Discovery of a novel quinoxalinhydrazide with a broad-spectrum anticancer activity

Previously, we discovered a novel class of salicylhydrazide compounds with remarkable activity in hormone-dependent and -independent human cancer cells. We then designed and synthesized numerous analogues. Among these analogues, a quinoxalinhydrazide compound, SC144, exhibited desirable physicochemical and drug-like properties and therefore was selected for further preclinical investigation. In the present study, we evaluated the in vitro activity of SC144 in a range of drug-sensitive and -resistant cancer cell lines as well as its in vivo efficacy in MDA-MB-435 and HT29 mice xenograft models. The broad-spectrum cytotoxicity of SC144 is especially highlighted by its potency in ovarian cancer cells resistant to cisplatin, breast-cancer cells resistant to doxorubicin, and colon cancer cells resistant to oxaliplatin. Furthermore, its activity was independent of p53, HER-2, estrogen and androgen receptor expressions. We also examined the effect of SC144 on cell cycle progression and apoptosis in select cell lines. Considering its cytotoxicity profile in a variety of in vitro and in vivo cancer models as well as its effects on cell cycle regulation and apoptosis, SC144 appears to represent a promising agent for further clinical development

Carbazoles: Role and Functions in Fighting Diabetes

Carbazole derivatives have gained a lot of attention in medicinal chemistry over the last few decades due to their wide range of biological and pharmacological properties, including antibacterial, antitumor, antioxidant, and anti-inflammatory activities. The therapeutic potential of natural, semi-synthetic or synthetic carbazole-containing molecules has expanded considerably owing to their role in the pathogenesis and development of diabetes. Several studies have demonstrated the ability of carbazole derivatives to reduce oxidative stress, block adrenergic hyperactivation, prevent damage to pancreatic cells and modulate carbohydrate metabolism. In this survey, we summarize the latest advances in the synthetic and natural carbazole-containing compounds involved in diabetes pathways

Quercetin derivatives as novel antihypertensive agents: Synthesis and physiological characterization

The antihypertensive flavonol quercetin (Q1) is endowedwith a cardioprotective effect againstmyocardial ischemic damage. Q1 inhibits angiotensin converting enzymeactivity, improves vascular relaxation, and decreases oxidative stress and gene expression. However, the clinical application of this flavonol is limited by its poor bioavailability and low stability in aqueous medium. In the aimto overcome these drawbacks and preserve the cardioprotective effects of quercetin, the present study reports on the preparation of five different Q1 analogs, in which all OH groups were replaced by hydrophobic functional moieties. Q1 derivatives have been synthesized by optimizing previously reported procedures and analyzed by spectroscopic analysis. The cardiovascular properties of the obtained compounds were also investigated in order to evaluate whether chemical modification affects their biological efficacy. The interaction with β-adrenergic receptors was evaluated by molecular docking and the cardiovascular efficacy was investigated on the ex vivo Langendorff perfused rat heart. Furthermore, the bioavailability and the antihypertensive properties of the most active derivative were evaluated by in vitro studies and in vivo administration (1month) on spontaneously hypertensive rats (SHRs), respectively. Among all studied Q1 derivatives, only the ethyl derivative reduced left ventricular pressure (at 10−8M÷10−6Mdoses) and improved relaxation and coronary dilation. NOSs inhibition by L-NAME abolished inotropism, lusitropism and coronary effects. Chronic administration of high doses of this compound on SHR reduced systolic and diastolic pressure. Differently, the acetyl derivative induced negative inotropism and lusitropism (at 10−10M and 10−8 ÷ 10−6 M doses), without affecting coronary pressure. Accordingly, docking studies suggested that these compounds bind both β1/β2-adrenergic receptors. Taking into consideration all the obtained results, the replacement of OHwith ethyl groups seems to improve Q1 bioavailability and stability; therefore, the ethyl derivative could represent a good candidate for clinical use in hypertension

Identification of novel 2-(1H-Indol-1-yl)benzohydrazides CXCR4 ligands impairing breast cancer growth and motility

