title: Synthetic strategy for increasing solubility of potential FLT3 inhibitor thieno[2,3-d]pyrimidine derivatives through structural modifications at the C2and C6positions.
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 C2and the C6positions of thieno[2,3-d]pyrimidine scaffold. Compound 13b, which possesses a thiazole moiety at the C2position, 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.
authors.affiliation: Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea.
authors.forename: Changmok
authors.initials: C
authors.lastname: Oh
authors.affiliation: 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.
authors.forename: Hyuntae
authors.initials: H
authors.lastname: Kim
authors.affiliation: Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Chungbuk 28116, Republic of Korea.
authors.forename: Jong Soon
authors.initials: JS
authors.lastname: Kang
authors.affiliation: Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Chungbuk 28116, Republic of Korea.
authors.forename: Jieun
authors.initials: J
authors.lastname: Yun
authors.affiliation: Department of Preventive Pharmacy, Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea.
authors.forename: Jaejun
authors.initials: J
authors.lastname: Sim
authors.affiliation: Department of Preventive Pharmacy, Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea.
authors.forename: Hwan-Mook
authors.initials: HM
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Gyoonhee
authors.initials: G
authors.lastname: Han
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C000601850:thieno(2,3-d)pyrimidine; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
keywords: Acute myeloid leukemia (AML); FLT3; Solubility; Thieno[2,3-d]pyrimidine