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Chromone-based monoamine oxidase B inhibitor with potential iron-chelating activity for the treatment of Alzheimer's disease.

ABSTRACT: Based on the multitarget-directed ligands (MTDLs) strategy, a series of chromone-hydroxypyridinone hybrids were designed, synthesised, and evaluated as potential multimodal anti-AD ligands. Prospective iron-chelating effects and favourable monoamine oxidase B (MAO-B) inhibitory activities were observed for most of the compounds. Pharmacological assays led to the identification of compound 17d, which exhibited favourable iron-chelating potential (pFe³⁺ = 18.52) and selective hMAO-B inhibitory activity (IC₅₀ = 67.02 ± 4.3 nM, SI = 11). Docking simulation showed that 17d occupied both the substrate and the entrance cavity of MAO-B, and established several key interactions with the pocket residues. Moreover, 17d was determined to cross the blood-brain barrier (BBB), and can significantly ameliorate scopolamine-induced cognitive impairment in AD mice. Despite its undesired pharmacokinetic property, 17d remains a promising multifaceted agent that is worth further investigation.

SUBMITTER: Zhang C

PROVIDER: S-EPMC9762789 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Chromone-based monoamine oxidase B inhibitor with potential iron-chelating activity for the treatment of Alzheimer's disease.

Zhang Changjun C Zhang Yujia Y Lv Yangjing Y Guo Jianan J Gao Bianbian B Lu Yi Y Zang Anjie A Zhu Xi X Zhou Tao T Xie Yuanyuan Y

Journal of enzyme inhibition and medicinal chemistry 20231201 1

Based on the multitarget-directed ligands (MTDLs) strategy, a series of chromone-hydroxypyridinone hybrids were designed, synthesised, and evaluated as potential multimodal anti-AD ligands. Prospective iron-chelating effects and favourable monoamine oxidase B (MAO-B) inhibitory activities were observed for most of the compounds. Pharmacological assays led to the identification of compound 17d, which exhibited favourable iron-chelating potential (pFe3+ = 18.52) and selective ...[more]

PMID: 36519319

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Project description:BACKGROUND:Monoamine oxidase (MAO) A catalyzes oxidative deamination of monoamine neurotransmitters and dietary amines and regulates brain development and functions. Recently, we showed that MAO A mediates the progression and migration of glioma and MAO A inhibitors reduce glioma cell growth. Glioblastoma (GBM) is a common and most malignant brain tumor which is difficult to treat. Temozolomide (TMZ) is the current standard chemotherapy for glioma, but tumors usually become resistant and recur. So far, no effective therapy for TMZ-resistant glioma is available. Natural plant antimicrobial solution (PAMs) is a Chinese herbal medicine which has been used for decades without toxicity and has multiple medical functions including anti- inflammatory effects. Here, we report the effects of PAMs on glioblastoma growth. METHODS:The growth of TMZ -sensitive (U251S),-resistant (U251R) human glioma cells, and mouse glioma cell line GL-26 were assessed by MTS colorimetric assay, colony formation, and cell migration assays. Male C57BL/6 mice were implanted subcutaneously or intracranial with luciferase-positive mouse glioma GL-26 cells and treated with vehicle; MAO A inhibitor clorgyline (10?mg/kg); TMZ (1?mg/kg); PAMs (48?mg/kg) alone or in combination with TMZ (1?mg/kg) for 14?days. At the end of the treatment, mice were sacrificed, MAO A catalytic activity in tumors was measured, and tumor sizes were determined by imaging and weight. RESULTS:These results show that PAMs inhibits MAO A catalytic activity in all three glioma cell lines studied U251S, U251R, and GL-26. PAMs reduced glioma growth and has greater effects in combination with low dose of TMZ than PAMS or TMZ alone in all three cell lines as shown by MTS, colony formation, and cell migration assays. Using the subcutaneous or intracranial GL-26 glioma mouse model, PAMs reduced the tumor growth and MAO A activity, similar to the MAO A inhibitor clorgyline. Combining PAMs with non-toxic dose TMZ increased survival to a greater extent than those of PAMs or TMZ alone. CONCLUSIONS:This is the first study which suggests that PAMs alone or co-administration with low doses of TMZ may be a potential adjuvant to reduce the toxicity of TMZ and to abrogate drug resistance for the effective treatment of glioma.

