Novel Structural Insight into Inhibitors of Heme Oxygenase-1 (HO-1) by New Imidazole-Based Compounds: Biochemical and In Vitro Anticancer Activity Evaluation

Abstract

In this paper, the design, synthesis, and molecular modeling of a new azole-based HO-1 inhibitors was reported, using compound 1 as a lead compound, in which an imidazole moiety is linked to a hydrophobic group by means of an ethanolic spacer. The tested compounds showed a good inhibitor activity and possessed IC50 values in the micromolar range. These results were obtained by targeting the hydrophobic western region. Molecular modeling studies confirmed a consolidated binding mode in which the nitrogen of the imidazolyl moiety coordinated the heme ferrous iron, meanwhile the hydrophobic groups were located in the western region of HO-1 binding pocket. Moreover, the new compounds were screened for in silico ADME-Tox properties to predict drug-like behavior with convincing results. Finally, the in vitro antitumor activity profile of compound 1 was investigated in different cancer cell lines and nanomicellar formulation was synthesized with the aim of improving compound’s 1 water solubility. Finally, compound 1 was tested in melanoma cells in combination with doxorubicin showing interesting synergic activity.

Cannabidiol Protects Dopaminergic Neurons in Mesencephalic Cultures against the Complex I Inhibitor Rotenone Via Modulation of Heme Oxygenase Activity and Bilirubin

“…Many tumor types benefit from upregulated HO-1, and a subsequently increased formation of CO or BR. Therefore, newly designed drugs capable of inhibiting HO activity in-vivo yielded promising results [78][79][80][81]. Interestingly, CBs have been shown to exert distinct antitumor effects (for review, see [82]).…”

Iron Metabolism in Cancer Progression

“…Recently, numerous imidazole-based non-porphyrin HO-1 inhibitors were developed. These compounds possess a high selectivity and specificity toward HO-1 and their effective antitumor activity has been demonstrated in vitro and in vivo [76]. On the contrary, notwithstanding in some cases chemo-or radio-therapy contribute to the increase of HO-1 expression, tumor cells expressing high levels of HO-1 are less sensitive to treatment with doxorubicin, cisplatin or gemcitabine in urothelial cancers, cholangiocarcinoma, pancreatic and lung cancer cells [77,78].…”

FABP4 inhibitors 3D-QSAR model and isosteric replacement of BMS309403 datasets

“…CAMD (computer aided molecular design) shows a promising and effective tool for the identification of FABP4 inhibitors [12] , [13] , [14] , [15] . In line with our recent interest in the development of QSAR models and related applications [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , in order to identify novel hit compounds, herein we report the dataset and the parameter used to build a 3D-QSAR model for FABP4. This dataset is reported in Tables 2 and 3 , were the molecules used in the training set (96) and in the test set (24) are reported, respectively.…”