{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T19:25:07Z","timestamp":1787081107211,"version":"build-2736575974"},"reference-count":43,"publisher":"American Chemical Society (ACS)","issue":"28","license":[{"start":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T00:00:00Z","timestamp":1752192000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004586","name":"Funda??o Carlos Chagas Filho de Amparo ? Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Type 2 diabetes mellitus is a multifactorial disease associated with insulin resistance and pancreatic \u03b2-cell dysfunction. Interestingly, this disease has also been associated with the aggregation of islet amyloid polypeptide (IAPP or amylin). This peptide can bind to physiological metal ions such as copper\u00ad(II), which enhances its aggregation and induces oxidative stress. For this reason, the use of moderate chelators constitutes a compelling potential therapeutic strategy. In this work, we synthesized and characterized the geometric isomers of a new compound, 1-methylimidazole-2-carboxaldehyde nicotinoyl hydrazone (X1NIC), aiming to evaluate their differential interactions with copper\u00ad(II) and the hIAPP18\u201322 peptide fragment. Both compounds demonstrated high aqueous stability and adequate lipophilicity for biological membrane crossing. Coordination studies revealed that both ML and ML2 complexes can be obtained in solution for the tridentate ligand X1NIC-(\u00a0E\u00a0), with the former being more stable. On the other hand, the bidentate ligand X1NIC-(\u00a0Z\u00a0) only forms ML species. Both isomers effectively set up ternary complexes with Cu2+ and hIAPP18\u201322, altering the redox behavior of the copper-peptide system. These results, obtained through cyclic voltammetry experiments, suggest a protective effect of the ligands with respect to metal-induced oxidative stress. This study constitutes the first comparative report on the coordination and reactivity of geometric isomers of a bioactive N-acylhydrazone, and the findings described herein highlight this class of compounds as promising chemical tools for the modulation of abnormal metal-peptide interactions implicated in type 2 diabetes pathogenesis.<\/jats:p>","DOI":"10.1021\/acsomega.5c04850","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T12:09:13Z","timestamp":1752235753000},"page":"31115-31127","source":"Crossref","is-referenced-by-count":4,"title":["Differential Modulation\nof Copper(II) Interactions\nwith the 18\u201322 Coordinating Amylin Fragment by the Geometric\nIsomers of a New Nicotinoyl Hydrazone: A First Study"],"prefix":"10.1021","volume":"10","author":[{"given":"Alessandra","family":"Carvalho","sequence":"first","affiliation":[{"name":"Pontifical Catholic University of Rio de Janeiro (PUC-Rio) , , ,","place":["Rio de Janeiro, Brazil, 22451-900"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karina C.","family":"Pougy","sequence":"additional","affiliation":[{"name":"Federal University of Rio de Janeiro (UFRJ) , , ,","place":["Rio de Janeiro, Brazil, 21941-909"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5118-6931","authenticated-orcid":true,"given":"Anderson S.","family":"Pinheiro","sequence":"additional","affiliation":[{"name":"Federal University of Rio de Janeiro (UFRJ) , , ,","place":["Rio de Janeiro, Brazil, 21941-909"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daphne S.","family":"Cukierman","sequence":"additional","affiliation":[{"name":"State University of Rio de Janeiro (UERJ) , , ,","place":["Rio de Janeiro, Brazil, 20550-013"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0624-7560","authenticated-orcid":true,"given":"Nicola\u0301s A.","family":"Rey","sequence":"additional","affiliation":[{"name":"Pontifical Catholic University of Rio de Janeiro (PUC-Rio) , , ,","place":["Rio de Janeiro, Brazil, 22451-900"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2025,7,11]]},"reference":[{"key":"2026081813074984600_cit1","doi-asserted-by":"publisher","first-page":"15019","DOI":"10.1038\/nrdp.2015.19","article-title":"Type 2 diabetes mellitus","volume":"1","author":"DeFronzo","year":"2015","journal-title":"Nat. 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Dis Primers"},{"issue":"2","key":"2026081813074984600_cit2","doi-asserted-by":"publisher","first-page":"241","DOI":"10.2337\/diabetes.48.2.241","article-title":"Islet amyloid: a long-recognized\nbut underappreciated pathological feature of type 2 diabetes","volume":"48","author":"Kahn","year":"1999","journal-title":"Diabetes"},{"issue":"3","key":"2026081813074984600_cit3","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1152\/physrev.00042.2009","article-title":"Islet amyloid\npolypeptide, islet\namyloid, and diabetes mellitus","volume":"91","author":"Westermark","year":"2011","journal-title":"Physiol Rev."