A novel Golgi mannosidase inhibitor: Molecular design,synthesis, enzyme inhibition,and inhibition of spheroid formation |
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Affiliation: | 1. Department of Chemistry, Arts and Sciences Faculty, Aksaray University, 68100, Aksaray, Turkey;2. Department of Science Education, Aksaray University, 68100, Aksaray, Turkey;3. Fırat University, Karakoçan Vocational High School, Department of Food Processing, 2360, Elazığ, Turkey;1. Laboratório de Bioquímica Microbiana, Departamento de Microbiologia Geral, IMPG, Universidade Federal do Rio de Janeiro, CEP 21949-900 Rio de Janeiro, RJ, Brazil;2. Instituto de Química de São Carlos, Universidade de São Paulo, CP 780, CEP 13560-970 São Carlos, SP, Brazil;3. Departamento de Virologia, IMPG, Universidade Federal do Rio de Janeiro, CEP 21949-900 Rio de Janeiro, RJ, Brazil;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, 11795 Helwan, Cairo, Egypt;2. Department of Chemistry, Faculty of Science, King Khalid University, 9004 Abha, Saudi Arabia;3. Department of Chemistry, Faculty of Science, Mansoura University, ET-35516 Mansoura, Egypt;4. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh 33516, Egypt;5. Drug Bioassay-Cell Culture Laboratory, Pharmacognosy Department, National Research Centre, Dokki, Giza 12622, Egypt;6. Labeled Compounds Department, Hot Labs Center, Atomic Energy Authority, P.O. Box 13759, Cairo, Egypt;7. Department of Microbiology and Immunology, Faculty of Pharmacy, Ahram Canadian University, 12451, Sixth of October City, Giza, Egypt;8. Radioactive Isotopes and Generators Department, Hot Laboratories Centre, Atomic Energy Authority, P.O. Code 13759 Cairo, Egypt;1. Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, Polo Universitario SS. Annunziata, University of Messina, Viale Palatucci 13, I-98168 Messina, Italy;2. Department of Life and Environment Sciences, University of Cagliari, I-09042 Monserrato, Cagliari, Italy;1. College of Pharmacy, College of Basic Medical Science, Dalian Medical University, Dalian 116044, PR China;2. Department of Hematology, Institute of Respiratory Diseases, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China;3. Dalian Buyun Biological Technology Co., Ltd., 116085, PR China |
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Abstract: | Effective chemotherapy for solid cancers is challenging due to a limitation in permeation that prevents anticancer drugs from reaching the center of the tumor, therefore unable to limit cancer cell growth. To circumvent this issue, we planned to apply the drugs directly at the center by first collapsing the outer structure. For this, we focused on cell–cell communication (CCC) between N-glycans and proteins at the tumor cell surface. Mature N-glycans establish CCC; however, CCC is hindered when numerous immature N-glycans are present at the cell surface. Inhibition of Golgi mannosidases (GMs) results in the transport of immature N-glycans to the cell surface. This can be employed to disrupt CCC. Here, we describe the molecular design and synthesis of an improved GM inhibitor with a non-sugar mimic scaffold that was screened from a compound library. The synthesized compounds were tested for enzyme inhibition ability and inhibition of spheroid formation using cell-based methods. Most of the compounds designed and synthesized exhibited GM inhibition at the cellular level. Of those, AR524 had higher inhibitory activity than a known GM inhibitor, kifunensine. Moreover, AR524 inhibited spheroid formation of human malignant cells at low concentration (10 µM), based on the disruption of CCC by GM inhibition. |
