Synthetic strategy for increasing solubility of potential FLT3 inhibitor thieno[2,3-d]pyrimidine derivatives through structural modifications at the C₂ and C₆ positions

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• 作者：Changmok Oh^a ; Hyuntae Kim^a ; ^b ; Jong Soon Kang^c ; Jieun Yun^c ; Jaejun Sim^d ; Hwan-Mook Kim^d ; Gyoonhee Han^a ; ^b ; ^{gyoonhee@yonsei.ac.kr}
• 关键词：FLT3 ; Thieno[2 ; 3-d]pyrimidine ; Acute myeloid leukemia (AML) ; Solubility
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：27
• 期：3
• 页码：496-500
• 全文大小：701 K
• 卷排序：27

文摘

Acute myeloid leukemia (AML) is a clonal disorder of hematopoietic progenitor cell. In AML, a mutation in FLT3 is commonly occurs and is associated with poor prognosis. We have previously reported that thieno[2,3-d]pyrimidine derivative compound 1 exhibited better antiproliferative activity against MV4-11 cells which harbor mutant FLT3 than AC220, which is a well-known FLT3 inhibitor, and has good microsomal stability. However, compound 1 had poor solubility. We then carried out further structural modification at the C2 and the C6 positions of thieno[2,3-d]pyrimidine scaffold. Compound 13b, which possesses a thiazole moiety at the C2 position, exhibited better antiproliferative activity than compound 1 and showed increased solubility and moderate microsomal stability. These results indicate that compound 13b could be a promising potential FLT inhibitor for AML chemotherapy.