Radi Marco, Crespan Emmanuele, Botta Giorgia, Falchi Federico, Maga Giovanni, Manetti Fabrizio, Corradi Valentina, Mancini Manuela, Santucci Maria Alessandra, Schenone Silvia, Botta Maurizio
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2, I-53100 Siena, Italy.
Bioorg Med Chem Lett. 2008 Feb 1;18(3):1207-11. doi: 10.1016/j.bmcl.2007.11.112. Epub 2007 Dec 4.
A series of substituted benzoylamino-2-[(4-benzyl)thio]-1,3,4-thiadiazoles has been discovered as potent Abl tyrosine kinase inhibitors. Molecular docking simulations on the Abl tyrosine kinase were conducted in order to rationalize the SAR of the synthesized inhibitors. The most active compound identified from the enzymatic screening (6a) showed interesting inhibitory activity on Imatinib-sensitive murine myeloid 3B clone and Bcr-Abl-independent Imatinib-resistant leukemia cells. Surprisingly, 6a was also proved to act as differentiating inducers in human promyelocytic leukemia cells (HL-60).
已发现一系列取代的苯甲酰氨基-2-[(4-苄基)硫代]-1,3,4-噻二唑是有效的Abl酪氨酸激酶抑制剂。为了阐明合成抑制剂的构效关系，对Abl酪氨酸激酶进行了分子对接模拟。从酶筛选中鉴定出的最具活性的化合物（6a）对伊马替尼敏感的小鼠髓系3B克隆和不依赖Bcr-Abl的伊马替尼耐药白血病细胞显示出有趣的抑制活性。令人惊讶的是，6a还被证明可作为人早幼粒细胞白血病细胞（HL-60）中的分化诱导剂。
