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Synthesis and biological evaluation of chalcone-linked pyrazolo[1,5-a]pyrimidines as potential anticancer agents
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2017-07-13 00:00:00 , DOI: 10.1039/c7md00193b Chandrakant Bagul 1, 2, 3, 4 , Garikapati Koteswara Rao 4, 5, 6, 7 , Venkata Krishna Kanth Makani 4, 5, 6, 7 , Jaki R. Tamboli 4, 6, 7, 8 , Manika Pal-Bhadra 4, 5, 6, 7 , Ahmed Kamal 1, 2, 3, 4, 8
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2017-07-13 00:00:00 , DOI: 10.1039/c7md00193b Chandrakant Bagul 1, 2, 3, 4 , Garikapati Koteswara Rao 4, 5, 6, 7 , Venkata Krishna Kanth Makani 4, 5, 6, 7 , Jaki R. Tamboli 4, 6, 7, 8 , Manika Pal-Bhadra 4, 5, 6, 7 , Ahmed Kamal 1, 2, 3, 4, 8
Affiliation
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A series of pyrazolo[1,5-a]pyrimidines substituted at C5 with 1-phenylprop-2-en-1-one (6a–q) and 3-phenylprop-2-en-1-one (7a–k) was synthesized and evaluated for antiproliferative activity. Among them, 6h was found to be the most active compound against the MDA-MB-231 cell line with an IC50 of 2.6 μM . The antiproliferative activity of this series of compounds ranged from 2.6 to 34.9 μM against A549 (lung cancer), MDA-MB-231 (breast cancer) and DU-145 (prostate cancer) cell lines. FACS analysis revealed that these hybrids arrest the cell cycle at the subG1 phase. Western blot analysis and an immunofluorescence assay showed the inhibition of the EGFR and STAT3 axis, which plays an important role in cell survival and apoptosis. Western blot and RT-PCR analyses that displayed an increase in apoptotic proteins such as p53, p21 and Bax and a decrease in the anti-apoptotic proteins Bcl-2 and procaspase-9 confirmed the ability of these hybrids to trigger cell death by apoptosis. Molecular docking studies described the binding of these hybrids to the ATP binding site of EGFR.
中文翻译：
查尔酮连接的吡唑并[1,5- a ]嘧啶类化合物的合成及生物学评价
一系列吡唑并[1,5- a ]嘧啶在C5处被1-苯基丙-2-烯-1-酮（6a–q）和3-苯基丙-2-烯-1-酮（7a–k）取代合成并评估其抗增殖活性。其中，发现6h是针对MDA-MB-231细胞系的最具活性的化合物，其IC 50为为2.6μM。该系列化合物对A549（肺癌），MDA-MB-231（乳腺癌）和DU-145（前列腺癌）细胞系的抗增殖活性范围为2.6至34.9μM。FACS分析表明，这些杂种将细胞周期阻滞在subG1期。Western印迹分析和免疫荧光分析表明，EGFR和STAT3轴受到抑制，这在细胞存活和凋亡中起着重要作用。Western印迹和RT-PCR分析显示凋亡蛋白（例如p53，p21和Bax）增加，而抗凋亡蛋白Bcl-2和procaspase-9减少，证实了这些杂种具有通过凋亡触发细胞死亡的能力。分子对接研究描述了这些杂种与EGFR ATP结合位点的结合。
更新日期：2017-09-21
中文翻译：
查尔酮连接的吡唑并[1,5- a ]嘧啶类化合物的合成及生物学评价
一系列吡唑并[1,5- a ]嘧啶在C5处被1-苯基丙-2-烯-1-酮（6a–q）和3-苯基丙-2-烯-1-酮（7a–k）取代合成并评估其抗增殖活性。其中，发现6h是针对MDA-MB-231细胞系的最具活性的化合物，其IC 50为为2.6μM。该系列化合物对A549（肺癌），MDA-MB-231（乳腺癌）和DU-145（前列腺癌）细胞系的抗增殖活性范围为2.6至34.9μM。FACS分析表明，这些杂种将细胞周期阻滞在subG1期。Western印迹分析和免疫荧光分析表明，EGFR和STAT3轴受到抑制，这在细胞存活和凋亡中起着重要作用。Western印迹和RT-PCR分析显示凋亡蛋白（例如p53，p21和Bax）增加，而抗凋亡蛋白Bcl-2和procaspase-9减少，证实了这些杂种具有通过凋亡触发细胞死亡的能力。分子对接研究描述了这些杂种与EGFR ATP结合位点的结合。
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