A Selective ALDH1A3 Inhibitor Impairs Mesothelioma 3-D Multicellular Spheroid Growth and Neutrophil Recruitment.

Aldehyde dehydrogenase 1A3 (ALDH1A3), one of the three members of the aldehyde dehydrogenase 1A subfamily, has been associated with increased progression and drug resistance in various types of solid tumours. Recently, it has been reported that high ALDH1A3 expression is prognostic of poor survival in patients with malignant pleural mesothelioma (MPM), an asbestos-associated chemoresistant cancer. We treated MPM cells, cultured as multicellular spheroids, with NR6, a potent and highly selective ALDH1A3 inhibitor. Here we report that NR6 treatment caused the accumulation of toxic aldehydes, induced DNA damage, CDKN2A expression and cell growth arrest. We observed that, in CDKN2A proficient cells, NR6 treatment induced IL6 expression, but abolished CXCL8 expression and IL-8 release, preventing both neutrophil recruitment and generation of neutrophil extracellular traps (NETs). Furthermore, we demonstrate that in response to ALDH1A3 inhibition, CDKN2A loss skewed cell fate from senescence to apoptosis. Dissecting the role of ALDH1A3 isoform in MPM cells and tumour microenvironment can open new fronts in the treatment of this cancer.

Aurones: A Golden Resource for Active Compounds.

Deemed as poorly represented in nature, aurones have been often overlooked by researchers compared to other members of the flavonoid superfamily. However, over the past two decades, they have been reassessed by the scientific community, who are increasingly appreciating their ability to modulate several biological pathways. This review summarizes the recent literature on this class of compounds, which has been analyzed from both a chemical and a functional point of view. Original articles, reviews and editorials featured in Pubmed and Scifinder over the last twenty years have been taken into account to provide the readers with a view of the chemical strategies to obtain them, their functional properties, and their potential of technological use. The resulting comprehensive picture aims at raising the awareness of these natural derivatives as effective drug candidates, fostering the development of novel synthetic analogues.

New Hybrid Compounds Incorporating Natural Products as Multifunctional Agents against Alzheimer's Disease.

A series of new hybrid derivatives 1a-c, 2a-c, 3a-c, 4a-c, 5a-c, inspired by nature, were synthesized and studied as multifunctional agents for the treatment of Alzheimer's disease (AD). These compounds were designed to merge together the trifluoromethyl benzyloxyaminic bioactive moiety, previously identified, with different acids available in nature. The ability of the synthesized compounds to chelate biometals, such as Cu2+, Zn2+ and Fe2+, was studied by UV-Vis spectrometer, and through a preliminary screening their antioxidant activity was evaluated by DPPH. Then, selected compounds were tested by in vitro ABTS free radical method and ex vivo rat brain TBARS assay. Compounds 2a-c, combining the strongest antioxidant and biometal chelators activities, were studied for their ability to contrast Aß1-40 fibrillization process. Finally, starting from the promising profile obtained for compound 2a, we evaluated if it could be able to induce a positive cross-interaction between transthyretin (TTR) and Aß in presence and in absence of Cu2+.

Nature-Inspired O-Benzyl Oxime-Based Derivatives as New Dual-Acting Agents Targeting Aldose Reductase and Oxidative Stress.

Aldose reductase (ALR2) is the enzyme in charge of developing cellular toxicity caused by diabetic hyperglycemia, which in turn leads to the generation of reactive oxygen species triggering oxidative stress. Therefore, inhibiting ALR2 while pursuing a concomitant anti-oxidant activity through dual-acting agents is now recognized as the gold standard treatment for preventing or at least delaying the progression of diabetic complications. Herein we describe a novel series of (E)-benzaldehyde O-benzyl oximes 6a-e, 7a-e, 8a-e, and 9-11 as ALR2 inhibitors endowed with anti-oxidant properties. Inspired by the natural products, the synthesized derivatives are characterized by a different polyhydroxy substitution pattern on their benzaldehyde fragment, which proved crucial for both the enzyme inhibitory activity and the anti-oxidant capacity. Derivatives (E)-2,3,4-trihydroxybenzaldehyde O-(3-methoxybenzyl) oxime (7b) and (E)-2,3,4-trihydroxybenzaldehyde O-(4-methoxybenzyl) oxime (8b) turned out to be the most effective dual-acting products, proving to combine the best ALR2 inhibitory properties with significant anti-oxidant efficacy.

Identification of novel SIRT1 activators endowed with cardioprotective profile.

