

Objectives: (1) To evaluate drug-drug interactions (DDIs) in general practitioners' (GPs) prescriptions; (2) to implement a cooperation project between pharmacists and GPs to improve DDI management and patient care.

Methods: In 2013, pharmacists from the Community Drug Assistance ASL TO1 launched a cooperation project involving 48 GPs. As a first step, GPs were asked to select, from a list, drug associations for which they recommended analysis of occurrence in their prescriptions.

Fluorescent Nitric Oxide Photodonors Based on BODIPY and Rhodamine Antennae.

Two novel NO photodonors (NOPDs) based on BODIPY and Rhodamine antennae activatable with the highly biocompatible green light are reported. Both NOPDs exhibit considerable fluorescence emission and release NO with remarkable quantum efficiencies. The combination of the photoreleasing and emissive performance for both compounds is superior to those exhibited by other NOPDs based on similar light-harvesting centres, making them very intriguing for image-guided phototherapeutic applications.

Hyaluronated liposomes containing H2S-releasing doxorubicin are effective against P-glycoprotein-positive/doxorubicin-resistant osteosarcoma cells and xenografts.

Doxorubicin (dox) is one of the first-line drug in osteosarcoma treatment but its effectiveness is limited by the efflux pump P-glycoprotein (Pgp) and by the onset of cardiotoxicity. We previously demonstrated that synthetic doxs conjugated with a HS-releasing moiety (Sdox) were less cardiotoxic and more effective than dox against Pgp-overexpressing osteosarcoma cells. In order to increase the active delivery to tumor cells, we produced hyaluronic acid (HA)-conjugated liposomes containing Sdox (HA-Lsdox), exploiting the abundance of the HA receptor CD44 in osteosarcoma.

Correction to "Light-Regulated NO Release as a Novel Strategy To Overcome Doxorubicin Multidrug Resistance".

[This corrects the article DOI: 10.1021/acsmedchemlett.7b00016.

A molecular hybrid producing simultaneously singlet oxygen and nitric oxide by single photon excitation with green light.

Combination of photosensitizers (PS) for photodynamic therapy with NO photodonors (NOPD) is opening intriguing horizons towards new and still underexplored multimodal anticancer and antibacterial treatments not based on "conventional" drugs and entirely controlled by light stimuli. In this contribution, we report an intriguing molecular hybrid based on a BODIPY light-harvesting antenna that acts simultaneously as PS and NOPD upon single photon excitation with the highly biocompatible green light. The presented hybrid offers a combination of superior advantages with respect to the other rare cases reported to date, meeting most of the key criteria for both PSs and NOPDs in the same molecular entity such as: (i) capability to generate O and NO with single photon excitation of biocompatible visible light, (ii) excellent O quantum yield and NO quantum efficiency, (iii) photogeneration of NO independent from the presence of oxygen, (iv) large light harvesting properties in the green region.

Design, Biological Evaluation, and Molecular Modeling of Tetrahydroisoquinoline Derivatives: Discovery of A Potent P-Glycoprotein Ligand Overcoming Multidrug Resistance in Cancer Stem Cells.

P-Glycoprotein is a well-known membrane transporter responsible for the efflux of an ample spectrum of anticancer drugs. Its relevance in the management of cancer chemotherapy is increased in view of its high expression in cancer stem cells, a population of cancer cells with strong tumor-promoting ability. In the present study, a series of compounds were synthesized through structure modulation of [4'-(6,7-dimethoxy-3,4-dihydro-1 H-isoquinolin-2-ylmethyl)biphenyl-4-ol] (MC70), modifying the phenolic group of the lead compound.

Endoplasmic reticulum-targeting doxorubicin: a new tool effective against doxorubicin-resistant osteosarcoma.

Doxorubicin is one of the most effective drugs for the first-line treatment of high-grade osteosarcoma. Several studies have demonstrated that the major cause for doxorubicin resistance in osteosarcoma is the increased expression of the drug efflux transporter ABCB1/P-glycoprotein (Pgp). We recently identified a library of HS-releasing doxorubicins (Sdox) that were more effective than doxorubicin against resistant osteosarcoma cells.

Anti-Pseudomonas activity of 3-nitro-4-phenylfuroxan.

Pseudomonas aeruginosa is a microorganism that is well adapted to both clinical and industrial settings, where it can form adherent communities that are difficult to eradicate. New anti-Pseudomonas compounds and strategies are necessary, as the current antimicrobial approaches for the inhibition of biofilm formation and, above all, the eradication of formed biofilms are ineffective. Compounds that belong to the furoxan family, which are well-known NO donors, have recently been shown to display anti-Pseudomonas activity.

New tetrahydroisoquinoline-based P-glycoprotein modulators: decoration of the biphenyl core gives selective ligands.

P-glycoprotein (P-gp, MDR1) is a membrane transporter expressed in several regions of our body. It plays a crucial defense role as it mediates the efflux of hundreds of potentially toxic substances. However, P-gp is one of the main causes of failure in cancer chemotherapy, as a number of chemotherapeutic agents are P-gp substrates.

New Tetrahydroisoquinoline Derivatives Overcome Pgp Activity in Brain-Blood Barrier and Glioblastoma Multiforme in Vitro.

P-glycoprotein (Pgp) determines resistance to a broad spectrum of drugs used against glioblastoma multiforme (GB). Indeed, Pgp is highly expressed in GB stem cells and in the brain-blood barrier (BBB), the peculiar endothelium surrounding the brain. Inhibiting Pgp activity in the BBB and GB is still an open challenge.

Atropisomerism in a 10-Membered Ring with Multiple Chirality Axes: (3 Z,9 Z)-1,2,5,8-Dithiadiazecine-6,7(5 H,8 H)-dione Series.

For the first time, chirality in (3 Z,9 Z)-1,2,5,8-dithiadiazecine-6,7(5 H,8 H)-dione series was recognized. Enantiomers of the 4,9-dimethyl-5,8-diphenyl analogue were isolated at room temperature, and their thermal stability was determined. X-ray crystallography confirmed the occurrence of a pair of enantiomers in the crystal.