Reem Aljanabi

Lung cancer is one of the most common causes of cancer-related deaths worldwide. Monoamine Oxidase-A (MAO-A) enzyme mediates the production of reactive oxygen species (ROS) that trigger DNA damage and oxidative injury of cells resulting in tumor initiation and progression. Available MAO-A inhibitors are used as antidepressants, however, their role as anticancer agents is still under investigation. Ligand- and structure-based drug design approaches guided the discovery and development of novel MAO-A inhibitors. A series of 1H indole-2-carboxamide derivatives was prepared and characterized using 1H-NMR, 13C-NMR, and IR. The antiproliferative effects of MAO-A inhibitors were evaluated using the cell viability assay (MTT), and MAO-A activity was evaluated using MAO-A activity assay. The presumed inhibitors significantly inhibited the growth of lung cell lines in a dose- and time dependent manner. The half maximal inhibitory concentration (IC₅₀) values of MAO-A inhibitors (S1, S2, S4, S7, and S10) were 33.37, 146.1, 208.99, 307.7, and 147.2 µM, respectively, in A549. Glide docking against MAO-A showed that the derivatives accommodate MAO-A binding cleft and engage with key binding residues. MAO-A inhibitors provide significant and consistent evidence on MAO-A activity in lung cancer and present a potential target for the development of new chemotherapeutic agents.

Monoamine oxidases (MAOs) are oxidative enzymes that catalyze the conversion of biogenic amines into their corresponding aldehydes and ketones through oxidative deamination. Owing to the crucial role of MAOs in maintaining functional levels of neurotransmitters, the implications of its distorted activity have been associated with numerous neurological diseases. Recently, an unanticipated role of MAOs in tumor progression and metastasis has been reported. The chemical inhibition of MAOs might be a valuable therapeutic approach for cancer treatment. In this review, we reported computational approaches exploited in the design and development of selective MAO inhibitors accompanied by their biological activities. Additionally, we generated a pharmacophore model for MAO-A active inhibitors to identify the structural motifs to invoke an activity.

MAOs are isoenzymes that occur in two isoforms Monoamine oxidases A and B. They are flavoproteins found in mitochondria and their role is to catalyze the oxidative deamination of monoamine neurotransmitters to their corresponding aldehydes. Both MAOs play a major role in the human body as they contribute to many illnesses. MAO plays an essential role in both peripheral; and central nervous system through affecting the levels of MAO neurotransmitters. MAO-A is generally concentrated in dopaminergic and norepinephrinergic neurons. Contrary to MAO-B, which is predominantly concentrated in serotoninergic neurons. By-product of MAOs which are aldehyde, ammonia, and H2O2 (which is considered reactive oxygen species) that is toxic at high concentration or it may lead to the generation of free Radicals. Free radicals considered as a starting signal in the generation of cancers. Also, MAO inhibition showed to decrease pressure overload and heart failure. This action is mainly related to the prevention of oxidative stress mainly (H2O2) apoptosis in cardiac muscle and improved bioavailability of Norepinephrine. MAO-A plays a totally different role from MAO—B in renal carcinoma. Ranging from Alzheimer disease, depression to cardiac myopathy, diabetes, kidney diseases, and cancers, MAO-A participates differently from MAO-B in these diseases. Therefore it is necessary to study their separate effect in human diseases and the consequences of their inhibition. In this review, we compare between MAO-A and MAO-B effect from many aspects that includes heart failure, renal carcinoma, breast cancer, esophageal cancer, prostate cancer, bladder cancer, glioma and diabetes. And finally, the role of MAO inhibitors and their effects also have been discussed.