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Keywords: | Golgi mannosidase Non-sugar mimic inhibitor Cancer stem cell Cell-cell communication Spheroid formation ACs" },{" #name" :" keyword" ," $" :{" id" :" k0045" }," $$" :[{" #name" :" text" ," _" :" asymmetric centers EtOH" },{" #name" :" keyword" ," $" :{" id" :" k0055" }," $$" :[{" #name" :" text" ," _" :" ethanol AcOEt" },{" #name" :" keyword" ," $" :{" id" :" k0065" }," $$" :[{" #name" :" text" ," _" :" ethyl acetate CCC" },{" #name" :" keyword" ," $" :{" id" :" k0075" }," $$" :[{" #name" :" text" ," _" :" cell-cell communication ConA-AF488" },{" #name" :" keyword" ," $" :{" id" :" k0085" }," $$" :[{" #name" :" text" ," _" :" Concanavalin A conjugated with Alexa Fluor 488 diethyl ether DCM" },{" #name" :" keyword" ," $" :{" id" :" k0105" }," $$" :[{" #name" :" text" ," _" :" dichloromethane DMJ" },{" #name" :" keyword" ," $" :{" id" :" k0115" }," $$" :[{" #name" :" text" ," _" :" deoxymannojirimycin DMSO" },{" #name" :" keyword" ," $" :{" id" :" k0125" }," $$" :[{" #name" :" text" ," _" :" dimethyl sulfoxide ER" },{" #name" :" keyword" ," $" :{" id" :" k0126" }," $$" :[{" #name" :" text" ," _" :" endoplasmic reticulum FA" },{" #name" :" keyword" ," $" :{" id" :" k0135" }," $$" :[{" #name" :" text" ," _" :" fluorescence area FI" },{" #name" :" keyword" ," $" :{" id" :" k0145" }," $$" :[{" #name" :" text" ," _" :" fluorescence intensity GH" },{" #name" :" keyword" ," $" :{" id" :" k0155" }," $$" :[{" #name" :" text" ," _" :" glycoside hydrolase family GM" },{" #name" :" keyword" ," $" :{" id" :" k0165" }," $$" :[{" #name" :" text" ," _" :" Golgi mannosidase HMs" },{" #name" :" keyword" ," $" :{" id" :" k0175" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" __text__" ," _" :" high mannose type " },{" #name" :" italic" ," _" :" N-" },{" #name" :" __text__" ," _" :" glycans HBAs" },{" #name" :" keyword" ," $" :{" id" :" k0185" }," $$" :[{" #name" :" text" ," _" :" hydrogen bond acceptors, HBDs, hydrogen bond donors KIF" },{" #name" :" keyword" ," $" :{" id" :" k0195" }," $$" :[{" #name" :" text" ," _" :" kifunensine LAH" },{" #name" :" keyword" ," $" :{" id" :" k0205" }," $$" :[{" #name" :" text" ," _" :" lithium aluminum hydride ManA" },{" #name" :" keyword" ," $" :{" id" :" k0215" }," $$" :[{" #name" :" text" ," _" :" mannostatin A MeOH" },{" #name" :" keyword" ," $" :{" id" :" k0225" }," $$" :[{" #name" :" text" ," _" :" methanol MGAT-1" },{" #name" :" keyword" ," $" :{" id" :" k0226" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" __text__" ," _" :" α-1,3-mannosyl-glycoprotein 2-β-" },{" #name" :" italic" ," _" :" N" },{" #name" :" __text__" ," _" :" -acetylglucosaminyltransferase MW" },{" #name" :" keyword" ," $" :{" id" :" k0235" }," $$" :[{" #name" :" text" ," _" :" molecular weight NBP" },{" #name" :" keyword" ," $" :{" id" :" k0245" }," $$" :[{" #name" :" text" ," _" :" non-subsite bonding pocket PBS" },{" #name" :" keyword" ," $" :{" id" :" k0255" }," $$" :[{" #name" :" text" ," _" :" phosphate-buffered saline SAR" },{" #name" :" keyword" ," $" :{" id" :" k0265" }," $$" :[{" #name" :" text" ," _" :" structure-activity relationship SWA" },{" #name" :" keyword" ," $" :{" id" :" k0275" }," $$" :[{" #name" :" text" ," _" :" swainsonine THF" },{" #name" :" keyword" ," $" :{" id" :" k0285" }," $$" :[{" #name" :" text" ," _" :" tetrahydrofuran tPSA" },{" #name" :" keyword" ," $" :{" id" :" k0295" }," $$" :[{" #name" :" text" ," _" :" topological polar surface area |
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