},{"issue":"5","key":"2026081813074984600_cit4","doi-asserted-by":"publisher","first-page":"634","DOI":"10.2337\/diabetes.39.5.634","article-title":"Evidence of cosecretion of islet\namyloid polypeptide and insulin by beta-cells","volume":"39","author":"Kahn","year":"1990","journal-title":"Diabetes"},{"issue":"1","key":"2026081813074984600_cit5a","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/0168-8227(92)90074-2","article-title":"Plasma islet amyloid polypeptide\nlevels in obesity, impaired glucose tolerance and non-insulin-dependent\ndiabetes mellitus","volume":"15","author":"Enoki","year":"1992","journal-title":"Diabetes Res. Clin Pract"},{"issue":"4","key":"2026081813074984600_cit5b","doi-asserted-by":"publisher","first-page":"607","DOI":"10.2337\/diab.46.4.607","article-title":"Elevated islet amyloid\npancreatic polypeptide and proinsulin in lean gestational diabetes","volume":"46","author":"Kautzky-Willer","year":"1997","journal-title":"Diabetes"},{"issue":"9","key":"2026081813074984600_cit6","doi-asserted-by":"publisher","first-page":"1765","DOI":"10.1016\/j.bbamem.2018.02.020","article-title":"IAPP in type II diabetes:\nBasic research on structure, molecular interactions, and disease mechanisms\nsuggests potential intervention strategies","volume":"1860","author":"Asthana","year":"2018","journal-title":"Biochim Biophys Acta Biomembr, Protein Aggregation and Misfolding\nat the Cell Membrane Interface"},{"issue":"1","key":"2026081813074984600_cit7","doi-asserted-by":"publisher","first-page":"17","DOI":"10.3390\/metabo13010017","article-title":"Potential Role of Copper in Diabetes and Diabetic Kidney\nDisease","volume":"13","author":"Gembillo","year":"2023","journal-title":"Metabolites"},{"issue":"1","key":"2026081813074984600_cit8a","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1039\/b817203j","article-title":"A perspective on\nthe role of metals in diabetes past\nfindings and possible future directions","volume":"1","author":"Meyer","year":"2009","journal-title":"Metallomics"},{"issue":"7","key":"2026081813074984600_cit8b","doi-asserted-by":"publisher","first-page":"1302","DOI":"10.2337\/dc09-0259","article-title":"Oxidative Stress\nand Insulin Resistance The Coronary Artery Risk Development in Young\nAdults study","volume":"32","author":"Park","year":"2009","journal-title":"Diabetes Care"},{"issue":"6","key":"2026081813074984600_cit9","doi-asserted-by":"publisher","first-page":"830","DOI":"10.3390\/pharmaceutics13060830","article-title":"Undercover Toxic Me\u0301nage a\u0300 Trois of Amylin,\nCopper (II) and Metformin in Human Embryonic Kidney Cells","volume":"13","author":"Congiu","year":"2021","journal-title":"Pharmaceutics"},{"issue":"1","key":"2026081813074984600_cit10","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/2251-6581-13-16","article-title":"Metals in the pathogenesis\nof type 2 diabetes","volume":"13","author":"Khan","year":"2014","journal-title":"J. Diabetes Metab. Disord."},{"issue":"4","key":"2026081813074984600_cit11","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1002\/iub.1614","article-title":"Dissecting\ncopper homeostasis\nin diabetes mellitus","volume":"69","author":"Lowe","year":"2017","journal-title":"IUBMB Life"},{"key":"2026081813074984600_cit12a","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.saa.2013.06.105","article-title":"Structural and vibrational study\nof 8-hydroxyquinoline-2-carboxaldehyde\nisonicotinoyl hydrazone--a potential metal-protein attenuating compound\n(MPAC) for the treatment of Alzheimer\u2019s disease","volume":"116","author":"de Freitas","year":"2013","journal-title":"Spectrochim Acta A Mol. 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Biochem."},{"issue":"8","key":"2026081813074984600_cit12d","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1097\/FBP.0000000000000578","article-title":"The aroylhydrazone\nINHHQ prevents memory impairment induced by Alzheimer\u2019s-linked\namyloid-\u03b2 oligomers in mice","volume":"31","author":"De\nFalco","year":"2020","journal-title":"Behav Pharmacol"},{"key":"2026081813074984600_cit12e","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2022.828654","article-title":"Tridentate N-Acylhydrazones\nas Moderate Ligands for the Potential Management of Cognitive Decline\nAssociated With Metal-Enhanced Neuroaggregopathies","volume":"13","author":"Cukierman","year":"2022","journal-title":"Front Neurol"},{"issue":"8","key":"2026081813074984600_cit13","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.1007\/s00775-018-1606-0","article-title":"Aroylhydrazones constitute a promising\nclass of \u2019metal-protein\nattenuating compounds\u2019 for the treatment of Alzheimer\u2019s\ndisease: a proof-of-concept based on the study of the interactions\nbetween zinc\u00ad(II) and pyridine-2-carboxaldehyde isonicotinoyl hydrazone","volume":"23","author":"Cukierman","year":"2018","journal-title":"J. 