Stromal-derived-factor-1 (SDF-1) and the G-protein-coupled receptor CXCR4 are involved in several physiological and pathological processes including breast cancer spread and progression. Several CXCR4 antagonists have currently reached advanced development stages as potential therapeutic agents for different diseases. Results: A small series of novel CXCR4 ligands, based on a 2-(1H-indol-1-yl)-benzohydrazide scaffold, has been designed and synthesized. The interaction with CXCR4-active site was predicted by molecular docking and confirmed by whole cell-based [125I]-SDF-1 ligand competition binding assays. One of the synthesized compounds was particularly active in blocking SDF-1-induced breast cancer cell motility, proliferation and downstream signaling activation in different breast cancer cell models and coculture systems. Conclusion: The newly synthesized compounds represent suitable leads for the development of innovative therapeutic agents targeting CXCR

Synthesis and biological evaluation of polyheterocyclic derivatives endowed with antiviral or anticancer activity

Dottorato di Ricerca in Metodologie per lo Sviluppo di Molecole di Interesse Farmacologico, Ciclo XIX, a.a. 2005-2006Università degli Studi della Calabri

Active manganese dioxide promoted cyclization of ortho-(1H-pyrrol-1-yl)aryl and heteroaryl carboxylic acids to 5H-pyrrolo[1,2-a][3,1]benzoxazin-5-one derivatives

The hitherto unknown lactone 5H-pyrrolo[1,2-a][3,1]benzoxazin-5-one and six of its substituted derivatives have been prepared by active manganese dioxide promoted oxidative cyclization of the corresponding ortho-(1H-pyrrol-1-yl)benzoic acids, under mild conditions, in moderate yields

ChemInform Abstract: Active Manganese Dioxide Promoted Cyclization of ortho-(1H-Pyrrol-1-yl)aryl and Heteroaryl Carboxylic Acids to 5H-Pyrrolo[1,2-a][3,1]benzoxazin-5-one Derivatives.

The hitherto unknown lactone 5H-pyrrolo[1,2-a][3,1]benzoxazin-5-one and six of its substituted derivatives have been prepared by active manganese dioxide promoted oxidative cyclization of the corresponding ortho-(1H-pyrrol-1-yl)benzoic acids, under mild conditions, in moderate yields

Napthoxazepine Inhibitors of HIV-1 Integrase: Synthesis and Biological Evaluation

HIV-1 integrase is an important target for the identification of novel antiretroviral compounds potentially active against HIV-1 replication. Previously, we discovered several novel thiazolothiazepine derivatives as IN inhibitors with antiviral activity on cell-based assays. Due to their low cytotoxicity, low molecular weight, drug-like properties, and structural novelty, we embarked on a study to optimize the original lead compounds

Photodegradation of Anti-Inflammatory Drugs: Stability Tests and Lipid Nanocarriers for Their Photoprotection

The present paper provides an updated overview of the methodologies applied in photodegradation studies of non-steroidal anti-inflammatory drugs. Photostability tests, performed according to international standards, have clearly demonstrated the photolability of many drugs belonging to this class, observed during the preparation of commercial forms, administration or when dispersed in the environment. The photodegradation profile of these drugs is usually monitored by spectrophotometric or chromatographic techniques and in many studies the analytical data are processed by chemometric procedures. The application of multivariate analysis in the resolution of often-complex data sets makes it possible to estimate the pure spectra of the species involved in the degradation process and their concentration profiles. Given the wide use of these drugs, several pharmaceutical formulations have been investigated to improve their photostability in solution or gel, as well as the pharmacokinetic profile. The use of lipid nanocarriers as liposomes, niosomes or solid lipid nanoparticles has demonstrated to both minimize photodegradation and improve the controlled release of the entrapped drugs

Promising Perspectives of the Antiproliferative GPER Inverse Agonist ERα17p in Breast Cancer

The estrogen receptor α (ERα) corresponds to a large platform in charge of the recruitment of a panel of molecules, including steroids and related heterocyclic derivatives, oligonucleotides, peptides and proteins. Its 295–311 region is particularly targeted by post-translational modifications, suggesting that it could be crucial for the control of transcription. In addition to anionic phospholipids, the ERα 295–311 fragment interacts with Ca2+-calmodulin, the heat shock protein 70 (Hsp70), ERα and possibly importins. More recently, we have demonstrated that it is prone to interacting with the G-protein-coupled estrogen receptor (GPER). In light of these observations, the pharmacological profile of the corresponding peptide, namely ERα17p, has been explored in breast cancer cells. Remarkably, it exerts apoptosis through GPER and induces a significant decrease (more than 50%) of the size of triple-negative breast tumor xenografts in mice. Herein, we highlight not only the promising therapeutic perspectives in the use of the first peptidic GPER modulator ERα17p, but also the opportunity to modulate GPER for clinical purposes