Minjae Jun , Veena Vijayan , Seungheon Shin , Ho Yeon Nam , Dasom Song , Jieun Choi , Shyam Vasvani , Steve K. Cho , In-Kyu Park , Jiwon Seo
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引用次数: 0
Abstract
Bleomycin (BLM) is a natural product with established anticancer activity, attributed to its ability to cleave intracellular DNA. BLM complexes with iron (BLM-Fe3+) exhibit peroxidase-like activity, generate reactive oxygen species (ROS), and cause DNA cleavage. Inspired by the mechanism of BLM, we synthesized a novel conjugate of manganese tetraphenylporphyrin (MnTPP) with a biomimetic peptoid (i.e., oligo-N-substituted glycines); this conjugate harnesses the oxidative capabilities of manganese porphyrins combined with the cell-penetrating ability of a previously reported mitochondria-targeting peptoid (MTP). UV–vis spectroscopy showed the formation of Mn(V)-oxo porphyrin, a potent oxidative species, in the presence of hydrogen peroxide, simulating metallobleomycin reactivity. Biological assays demonstrated that MnTPP-MTP significantly boosted ROS production and induced cytotoxicity toward cancer cells, while sparing normal fibroblasts. Tetramethylrhodamine ethyl ester (TMRE) assay revealed reversible, dose-dependent impairment of the mitochondrial membrane potential by MnTPP-MTP treatment. DNA cleavage assays showed that MnTPP-MTP, specifically in the presence of hydrogen peroxide, could elicit substantial DNA damage, in a similar way to BLM. In vivo studies using liposome-encapsulated MnTPP-MTP (lipo-peptoid) indicated superior tumor suppression, without systemic toxicity, when administered locally. Immunofluorescence staining for Ki67 and TUNEL confirmed reduced cell proliferation and increased apoptosis, respectively, validating the anticancer efficacy of lipo-peptoid. These results suggest that MnTPP-MTP, particularly in a liposomal formulation, is a promising new chemotherapeutic agent with robust oxidative mechanisms, poised for further development and application against diverse cancers.
期刊介绍:
Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides.
The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.