Itaconimides derivatives induce relaxation in mesenteric artery and negative inotropism by inhibition of CA2+ influx.

BACKGROUND: The aim of this study was to evaluate the cardiovascular effects of N-phenyl-itaconimide (Imide-1), N-4-methyl-phenyl-itaconimide (Imide-2), N-4-methoxy-phenyl-itaconimide (Imide-3) and N-4-chloro-phenyl-itaconimide (Imide-4), and investigate the mechanisms of action involved in the observed responses. METHODS: The relaxant effect was investigated in rat superior mesenteric arteries by using isometric tension measurements. Additionally, in isolated atria were evaluated the heart rate and force of cardiac contraction and in vivo experiments was evaluated blood pressure and heart rate. RESULTS: Cumulative administration of itaconimides (3 × 10-8 to 3 × 10-4 M) in pre-contracted mesenteric artery rings with phenylephrine, 1 µM, induced endothelium-independent vasorelaxation. The itaconimides showed similar maximum efficacies. Additionally, Imide-3 induced vasorelaxation in rings exposed to a depolarizing-tyrode solution containing 60 mM KCl or 20 mM KCl similar to the control, suggesting the non-participation of K+ channels. Imide-3 attenuated Ca2+ influx in a concentration-dependent manner. As well, imide-3 reduced CaCl2-induced contraction in nominally calcium-free medium, in the presence of cyclopiazonic acid (20 µM), phenylephrine (1 µM) and nifedipine (1 µM), indicating a reduction of Ca2+ influx by receptor-operated channels (ROC) and store-operated channels (SOC). The presence of SKF 96365 (10-5 M), SOC blocker, did not significantly alter the vasorelaxant effect induced by imide-3. Moreover, imide-3 induced a negative inotropic effect. In vivo studies, in non-anesthetized normotensive rats, imide-3 lowered blood pressure and induced bradycardia. CONCLUSIONS: These results suggest that itaconimides have concentration-dependent vascular effects and the vasorelaxation seems to be endothelium-independent. The vasodilatory effect induced by imide-3 may be due to a possible influence on the CaV and ROC. In addition, imide-3 is able to reduce force of cardiac contraction, blood pressure and promote bradycardia.

Biological and Toxicological Evaluation of N-(4methyl-phenyl)-4-methylphthalimide on Bone Cancer in Mice.

BACKGROUND: It was recently demonstrated that the phthalimide N-(4-methyl-phenyl)-4- methylphthalimide (MPMPH-1) has important effects against acute and chronic pain in mice, with a mechanism of action correlated to adenylyl cyclase inhibition. Furthermore, it was also demonstrated that phthalimide derivatives presented antiproliferative and anti-tumor effects. Considering the literature data, the present study evaluated the effects of MPMPH-1 on breast cancer bone metastasis and correlated painful symptom, and provided additional toxicological information about the compound and its possible metabolites. METHODS: In silico toxicological analysis was supported by in vitro and in vivo experiments to demonstrate the anti-tumor and anti-hypersensitivity effects of the compound. RESULTS: The data obtained with the in silico toxicological analysis demonstrated that MPMPH-1 has mutagenic potential, with a low to moderate level of confidence. The mutagenicity potential was in vivo confirmed by micronucleus assay. MPMPH-1 treatments in the breast cancer bone metastasis model were able to prevent the osteoclastic resorption of bone matrix. Regarding cartilage, degradation was considerably reduced within the zoledronic acid group, while in MPMPH-1, chondrocyte multiplication was observed in random areas, suggesting bone regeneration. Additionally, the repeated treatment of mice with MPMPH-1 (10 mg/kg, i.p.), once a day for up to 36 days, significantly reduces the hypersensitivity in animals with breast cancer bone metastasis. CONCLUSION: Together, the data herein obtained show that MPMPH-1 is relatively safe, and significantly control the cancer growth, allied to the reduction in bone reabsorption and stimulation of bone and cartilage regeneration. MPMPH-1 effects may be linked, at least in part, to the ability of the compound to interfere with adenylylcyclase pathway activation.

