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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Synthesis of substituted 3-amino-N-phenyl-1H-indazole-1-carboxamides endowed with antiproliferative activity.
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Synthesis of substituted 3-amino-N-phenyl-1H-indazole-1-carboxamides endowed with antiproliferative activity.

机译：具有抗增殖活性的取代的3-氨基-N-苯基-1H-吲唑-1-羧酰胺的合成。

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摘要

Several new N-phenyl-1H-indazole-1-carboxamides 1c-h and 4l,m were prepared by reacting phenyl isocyanate derivatives 3a,b with 3-amino-1H-indazole derivatives 2c,e,g or 1H-indazole 2l respectively. Chemical transformations of compounds 1a,b and 1g,h gave 3-acetamido-N-phenyl-1H-indazole-1-carboxamide derivatives 5a,b, and 3,5-diamino-N-phenyl-1H-indazole-1-carboxamide derivatives 4i,j respectively. Finally, 3,5-diacetamido-N-phenyl-1H-indazole-1-carboxamide derivatives 6a,b were prepared by acetylation of 4i,j. Some of synthesized compounds were evaluated for their in vitro antiproliferative activity against the full NCI tumor cell lines panel derived from nine clinically isolated cancer types (leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast). Compound 1c, the most active of the series, was able to inhibit cell growth showing GI(50) values in the 0.041-33.6 muM range, mean GI(50) 1.90 muM, being very effective against colon and melanoma cell lines. Cell cycle analysis in K562 cells showed that 1c causes a marked increase of cells in G0-G1 phase. Moreover, it increases the ratio between hypophosphorylated pRb and total pRb.
机译：分别通过使异氰酸苯酯衍生物3a，b与3-氨基-1H-吲唑衍生物2c，e，g或1H-吲唑2l反应来制备几种新的N-苯基-1H-吲唑-1-羧酰胺1c-h和4l，m。 。化合物1a，b和1g，h的化学转化反应产生了3-乙酰氨基-N-苯基-1H-吲唑-1-羧酰胺衍生物5a，b和3,5-二氨基-N-苯基-1H-吲唑-1-羧酰胺导数4i，j最后，通过4i，j的乙酰化制备3，5-二乙酰氨基-N-苯基-1H-吲唑-1-羧酰胺衍生物6a，b。评估了一些合成化合物对全部NCI肿瘤细胞系的体外抗增殖活性，这些细胞系来自9种临床分离的癌症类型（白血病，非小细胞肺癌，结肠癌，CNS，黑素瘤，卵巢癌，肾癌，前列腺癌和乳腺癌） 。该化合物系列中最活跃的化合物1c能够抑制细胞生长，显示GI（50）值在0.041-33.6μM范围内，平均GI（50）为1.90μM，对结肠和黑色素瘤细胞系非常有效。 K562细胞的细胞周期分析表明1c导致G0-G1期细胞明显增加。此外，它增加了次磷酸化的pRb与总pRb之间的比率。

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