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Design, synthesis, molecular modelling and biological evaluation of novel 6-amino-5-cyano-2-thiopyrimidine derivatives as potent anticancer agents against leukemia and apoptotic inducers.
Ahmed, Naglaa M; Mohamed, Mosaad S; Awad, Samir M; Abd El-Hameed, Rania H; El-Tawab, Neama A Abd; Gaballah, Mohamed S; Said, Ahmed M.
Afiliación
  • Ahmed NM; Pharmaceutical Organic Chemistry Department, Helwan University, Ein-Helwan, Egypt.
  • Mohamed MS; Pharmaceutical Organic Chemistry Department, Helwan University, Ein-Helwan, Egypt.
  • Awad SM; Pharmaceutical Organic Chemistry Department, Helwan University, Ein-Helwan, Egypt.
  • Abd El-Hameed RH; Pharmaceutical Organic Chemistry Department, Helwan University, Ein-Helwan, Egypt.
  • El-Tawab NAA; Pharmaceutical Organic Chemistry Department, Helwan University, Ein-Helwan, Egypt.
  • Gaballah MS; Biochemistry and Molecular Biology Department, Helwan University, Ein-Helwan, Egypt.
  • Said AM; Pharmaceutical Organic Chemistry Department, Helwan University, Ein-Helwan, Egypt.
J Enzyme Inhib Med Chem ; 39(1): 2304625, 2024 Dec.
Article en En | MEDLINE | ID: mdl-38348824
ABSTRACT
Herein, a novel series of 6-amino-5-cyano-2-thiopyrimidines and condensed pyrimidines analogues were prepared. All the synthesized compounds (1a-c, 2a-c, 3a-c, 4a-r and 5a-c) were evaluated for in vitro anticancer activity by the National Cancer Institute (NCI; MD, USA) against 60 cell lines. Compound 1c showed promising anticancer activity and was selected for the five-dose testing. Results demonstrated that compound 1c possessed broad spectrum anti-cancer activity against the nine cancerous subpanels tested with selectivity ratio ranging from 0.7 to 39 at the GI50 level with high selectivity towards leukaemia. Mechanistic studies showed that Compound 1c showed comparable activity to Duvelisib against PI3Kδ (IC50 = 0.0034 and 0.0025 µM, respectively) and arrested cell cycle at the S phase and displayed significant increase in the early and late apoptosis in HL60 and leukaemia SR cells. The necrosis percentage showed a significant increase from 1.13% to 3.41% in compound 1c treated HL60 cells as well as from 1.51% to 4.72% in compound 1c treated leukaemia SR cells. Also, compound 1c triggered apoptosis by activating caspase 3, Bax, P53 and suppressing Bcl2. Moreover, 1c revealed a good safety profile against human normal lung fibroblast cell line (WI-38 cells). Molecular analysis of Duvelisib and compound 1c in PI3K was performed. Finally, these results suggest that 2-thiopyrimidine derivative 1c might serve as a model for designing novel anticancer drugs in the future.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia / Antineoplásicos Límite: Humans Idioma: En Revista: J Enzyme Inhib Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Egipto Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia / Antineoplásicos Límite: Humans Idioma: En Revista: J Enzyme Inhib Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Egipto Pais de publicación: Reino Unido