{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T08:01:44Z","timestamp":1785484904831,"version":"3.56.0"},"reference-count":38,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004410","name":"T\u00fcrkiye Bilimsel ve Teknolojik Ara\u015ftirma Kurumu","doi-asserted-by":"publisher","award":["124Z267"],"award-info":[{"award-number":["124Z267"]}],"id":[{"id":"10.13039\/501100004410","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chemistry &amp;amp; Biodiversity"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Molecular targeted therapies have significantly advanced non\u2010small cell lung cancer (NSCLC) treatment; however, acquired resistance in advanced stages remains a critical challenge. To overcome this, novel therapeutic targets or combination strategies are urgently needed. In this study, a new series of pyrazolo[1,5\u2010\n                    <jats:italic>a<\/jats:italic>\n                    ]pyrazin\u20104(5\n                    <jats:italic>H<\/jats:italic>\n                    )\u2010one derivatives (compounds\n                    <jats:bold>12\u201341<\/jats:bold>\n                    ) was designed and synthesized. Their antiproliferative activities were assessed in the A549 NSCLC cell line. Compounds\n                    <jats:bold>15<\/jats:bold>\n                    ,\n                    <jats:bold>16<\/jats:bold>\n                    ,\n                    <jats:bold>21<\/jats:bold>\n                    , and\n                    <jats:bold>26<\/jats:bold>\n                    \u2013\n                    <jats:bold>28<\/jats:bold>\n                    showed strong cytotoxicity, with IC\n                    <jats:sub>50<\/jats:sub>\n                    values of 8.19\u00a0\u00b5M (compound\n                    <jats:bold>27<\/jats:bold>\n                    ) and 7.01\u00a0\u00b5M (compound\n                    <jats:bold>28<\/jats:bold>\n                    ). Notably, compounds\n                    <jats:bold>21<\/jats:bold>\n                    and\n                    <jats:bold>26<\/jats:bold>\n                    \u2013\n                    <jats:bold>28<\/jats:bold>\n                    significantly reduced phosphoinositide 3\u2010kinase (PI3K) protein levels in A549 cells. To better understand their mode of action, molecular docking studies were performed using the crystal structure of PI3K (PDB ID: 4XE0), revealing favorable binding affinities and conserved interactions within the active site. Compounds\n                    <jats:bold>27<\/jats:bold>\n                    and\n                    <jats:bold>28<\/jats:bold>\n                    , which showed the strongest in vitro activity, also exhibited the most stable binding modes and docking scores, consistent with the biological data. Structure\u2013activity relationship (SAR) analysis indicated that a high electron\u2010density benzene ring on the pyrazole moiety and a low electron\u2010density ring on the pyrazine enhanced cytotoxic activity. Drug\u2010likeness and pre\u2013absorption, distribution, metabolism, excretion, and toxicity (ADMET) evaluations suggested favorable pharmacokinetic properties.\n                  <\/jats:p>","DOI":"10.1002\/cbdv.202502844","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T18:11:18Z","timestamp":1764094278000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis of New Pyrazolo[1,5\u2010\n                    <i>a<\/i>\n                    ]Pyrazin\u20104(5\n                    <i>H<\/i>\n                    )\u2010One Derivatives and Effects on PI3K Protein Levels in A549 Lung Adenocarcinoma Cell Line"],"prefix":"10.1002","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7305-7177","authenticated-orcid":false,"given":"Burak","family":"Kuzu","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Van Yuzuncu Yil University  Van Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3239-4855","authenticated-orcid":false,"given":"Ege","family":"Arzuk","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Toxicology, Faculty of Pharmacy Ege University  \u0130zmir Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4190-6047","authenticated-orcid":false,"given":"Meltem","family":"Tan\u2010Uygun","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Van Yuzuncu Yil University  Van Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.115891"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.21037\/atm.2016.03.11"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2017.11.036"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12272-012-0306-5"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00706-017-1960-6"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.31788\/RJC.2021.1426137"},{"key":"e_1_2_8_8_1","first-page":"210","article-title":"Synthesis and Cytotoxic Activity of New Pyrazolo[1, 5\u2010a]Pyrimidines and Determination of Pyrimidine Regiospecific Ring Formation With 2D NMR","volume":"2016","author":"Abdelall E. 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