Project description:BackgroundHigh expression of monoamine oxidase A (MAOA) in non-small cell lung cancer (NSCLC) is related to epithelial-mesenchymal transition (EMT) and the development of clinicopathological features of NSCLC. Nevertheless, the role of MAOA in drug resistance still remains unclear. Hence, the aim of this article was to evaluate a previously synthesized MAOA inhibitor (G11) on inhibiting paclitaxel-resistant NSCLC metastasis and growth.MethodsFirst, MAOA expression level was evaluated in several NSCLC cell lines. An MTT assay was used to validate the inhibitory effect of G11 on NSCLC cells in vitro. Second, gene expression in G11-treated H460/PTX cells was analyzed by microarray gene expression. Third, transwell assay was performed to assess the invasion and metastasis of G11-treated A549/PTX and H460/PTX cells and western blot assay used to analyze vital protein expression level in G11-treated H460/PTX cells. Finally, the antimetastatic effect of G11 was tested in an NSCLC in vivo model.ResultsOur data revealed that G11 significantly inhibited the viability of paclitaxel (PTX)-resistant NSCLC cell lines (A549/PTX and H460/PTX). G11 dramatically reduced the expression of MAOA in A549/PTX and H460/PTX cells, which exhibited relatively high MAOA expression levels. Additionally, G11 was found to hinder A549/PTX and H460/PTX cell migration and invasion. Furthermore, the in vivo study indicated that the coadministration of G11 and paclitaxel significantly suppressed tumor metastasis in H460/PTX lung metastasis models.ConclusionsThese findings indicated G11 showed a moderate inhibitory effect on paclitaxel-resistant NSCLC metastasis and growth, and support further investigation on MAOA potentially as a promising therapeutic target for paclitaxel-resistant NSCLC treatment.Key pointsSIGNIFICANT FINDINGS OF THE STUDY: Inhibition of MAOA might contribute to the suppression of metastasis and growth in PTX-resistant NSCLC cells. What this study adds This study explored the potential function of MAOA in drug-resistant NSCLC and might consider MAOA as a promising target for the treatment of drug-resistant NSCLC.

Project description:PurposeMonoamine oxidase A (MAOA) influences prostate cancer growth and metastasis in pre-clinical models. We examined effects of phenelzine (a monoamine oxidase inhibitor) in patients with biochemical recurrent castrate-sensitive prostate cancer.Materials and methodsAn open-label single arm clinical trial enrolled subjects with biochemical recurrent prostate cancer defined by PSA ≥ 0.4 ng/ml (post prostatectomy) or PSA ≥ 2 ng/ml above nadir (post-radiation therapy); no evidence of metastasis on imaging; and normal androgen levels. Subjects received phenelzine 30 mg orally twice daily. Mood symptoms were assessed with the hospital anxiety depression score (HADS) questionnaire. The primary endpoint was the proportion of patients who achieved a PSA decline of ≥50% from baseline.ResultsCharacteristics of the 20 eligible patients enrolled included: mean ± SD age 66.9 ± 4.8 years and PSA 4.7 ± 5.8 ng/dl. Maximal PSA declines ≥30% and ≥50% were observed in 25% (n = 5/20) and 10% (n = 2/20) of subjects, respectively. At 12 weeks, 17 subjects remained on treatment with PSA declines ≥30% and ≥50% of 24% (n = 4/17) and 6% (n = 1/17), respectively. Common toxicities observed included dizziness (grade 1 = 45%, grade 2 = 35%), hypertension (grade ≥ 2 = 30%), and edema (grade 1 = 25%, grade 2 = 10%). There was one episode of grade 4 hypertension (cycle 4) and two episodes of grade 3 syncope (cycle 12 and cycle 14) requiring treatment discontinuation. HADS questionnaires demonstrated a significant decrease in anxiety with no change in depressive symptoms on treatment.ConclusionsPhenelzine demonstrated efficacy in patients with biochemical recurrent castrate-sensitive prostate cancer. Most treatment-related toxicities were mild, but rare significant and reversible cardiovascular toxicities were observed. Therapies directed at MAOA may represent a new avenue for treatment in patients with recurrent prostate cancer.

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Chromone-based monoamine oxidase B inhibitor with potential iron-chelating activity for the treatment of Alzheimer's disease.

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Chromone-based monoamine oxidase B inhibitor with potential iron-chelating activity for the treatment of Alzheimer's disease.

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