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Cytotoxic 1,2,3-Triazoles as Potential Leads Targeting the S100A2-p53 Complex: Synthesis and Cytotoxicity.
Sun, Jufeng; Baker, Jennifer R; Russell, Cecilia C; Cossar, Peter J; Ngoc Thuy Pham, Hong; Sakoff, Jennette A; Scarlett, Christopher J; McCluskey, Adam.
Afiliación
  • Sun J; Chemistry, School of Environmental & Life Sciences The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
  • Baker JR; Medicinal Chemistry, School of Pharmacy, Binzhou Medical University, Yantai, 264003, China.
  • Russell CC; Chemistry, School of Environmental & Life Sciences The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
  • Cossar PJ; Chemistry, School of Environmental & Life Sciences The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
  • Ngoc Thuy Pham H; Chemistry, School of Environmental & Life Sciences The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
  • Sakoff JA; School of Environmental & Life Sciences, The University of Newcastle, Ourimbah, NSW 2258, Australia.
  • Scarlett CJ; Nha Trang University No. 2 Nguyen Dinh Chieu Street, Nha Trang City, Khanh Hoa, 8458, Vietnam.
  • McCluskey A; Experimental Therapeutics Group Department of Medical Oncology, Calvary Mater Newcastle Hospital Edith Street, Waratah, NSW 2298, Australia.
ChemMedChem ; 16(18): 2864-2881, 2021 09 16.
Article en En | MEDLINE | ID: mdl-34047450
In silico screening predicted 1 (N-(4-((4-(3-(4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)propyl)piperazin-1-yl) sulfonyl)-phenyl)acetamide) as an inhibitor of the S100A2-p53 protein-protein interaction. S100A2 is a validated pancreatic cancer drug target. In the MiaPaCa-2 pancreatic cell line, 1 was a ∼50 µM growth inhibitor. Synthesis of five focused compound libraries and cytotoxicity screening revealed increased activity from the presence of electron withdrawing moieties on the sulfonamide aromatic ring, with the 3,5-bis-CF3 Library 3 analogues the most active, with GI50 values of 0.91 (3-ClPh; 13 i; BxPC-3, Pancreas) to 9.0 µM (4-CH3 ; 13 d; PANC-1, Pancreas). Activity was retained against an expanded pancreatic cancer cell line panel (MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, PANC-1 and HPAC) and the normal cell line MCF10A (breast). Bulky 4-disposed substituents on the terminal phenyl ring enhanced broad spectrum activity with growth inhibition values spanning 1.1 to 3.1 µM (4-C(CH3 )3 ; 13 e; BxPC-3 and AsPC-1 (pancreas), respectively). Central alkyl spacer contraction from propyl to ethyl proved detrimental to activity with Library 4 and 5.5- to 10-fold less cytotoxic than the propyl linked Library 2 and Library 3. The data herein was consistent with the predicted binding poses of the compounds evaluated. The highest levels of cytotoxicity were observed with those analogues best capable of adopting a near identical pose to the p53-peptide in the S100A2-p53 binding groove.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Triazoles / Proteínas S100 / Factores Quimiotácticos / Proteína p53 Supresora de Tumor / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: ChemMedChem Asunto de la revista: FARMACOLOGIA / QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Triazoles / Proteínas S100 / Factores Quimiotácticos / Proteína p53 Supresora de Tumor / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: ChemMedChem Asunto de la revista: FARMACOLOGIA / QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Alemania