Synthetic strategy for increasing solubility of potential FLT3 inhibitor thieno[2,3-d]pyrimidine derivatives through structural modifications at the C2and C6positions

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 C₂and C₆positions

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

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

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.

Original language	English
Pages (from-to)	496-500
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	27
Issue number	3
DOIs	https://doi.org/10.1016/j.bmcl.2016.12.034
Publication status	Published - 2017

Bibliographical note

Funding Information:
This research was supported by a grant from the Translational Research Center for Protein Function Control (Grant NRF-2009-0083522), the Ministry of Science, ICT and Future Planning (Grant NRF-2013M3A6A4072536), the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C1324), and the KRIBB Research Initiative Program.

Publisher Copyright:
© 2016 Elsevier Ltd

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2016.12.034

Cite this

@article{db041f8c050a4b78bea13fedf1c708ae,

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.",

author = "Changmok Oh and Hyuntae Kim and Kang, {Jong Soon} and Jieun Yun and Jaejun Sim and Kim, {Hwan Mook} and Gyoonhee Han",

note = "Funding Information: This research was supported by a grant from the Translational Research Center for Protein Function Control (Grant NRF-2009-0083522), the Ministry of Science, ICT and Future Planning (Grant NRF-2013M3A6A4072536), the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C1324), and the KRIBB Research Initiative Program. Publisher Copyright: {\textcopyright} 2016 Elsevier Ltd",

year = "2017",

doi = "10.1016/j.bmcl.2016.12.034",

language = "English",

volume = "27",

pages = "496--500",

journal = "Bioorganic and Medicinal Chemistry Letters",

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Synthetic strategy for increasing solubility of potential FLT3 inhibitor thieno[2,3-d]pyrimidine derivatives through structural modifications at the C₂and C₆positions. / Oh, Changmok; Kim, Hyuntae; Kang, Jong Soon; Yun, Jieun; Sim, Jaejun; Kim, Hwan Mook; Han, Gyoonhee.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 27, No. 3, 2017, p. 496-500.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Synthetic strategy for increasing solubility of potential FLT3 inhibitor thieno[2,3-d]pyrimidine derivatives through structural modifications at the C2and C6positions

AU - Oh, Changmok

AU - Kim, Hyuntae

AU - Kang, Jong Soon

AU - Yun, Jieun

AU - Sim, Jaejun

AU - Kim, Hwan Mook

AU - Han, Gyoonhee

N1 - Funding Information: This research was supported by a grant from the Translational Research Center for Protein Function Control (Grant NRF-2009-0083522), the Ministry of Science, ICT and Future Planning (Grant NRF-2013M3A6A4072536), the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C1324), and the KRIBB Research Initiative Program. Publisher Copyright: © 2016 Elsevier Ltd

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

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