New Multitarget Approaches in the War Against Glioblastoma: A Mini-Perspective

Glioblastoma multiforme (GBM) is the most common tumor of the CNS, and the deadliest form of brain cancer. The rapid progression, the anatomic location in the brain and a deficient knowledge of the pathophysiology, often limit the effectiveness of therapeutic interventions. Current pillars of GBM therapies include surgical resection, radiotherapy and chemotherapy, but the low survival rate and the short life expectation following these treatments strongly underline the urgency to identify innovative and more effective therapeutic tools. Frequently, patients subjected to a mono-target therapy, such as Temozolomide (TMZ), develop drug resistance and undergo relapse, indicating that targeting a single cellular node is not sufficient for eradication of this disease. In this context, a multi-targeted therapeutic approach aimed at using compounds, alone or in combination, capable of inhibiting more than one specific molecular target, offers a promising alternative. Such strategies have already been well integrated into drug discovery campaigns, including in the field of anticancer drugs. In this miniperspective, we will discuss the recent progress in the treatment of GBM focusing on innovative and effective preclinical strategies, which are based on a multi-targeted approach

Oxidative stress, mitochondrial abnormalities and proteins deposition: multitarget approaches in Alzheimer's disease

Alzheimer diseases (AD) is a multifactorial pathology characterized by a complex etiology. The hallmarks of AD, such as Aβ deposits in senile plaque and neurofibrillary tangles (NFT), are strongly intertwined with reactive oxygen species (ROS)production and oxidative stress (OS),which are considered the common effectors of the cascade of degenerative events. An increasing body of evidence reveals that both mitochondrial abnormalities and metal accumulations synergistically act as major producers of ROS, thus contributing to neuronal toxicity. Consequently, the detrimental role of ROS production together with the neurodegenerative events involved in AD has been widely investigated as new potential therapeutic strategies. This review will concisely summarize the link between OS and the hallmarks of AD, emphasizing on their strong correlation with neurodegenerative events and elucidating the pivotal role of ROS in AD pathology. Furthermore, through this review, we will provide a short account of some of the efforts, challenges and opportunities in developing multitarget drugs by addressing ROS production, metal accumulation and protein depositions

Hydrogen sulfide: A worthwhile tool in the design of new multitarget drugs

H2S is a gaseous molecule able to trigger a plethora of central physiological and pharmacological effects as antioxidant, pro- and anti-inflammatory, pro- and anti-nociceptive, neuromodulator, and cytoprotective. The polypharmacology of H2S depends on the wide variety of targets implicated, but, despite the efforts, the mechanisms of action that should clarify its activity are still not completely unrevealed. Nevertheless, many attempts to exploit the multifaceted profile of this molecule have already been accomplished and many chemical entities containing an H2S-releasing pharmacophore have been synthetized. Here we discuss recent investigations on multitarget molecules able to release H2S, with a particular focus on the combinations of "native drug" with moieties structurally able to release H2S and their applications as therapeutic tools in bone disease, gastrointestinal system and neurodegenerative disorders

Synthesis and functional evaluation of novel aldose reductase inhibitors bearing a spirobenzopyran scaffold

Background: Aldose reductase, the first enzyme of the polyol pathway, is the key determinant for the pathogenesis of long term diabetic complications. Accordingly, its inhibition represents the major therapeutic strategy to treat this kind of pathologies. Objectives: In this work we describe the synthesis and the functional evaluation of a number of spiro-oxazolidinone and spiro-morpholinone acetic acid derivatives, and their benzyloxy analogs, developed as aldose reductase inhibitors. Results: Most of them proved to inhibit the target enzyme, showing IC50 values in the micromolar/low micromolar range. SARs observed among the three different series allowed to highlight their key pharmacophoric elements, thus creating sound basis for the design of novel and more effective inhibitors. Conclusion: Although further substitution patterns are needed, the novel compounds here proposed represent a good starting point for the development of novel and effective ARIs

Development of Classification Models for Identifying “True” P-glycoprotein (P-gp) Inhibitors Through Inhibition, ATPase Activation and Monolayer Efflux Assays