Drugs targeting epigenetic mechanisms are attracting the attention of scientists since it was observed that the modulation of this post-translational apparatus, could help to identify innovative therapeutic strategies. Among the epigenetic druggable targets, the positive modulation of SIRT1 has also been related to significant cardioprotective effects. Unfortunately, actual SIRT1 activators (natural products and synthetic molecules) suffer from several drawbacks, particularly poor pharmacokinetic profiles. Accordingly, in this article we present the development of an integrated screening platform aimed at identifying novel SIRT1 activators with favorable drug-like features as cardioprotective agents. Encompassing several competencies (in silico, medicinal chemistry, and pharmacology), we describe a multidisciplinary approach for rapidly identifying SIRT1 activators and their preliminary pharmacological characterization. In the first step, we virtually screened an in-house chemical library comprising synthetic molecules inspired by nature, against SIRT1 enzyme. To this end, we combined molecular docking-based approach with the estimation of relative ligand binding energy, using the crystal structure of SIRT1 enzyme in complex with resveratrol. Eleven computational hits were identified, synthesized and tested against the isolated enzyme for validating the in silico strategy. Among the tested molecules, five of them behave as SIRT1 enzyme activators. Due to the superior response in activating the enzyme and its favorable calculated physico-chemical properties, compound 8 was further characterized in ex vivo studies on isolated and perfused rat hearts submitted to ischemia/reperfusion (I/R) period. The pharmacological profile of compound 8, suggests that this molecule represents a prototypic SIRT1 activator with satisfactory drug-like profile, paving the way for developing novel epigenetic cardioprotective agents.

A Selective Competitive Inhibitor of Aldehyde Dehydrogenase 1A3 Hinders Cancer Cell Growth, Invasiveness and Stemness In Vitro.

Aldehyde dehydrogenase 1A3 (ALDH1A3) belongs to an enzymatic superfamily composed by 19 different isoforms, with a scavenger role, involved in the oxidation of a plethora of aldehydes to the respective carboxylic acids, through a NAD+-dependent reaction. Previous clinical studies highlighted the high expression of ALDH1A3 in cancer stem cells (CSCs) correlated to a higher risk of cancer relapses, chemoresistance and a poor clinical outcome. We report on the structural, biochemical, and cellular characterization of NR6, a new selective ALDH1A3 inhibitor derived from an already published ALDH non-selective inhibitor with cytotoxic activity on glioblastoma and colorectal cancer cells. Crystal structure, through X-Ray analysis, showed that NR6 binds a non-conserved tyrosine residue of ALDH1A3 which drives the selectivity towards this isoform, as supported by computational binding simulations. Moreover, NR6 shows anti-metastatic activity in wound healing and invasion assays and induces the downregulation of cancer stem cell markers. Overall, our work confirms the role of ALDH1A3 as an important target in glioblastoma and colorectal cells and propose NR6 as a promising molecule for future preclinical studies.

Aldehyde Dehydrogenases and Prostate Cancer: Shedding Light on Isoform Distribution to Reveal Druggable Target.

Prostate cancer represents the most common malignancy diagnosed in men, and is the second-leading cause of cancer death in this population. In spite of dedicated efforts, the current therapies are rarely curative, requiring the development of novel approaches based on innovative molecular targets. In this work, we validated aldehyde dehydrogenase 1A1 and 1A3 isoform expressions in different prostatic tissue-derived cell lines (normal, benign and malignant) and patient-derived primary prostate tumor epithelial cells, demonstrating their potential for therapeutic intervention using a small library of aldehyde dehydrogenase inhibitors. Compound 3b, 6-(4-fluorophenyl)-2-phenylimidazo [1,2-a]pyridine exhibited not only antiproliferative activity in the nanomolar range against the P4E6 cell line, derived from localized prostate cancer, and PC3 cell lines, derived from prostate cancer bone metastasis, but also inhibitory efficacy against PC3 colony-forming efficiency. Considering its concomitant reduced activity against normal prostate cells, 3b has the potential as a lead compound to treat prostate cancer by means of a still untapped molecular target.

Progress in the Field of Aldehyde Dehydrogenase Inhibitors: Novel Imidazo[1,2-a]pyridines against the 1A Family.

Members of the aldehyde dehydrogenase 1A family are commonly acknowledged as hallmarks of cancer stem cells, and their overexpression is significantly associated with poor prognosis in different types of malignancies. Accordingly, treatments targeting these enzymes may represent a successful strategy to fight cancer. In this work we describe a novel series of imidazo[1,2-a]pyridines, designed as aldehyde dehydrogenase inhibitors by means of a structure-based optimization of a previously developed lead. The novel compounds were evaluated in vitro for their activity and selectivity against the three isoforms of the ALDH1A family and investigated through crystallization and modeling studies for their ability to interact with the catalytic site of the 1A3 isoform. Compound 3f emerged as the first in class submicromolar competitive inhibitor of the target enzyme.