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

Changmok Oh; Hyuntae Kim; Jong Soon Kang; Jieun Yun; Jaejun Sim; Hwan-Mook Kim; Gyoonhee Han

doi:10.1016/j.bmcl.2016.12.034

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. Epub 2016 Dec 23.

Authors

Changmok Oh¹, Hyuntae Kim², Jong Soon Kang³, Jieun Yun³, Jaejun Sim⁴, Hwan-Mook Kim⁴, Gyoonhee Han⁵

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Solubility
Structure-Activity Relationship
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
fms-Like Tyrosine Kinase 3 / genetics
fms-Like Tyrosine Kinase 3 / metabolism

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidines
thieno(2,3-d)pyrimidine
FLT3 protein, human
fms-Like Tyrosine Kinase 3