Discovery of New Aminosubstituted Pyrrolopyrimidines with Antiproliferative Activity Against Breast Cancer Cells and Investigation of their Effect Towards the PI3K alpha Enzyme

作者：Daniilides Konstantinos; Lougiakis Nikolaos; Evangelidis Thomas; Kostakis Ioannis K; Pouli Nicole; Marakos Panagiotis^*; Mikros Emmanuel; Skaltsounis Alexios Leandros; Bach Stephane; Baratte Blandine; Ruchaud Sandrine; Karamani Valia; Papafotika Alexandra; Christoforidis Savvas; Argyros Orestis; Kouvari Eva; Tamvakopoulos Constantin

来源：Anti-Cancer Agents in Medicinal Chemistry, 2017, 17(7): 990-1002.

DOI：10.2174/1871520616666161207143450

• 9-deazapurine
• pyrrolo[3,2-d] pyrimidine
• cytotoxicity
• breast cancer
• PI3K inhibition
• docking scoring
• molecular dynamics

Objective: A series of novel 2,4-diaminosubstituted pyrrolo[3,2-d] pyrimidines was synthesized together with their corresponding 7-phenyl or 7-isopropyl counterparts.
Results: Among the target derivatives, the 7-substituted analogues exhibited interesting cytotoxic activity against a panel of PI3K alpha related human breast cancer cell lines, namely MCF7, T47D, MDA-MB-231 and HCC1954. Selected compounds were tested for potential PI3Ka inhibitory activity as well as for their cytotoxic effect in prostate cancer cell lines (DU145 and PC3).
Conclusion: Derivatives bearing a specific substitution pattern consisting of 7-phenyl as well as a 2-(4-aminocyclohexylamino) moiety (16c, 16f) display kinase inhibitory activity, elucidated on the basis of molecular simulation studies, which revealed their interaction with the DFG motif of the kinase.

• 出版日期2017