Anti-hypersensitivity effects of the phthalimide derivative N-(4methyl-phenyl)-4-methylphthalimide in different pain models in mice.

The treatment of chronic pain remains a challenge for clinicians worldwide, independent of its pathogenesis. It motivates several studies attempting to discover strategies to treat the disease. The in silico analysis using molecular docking approach demonstrated that the phthalimide N-(4methyl-phenyl)-4-methylphthalimide (MPMPH-1) presented high affinity to adenylyl-cyclase enzyme (AC). It also prominently reduced the mechanical hypersensitivity of mice challenged by Forskolin, an AC activator. This effect lasted for up to 48h after Forskolin injection, presenting activity longer than MDL-12330A (AC inhibitor). MPMPH-1 was also effective in reducing the hypersensitivity induced by IL-1ß, bradykinin, prostaglandin E2 or epinephrine, chemical mediators that have, among others, AC as pivotal protein in their signalling cascade to induce mechanical-pain behaviour. The compound presented marked inhibition in inflammatory-pain models induced by carrageenan, lipopolysaccharide or complete Freund's adjuvant, including neutrophil migration inhibition. Furthermore, it also seems to act in both peripheral and pain central-control pathways, being also effective in reducing the persistent cancer-pain behaviour induced by melanoma cells in mice. MPMPH-1 could represent a promising pharmacological tool to treat acute and chronic painful diseases, with good bioavailability, local activity, and lack of locomotor-activity interference. Further studies are necessary to determine the exact mechanism of action but it seems to involve AC enzyme as possible target.

Antiproliferative effect of synthetic cyclic imides (methylphtalimides, carboxylic acid phtalimides and itaconimides) against human cancer cell lines.

This work describes the antiproliferative potential of 14 cyclic imides (methylphtalimides, carboxylic acid phtalimides and itaconimides) against several human cancer cell lines. The antiproliferative effect was evaluated using the sulforhodamine B assay. Although some compounds from methylphtalimide and carboxylic acid phtalimide classes exhibited a selective antiproliferative activity, the itaconimides (11-14) exhibited the best results, especially compound 14, which presented a TGI (concentration that produces total growth inhibition) value of 0.0043 µM against glioma (U251), being inactive against the non-tumor cell line (HaCat). Absorption, distribution, metabolism and excretion in silico evaluations suggest that these compounds are promising candidates.

Synthesis of Cyclic Imides (Methylphtalimides, Carboxylic Acid Phtalimides and Itaconimides) and Evaluation of their Antifungal Potential.

BACKGROUND: This paper describes the synthesis of three different subfamilies of cyclic imides: methylphtalimides, carboxyl acid phtalimides and itaconimides. METHODS: Fifteen compounds (five of each sub-family) were obtained by the reaction of appropriated anhydrides and different aromatic amines, using the manual Topliss method. Their structures were confirmed by spectral data (IR and NMR). The antifungal activity of the synthesized compounds was investigated by broth microdilution to determine the minimal inhibitory concentration (MIC). The ability to inhibit the biofilm formation or destroy mature Candida albicans biofilm was also evaluated for the most active substances. RESULTS: The results indicated that only the itaconimides 11-15 exhibited potent and promising antifungal properties, with MIC100 between 1 and 64 µg mL-1, being several times more potent than the reference drug, Fluconazole. Compounds 11-15 inhibited between 64% and 95% of biofilm formation, and destroyed between 78% and 99% of mature biofilm at a concentration of 64 µg mL-1. ADME (absorption, distribution, metabolism and excretion) in silico evaluations were carried out to predict whether the molecules under study are good drug candidates. CONCLUSIONS: Itaconimides appear to be promising and relevant as tools for the future development of new and effective medicinal agents to treat fungal diseases.