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Drug Target"},{"issue":"1\u20133","key":"2026081813074984600_cit24","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","article-title":"Experimental and\ncomputational approaches to estimate solubility and permeability in\ndrug discovery and development settings","volume":"46","author":"Lipinski","year":"2001","journal-title":"Adv.\nDrug Deliv Rev."},{"issue":"4","key":"2026081813074984600_cit25","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1602\/neurorx.2.4.541","article-title":"Medicinal chemical\nproperties of successful central\nnervous system drugs","volume":"2","author":"Pajouhesh","year":"2005","journal-title":"NeuroRx"},{"issue":"8","key":"2026081813074984600_cit26","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.1007\/s10953-016-0504-8","article-title":"Acid\u2013Base Properties and Kinetics\nof Hydrolysis\nof Aroylhydrazones Derived from Nicotinic Acid Hydrazide","volume":"45","author":"Benkovic\u0301","year":"2016","journal-title":"J. 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Chem."},{"key":"2026081813074984600_cit27b","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2021.104943","article-title":"Synthesis, in silico, in vitro and in vivo evaluations of isatin\naroylhydrazones as highly potent anticonvulsant agents","volume":"112","author":"Emami","year":"2021","journal-title":"Bioorg Chem."},{"issue":"36","key":"2026081813074984600_cit28","doi-asserted-by":"publisher","first-page":"4050","DOI":"10.2174\/0929867329666220915140852","article-title":"Interactions\nof Copper\u00ad(II) and Zinc\u00ad(II) Ions with the Peptide Fragments of Proteins\nRelated to Neurodegenerative Disorders: Similarities and Differences","volume":"30","author":"So\u0301va\u0301go\u0301","year":"2023","journal-title":"Curr. Med. Chem."},{"issue":"8","key":"2026081813074984600_cit29","doi-asserted-by":"publisher","first-page":"3788","DOI":"10.1021\/ic502945k","article-title":"Structural\nBasis for the Inhibition of Truncated Islet Amyloid Polypeptide Aggregation\nby Cu\u00ad(II): Insights into the Bioinorganic Chemistry of Type II Diabetes","volume":"54","author":"Rivillas-Acevedo","year":"2015","journal-title":"Inorg. Chem."},{"issue":"20","key":"2026081813074984600_cit30","doi-asserted-by":"publisher","first-page":"10727","DOI":"10.1021\/acs.inorgchem.6b01963","article-title":"Copper Coordination\nFeatures of Human Islet Amyloid Polypeptide: The Type 2 Diabetes Peptide","volume":"55","author":"Sa\u0301nchez-Lo\u0301pez","year":"2016","journal-title":"Inorg. Chem."},{"issue":"1","key":"2026081813074984600_cit31","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1021\/acs.inorgchem.7b02266","article-title":"Active-Site Environment\nof Copper-Bound Human Amylin\nRelevant to Type 2 Diabetes","volume":"57","author":"Seal","year":"2018","journal-title":"Inorg. Chem."},{"issue":"1","key":"2026081813074984600_cit32","doi-asserted-by":"publisher","first-page":"5686","DOI":"10.1038\/s41598-020-62560-4","article-title":"Copper\u00ad(II)-binding\nequilibria in human blood","volume":"10","author":"Kirsipuu","year":"2020","journal-title":"Sci. Rep."},{"issue":"22","key":"2026081813074984600_cit33","doi-asserted-by":"publisher","first-page":"16927","DOI":"10.1021\/acs.inorgchem.1c03084","article-title":"Ternary Cu\u00ad(2+)\nComplexes of Human Serum Albumin and Glycyl-l-histidyl-l-lysine","volume":"60","author":"Bossak-Ahmad","year":"2021","journal-title":"Inorg. Chem."},{"issue":"1","key":"2026081813074984600_cit34","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1007\/s12011-016-0877-y","article-title":"Copper in\nDiabetes Mellitus: a Meta-Analysis and Systematic Review of Plasma\nand Serum Studies","volume":"177","author":"Qiu","year":"2017","journal-title":"Biol. Trace Elem Res."}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.5c04850","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/10\/28\/31115\/40845016\/ao5c04850.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/10\/28\/31115\/40845016\/ao5c04850.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T18:38:11Z","timestamp":1787078291000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/10\/28\/31115\/3655101\/Differential-Modulation-of-Copper-II-Interactions"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,11]]},"references-count":43,"journal-issue":{"issue":"28","published-online":{"date-parts":[[2025,7,11]]},"published-print":{"date-parts":[[2025,7,22]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.5c04850","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,11]]}}}