Structural modifications at the 6-position of thieno[2,3-d]pyrimidines and their effects on potency at FLT3 for treatment of acute myeloid leukemia

Kim, Hyun-Tae; Lee, Chulho; Yang, Jaeseok; Choi, Seonghwi; Park, Chun Ho; Kang, Jong Soon; Oh, Soo Jin; Yun, Jieun; Kim, Myung Hwa; Han, Gyoonhee

doi:10.1016/j.ejmech.2016.05.022

Cited by 14 publications

(5 citation statements)

References 23 publications

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“…Most of the synthesized anticancer compounds have an heterocyclic core derivatized from pyrimidine, and many of them are thienopyrimidines. Interestingly, they have recently been investigated as scaffolds for protein kinase (PKs) inhibitors [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of New Thiophene/Thieno[2,3-d]pyrimidines along with Their Cytotoxic Biological Evaluation as Tyrosine Kinase Inhibitors in Addition to Their Apoptotic and Autophagic Induction

et al. 2021

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This work describes the synthesis and anticancer activity against kinase enzymes of newly designed thiophene and thieno[2,3-d]pyrimidine derivatives, along with their potential to activate autophagic and apoptotic cell death in cancer cells. The designed compounds were scanned for their affinity for kinases. The results were promising with affinity ranges from 46.7% to 13.3%. Molecular docking studies were performed, and the compounds were then screened for their antiproliferative effects. Interestingly, compounds 8 and 5 resulted in higher cytotoxic effects than the reference standard against MCF-7 and HepG-2. The compounds were evaluated for their induction of apoptosis and/or necrosis on HT-29 and HepG-2. Three compounds induced significant early apoptosis compared to untreated control HT-29 cells, and four derivatives were more significant compared to untreated HepG-2 cells. We further investigated the effect of four compounds on the autophagy process within HT-29, HepG-2, and MCF-7 cells with flow cytometry. Similar to the apoptosis results, compound 5 showed the highest autophagic induction among all compounds. The potential inhibitory activity of the synthesized compounds on kinases was assessed. Screened compounds showed inhibition activity ranging from 41.4% to 83.5%. Compounds recorded significant inhibition were further investigated for their specific FLT3 kinase inhibitory activity. Noticeably, Compound 5 exhibited the highest inhibitory activity against FLT3.

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Section: Introductionmentioning

confidence: 99%

Design and Synthesis of New Thiophene/Thieno[2,3-d]pyrimidines along with Their Cytotoxic Biological Evaluation as Tyrosine Kinase Inhibitors in Addition to Their Apoptotic and Autophagic Induction

et al. 2021

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“…In 2016, Kim et al developed thieno [2,3-d] pyrimidine derivatives to potentially act as FLT3 inhibitors for the treatment of AML (Fig. 12) [101]. Effective antiproliferative activity against the leukemia cell line MV4-11 was shown by compounds 43a-d, with GI 50 of 0.366, 0.585, 0.540, and 0.278 µM, respectively.…”

Section: Thienopyrimidine Derivatives As Fms-like Tyrosine Kinase-3 (...mentioning

confidence: 99%

Recent updates on thienopyrimidine derivatives as anticancer agents

et al. 2023

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Thienopyrimidine derivatives hold a unique place between fused pyrimidine compounds. They are important and widely represented in medicinal chemistry as they are structural analogs of purines. Thienopyrimidine derivatives have various biological activities. The current review discusses different synthetic methods for the preparation of heterocyclic thienopyrimidine derivatives. It also highlights the most recent research on the anticancer effects of thienopyrimidines through the inhibition of various enzymes and pathways, which was published within the last 9 years. Graphical Abstract

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“…Hence, further structure modification at the 6-position was carried out for the identification of potent FLT3 inhibitors with increased metabolic stability. Compound Han-16d , possessing a 4-(2-methylaminoethoxy) phenyl group at the C-6, displayed effective inhibition against FLT3 kinase and several leukemia cell lines with relatively high metabolic stability (Figure a) …”

Section: Small-molecule Flt3 Inhibitorsmentioning

confidence: 99%

“…Compound Han-16d, possessing a 4-(2-methylaminoethoxy) phenyl group at the C-6, displayed effective inhibition against FLT3 kinase and several leukemia cell lines with relatively high metabolic stability (Figure 15a). 110 Nevertheless, low water solubility was an obstacle to the development of compound Han-16d as a potential FLT3 inhibitor for AML chemotherapy, which urged researchers to conduct further structural optimization on the thieno[2,3d]pyrimidine scaffold. In an attempt to develop novel derivatives with improved solubility of compound Han-16d while retaining its advantageous activity and microsomal stability, 19 compounds were synthesized through the manner of fixing diverse moieties at the thieno[2,3-d]pyrimidine scaffold.…”

Section: Small-molecule Flt3 Inhibitorsmentioning

confidence: 99%

Small-Molecule Fms-like Tyrosine Kinase 3 Inhibitors: An Attractive and Efficient Method for the Treatment of Acute Myeloid Leukemia

et al. 2020

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Fms-like tyrosine kinase 3 (FLT3) is an important member of the class III receptor tyrosine kinase (RTK) family, which is involved in the proliferation of hematopoietic cells and lymphocytes. In recent years, increasing evidence have demonstrated that the activation and mutation of FLT3 is closely implicated in the occurrence and development of acute myeloid leukemia (AML). The exploration of small-molecule inhibitors targeting FLT3 has aroused wide interest of pharmaceutical chemists and is expected to bring new hope for AML therapy. In this review, we specifically highlighted FLT3 mediated JAK/STAT, RAS/MAPK, and PI3K/AKT/mTOR signaling. The structural properties and biological activities of representative FLT3 inhibitors reported from 2014 to the present were also summarized. In addition, the major challenges in the current advance of novel FLT3 inhibitors were further analyzed, with the aim to guide future drug discovery.

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Structural modifications at the 6-position of thieno[2,3-d]pyrimidines and their effects on potency at FLT3 for treatment of acute myeloid leukemia

Cited by 14 publications

References 23 publications

Design and Synthesis of New Thiophene/Thieno[2,3-d]pyrimidines along with Their Cytotoxic Biological Evaluation as Tyrosine Kinase Inhibitors in Addition to Their Apoptotic and Autophagic Induction

Design and Synthesis of New Thiophene/Thieno[2,3-d]pyrimidines along with Their Cytotoxic Biological Evaluation as Tyrosine Kinase Inhibitors in Addition to Their Apoptotic and Autophagic Induction

Recent updates on thienopyrimidine derivatives as anticancer agents

Small-Molecule Fms-like Tyrosine Kinase 3 Inhibitors: An Attractive and Efficient Method for the Treatment of Acute Myeloid Leukemia

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