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

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

  • Bioorg Med Chem Lett. 2017 Feb 1;27(3):496-500. doi: 10.1016/j.bmcl.2016.12.034.
Changmok Oh 1,  Hyuntae Kim 2,  Jong Soon Kang 3,  Jieun Yun 3,  Jaejun Sim 4,  Hwan-Mook Kim 4,  Gyoonhee Han 5
Affiliations

Affiliations

  • 1 Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea.
  • 2 Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea; Department of Integrated OMICS for Biomedical Sciences (WCU Program), Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea.
  • 3 Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Chungbuk 28116, Republic of Korea.
  • 4 Department of Preventive Pharmacy, Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea.
  • 5 Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea; Department of Integrated OMICS for Biomedical Sciences (WCU Program), Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea. Electronic address: gyoonhee@yonsei.ac.kr.
PMID: 28043794 DOI: 10.1016/j.bmcl.2016.12.034
Abstract

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.

Keywords

Acute myeloid leukemia (AML); FLT3; Solubility; Thieno[2,3-d]pyrimidine.

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