Furan-conjugated tripeptides as potent antitumor drugs
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MDPI AG
Abstract
Cervical cancer is among the leading causes of death in women. Chemotherapy options available for cervical cancer include highly cytotoxic drugs such as taxol, cisplatin, 5-florouracil, and doxorubicin, which are not specific. In the current study, we have identified a new peptide conjugate (Fur4-2-Nal3-Ala2-Phe1-CONH2) (conjugate 4), from screening of a small library of tripeptide-conjugates of furan, as highly potent anticancer compound against human cervical cancer cells (HeLa cells) (IC50 = 0.15 ± 0.05 µg/mL or 0.28 +/− 0.09 µM). Peptides were constructed on Rink amide resin from C-to N-terminus followed by capping by α-furoic acid moiety. The synthesized peptides were purified by recycling RP-HPLC, and structures of all the peptides were confirmed by using FABMS/ESIMS,1H-NMR,13C-NMR, and HR-FABMS. Conjugate 4 was furthermore found to be specifically active against human cervical cancer cells since it did not inhibit the proliferation of other human normal cells (HUVEC (human umbilical vein endothelial cells) and IMR-90 (normal human fibroblasts)), and cancer cells tested (HUVEC, MCF-7, and MDA-MB-231 cells), as well as in mice 3T3 cells (normal fibroblasts). This study revealed a good structure activity relationship of various peptide conjugates. Conjugate 4 in branched forms (4a and 4b) were also synthesized and evaluated against HeLa cells, and results revealed that both were inactive. Atomic force microscopy (AFM) studies and staining with rhodamine 123 and propidium iodide (PI) revealed that conjugate 4 possesses a membranolytic effect and causes the loss of mitochondrial membrane potential. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
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Anticancer, Furan-based tripeptides, Hela cell line, Heterocycles, Peptide conjugates, Rink amide resin, 3t3 cells, Amides, Animals, Antineoplastic agents, Apoptosis, Cell line, tumor, Cell proliferation, Cell survival, Doxorubicin, Drug screening assays, antitumor, Endothelial cells, Female, Furans, Hela cells, Human umbilical vein endothelial cells, Humans, Inhibitory concentration 50, Magnetic resonance spectroscopy, Mcf-7 cells, Mice, Microscopy, atomic force, Peptides, Protein domains, Uterine cervical neoplasms, 2 furoic acid, Antineoplastic agent, Furan, Propidium iodide, Resin, Rhodamine 123, Tripeptide derivative, Trypsin, Amide, Furan derivative, Peptide, Amino acid sequence, Amino terminal sequence, Antibacterial activity, Antineoplastic activity, Antiproliferative activity, Article, Atomic force microscopy, Biotransformation, Carbon nuclear magnetic resonance, Cell membrane, Cell viability, Circular dichroism, Colorimetry, Conjugate, Controlled study, Drug synthesis, Electrospray mass spectrometry, Elemental analysis, Fast atom bombardment mass spectrometry, Growth inhibition, High performance liquid chromatography, Huvec cell line, Ic50, Infrared spectroscopy, Mass spectrometry, Mcf-7 cell line, Mda-mb-231 cell line, Mitochondrial membrane potential, Mtt assay, Photon correlation spectroscopy, Proton nuclear magnetic resonance, Resazurin assay, Reversed phase high performance liquid chromatography, Screening, Structure activity relation, Ultra performance liquid chromatography, Umbilical vein endothelial cell, X ray diffraction, 3t3 cell line, Animal, Chemistry, Drug effect, Drug screening, Endothelium cell, Human, Mouse, Nuclear magnetic resonance spectroscopy, Protein domain, Tumor cell line, Uterine cervix tumor