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Design, Synthesis and Biological Evaluation of Syn and Anti-like Double Warhead Quinolinones Bearing Dihydroxy Naphthalene Moiety as Epidermal Growth Factor Receptor Inhibitors with Potential Apoptotic Antiproliferative Action.
El-Sheref, Essmat M; Ameen, Mohamed A; El-Shaieb, Kamal M; Abdel-Latif, Fathy F; Abdel-Naser, Asmaa I; Brown, Alan B; Bräse, Stefan; Fathy, Hazem M; Ahmad, Iqrar; Patel, Harun; Gomaa, Hesham A M; Youssif, Bahaa G M; Mohamed, Asmaa H.
Afiliação
  • El-Sheref EM; Chemistry Department, Faculty of Science, Minia University, El Minia 61519, Egypt.
  • Ameen MA; Chemistry Department, Faculty of Science, Minia University, El Minia 61519, Egypt.
  • El-Shaieb KM; Chemistry Department, Faculty of Science, Minia University, El Minia 61519, Egypt.
  • Abdel-Latif FF; Chemistry Department, Faculty of Science, Minia University, El Minia 61519, Egypt.
  • Abdel-Naser AI; Chemistry Department, Faculty of Science, Minia University, El Minia 61519, Egypt.
  • Brown AB; Chemistry Department, Florida Institute of Technology, 150 W University Blvd, Melbourne, FL 32901, USA.
  • Bräse S; Institute of Biological and Chemical Systems, IBCS-FMS, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany.
  • Fathy HM; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt.
  • Ahmad I; Division of Computer Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur 425405, Maharashtra, India.
  • Patel H; Department of Pharmaceutical Chemistry, Prof. Ravindra Nikam College of Pharmacy, Gondur, Dhule 424002, Maharashtra, India.
  • Gomaa HAM; Division of Computer Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur 425405, Maharashtra, India.
  • Youssif BGM; Pharmacology Department, College of Pharmacy, Jouf University, Sakaka 72314, Saudi Arabia.
  • Mohamed AH; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
Molecules ; 27(24)2022 Dec 10.
Article em En | MEDLINE | ID: mdl-36557897
Our investigation includes the synthesis of new naphthalene-bis-triazole-bis-quinolin-2(1H)-ones 4a−e and 7a−e via Cu-catalyzed [3 + 2] cycloadditions of 4-azidoquinolin-2(1H)-ones 3a−e with 1,5-/or 1,8-bis(prop-2-yn-1-yloxy)naphthalene (2) or (6). All structures of the obtained products have been confirmed with different spectroscopic analyses. Additionally, a mild and versatile method based on copper-catalyzed [3 + 2] cycloaddition (Meldal−Sharpless reaction) was developed to tether quinolinones to O-atoms of 1,5- or 1,8-dinaphthols. The triazolo linkers could be considered as anti and syn products, which are interesting precursors for functionalized epidermal growth factor receptor (EGFR) inhibitors with potential apoptotic antiproliferative action. The antiproliferative activities of the 4a−e and 7a−e were evaluated. Compounds 4a−e and 7a−e demonstrated strong antiproliferative activity against the four tested cancer cell lines, with mean GI50 ranging from 34 nM to 134 nM compared to the reference erlotinib, which had a GI50 of 33 nM. The most potent derivatives as antiproliferative agents, compounds 4a, 4b, and 7d, were investigated for their efficacy as EGFR inhibitors, with IC50 values ranging from 64 nM to 97 nM. Compounds 4a, 4b, and 7d demonstrated potent apoptotic effects via their effects on caspases 3, 8, 9, Cytochrome C, Bax, and Bcl2. Finally, docking studies show the relevance of the free amino group of the quinoline moiety for antiproliferative action via hydrogen bond formation with essential amino acids.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Quinolonas / Antineoplásicos Idioma: En Revista: Molecules Assunto da revista: BIOLOGIA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Egito País de publicação: Suíça

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Quinolonas / Antineoplásicos Idioma: En Revista: Molecules Assunto da revista: BIOLOGIA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Egito País de publicação: Suíça