P-glycoprotein (P-gp) is an efflux pump involved in the protection of tissues of several organs by influencing xenobiotic disposition. P-gp plays a key role in multidrug resistance and in the progression of many neurodegenerative diseases. The development of new and more effective therapeutics targeting P-gp thus represents an intriguing challenge in drug discovery. P-gp inhibition may be considered as a valid approach to improve drug bioavailability as well as to overcome drug resistance to many kinds of tumours characterized by the over-expression of this protein. This study aims to develop classification models from a unique dataset of 59 compounds for which there were homogeneous experimental data on P-gp inhibition, ATPase activation and monolayer efflux. For each experiment, the dataset was split into a training and a test set comprising 39 and 20 molecules, respectively. Rational splitting was accomplished using a sphere-exclusion type algorithm. After a two-step (internal/external) validation, the best-performing classification models were used in a consensus predicting task for the identification of compounds named as “true” P-gp inhibitors, i.e., molecules able to inhibit P-gp without being effluxed by P-gp itself and simultaneously unable to activate the ATPase function

Mitochondrial Potassium Channels as Pharmacological Target for Cardioprotective Drugs

Brief periods of ischemia are known to confer to the myocardium an increased resistance to the injury due to a later and more prolonged ischemic episode. This phenomenon, known as ischemic preconditioning (IPreC), is ensured by different biological mechanisms. Although an exhaustive comprehension of them has not been reached yet, it is widely accepted that mitochondria are pivotally involved in controlling cell life and death, and thus in IPreC. Among the several signaling pathways involved, as triggers and/or end effectors, in the mitochondrial mechanisms of cardioprotection, an important role is played by the activation of potassium channels located in the mitochondrial inner membrane (mitoK) of cardiomyocytes. Presently, different types of mitoK channels have been recognized in the heart, such as ATP-sensitive (mitoK(ATP)) and calcium-activated (mitoBK(Ca) and mitoSK(Ca)) potassium channels. Consistently, drugs modulating mitoK, on one hand, have been employed as useful experimental tools for early basic studies on IPreC. On the other hand, activators of mitoK are promising and innovative therapeutic agents for limiting the myocardial injury due to ischemic episodes. In this review, we report the experimental evidence supporting the role of mitoK in signaling pathways in the mechanisms of cardioprotection and an overview on the most important molecules acting as modulators of these channels, with their profiles of selectivity. Some innovative pharmaceutical strategies for mitochondriotropic drugs have been also reported. Finally, an appendix describing the main experimental approaches usually employed to study mitoK in isolated mitochondria or in intact cells has been added

Combined inhibition of AKT/mTOR and MDM2 enhances Glioblastoma Multiforme cell apoptosis and differentiation of cancer stem cells

The poor prognosis of Glioblastoma Multiforme (GBM) is due to a high resistance to conventional treatments and to the presence of a subpopulation of glioma stem cells (GSCs). Combination therapies targeting survival/self-renewal signals of GBM and GSCs are emerging as useful tools to improve GBM treatment. In this context, the hyperactivated AKT/mammalian target of the rapamycin (AKT/mTOR) and the inhibited wild-type p53 appear to be good candidates. Herein, the interaction between these pathways was investigated, using the novel AKT/mTOR inhibitor FC85 and ISA27, which re-activates p53 functionality by blocking its endogenous inhibitor murine double minute 2 homologue (MDM2). In GBM cells, FC85 efficiently inhibited AKT/mTOR signalling and reactivated p53 functionality, triggering cellular apoptosis. The combined therapy with ISA27 produced a synergic effect on the inhibition of cell viability and on the reactivation of p53 pathway. Most importantly, FC85 and ISA27 blocked proliferation and promoted the differentiation of GSCs. The simultaneous use of these compounds significantly enhanced GSC differentiation/apoptosis. These findings suggest that FC85 actively enhances the downstream p53 signalling and that a combination strategy aimed at inhibiting the AKT/mTOR pathway and re-activating p53 signalling is potentially effective in GBM and in GSCs

sg 2 a promising lipolytic and pro autophagic hit compound to treat alzheimer s disease

The identification of efficient pharmacological tools for treatment of Alzheimer's disease (AD) represents one of the main challenges of our century. Due to the complex etiopathology and the several biological processes resulting impaired in AD, the drug discovery process should focus on the development of new chemical entities able to target this multi-faceted impairment. We designed and synthetized a new analogue of 3-iodothyronamine, namely SG-2, which shares an interesting pleiotropic activity. Within this study, we explored SG-2 ability to promote beneficial effects in a C. Elegans model of AD, using a novel technique developed at Cambridge University, which exploits an automated system of high-resolution cameras to evaluate in parallel the motility of a huge number of nematodes (up to 5000 at time) in response to drug administration. Our results showed that SG-2 can promote lifespan and restores motility of worms back to the wildtype

Synthesis and AT1 affinity evaluation of benzamidophenyl analogs of known AT1 receptor ligands with similar aromatic skeleton

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