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Synthesis of 6-unsubstituted 2-oxo, 2-thioxo, and 2-amino-3,4-dihydropyrimidines and their antiproliferative effect on HL-60 cells
Tetrahedron Letters ( IF 1.5 ) Pub Date : 2020-05-07 , DOI: 10.1016/j.tetlet.2020.151967
Yoshio Nishimura , Hidetomo Kikuchi , Takanori Kubo , Yuki Gokurakuji , Yuri Nakamura , Rie Arai , Bo Yuan , Katsuyoshi Sunaga , Hidetsura Cho

A general and efficient synthetic method for 6-unsubstituted 3,4-dihydropyrimidin-2(1H)-thiones 6 and -ones 7 has been developed. In three-component reactions, the reactivity of reagents serving as the C5–C6 fragment of the dihydropyrimidine ring was compared. The reaction of thiourea or urea 12, aldehydes 13, and ethyl 3-dimethylaminoacrylate 9 in the presence of a catalytic amount of AlCl3 by heating smoothly proceeds to give 6 and 7 in high yields. A synthetic novelty of our protocol is as follows: 1) Lewis acid-mediated reaction, 2) good to high yields, 3) broad scope as for aldehydes, and ureas. Hitherto unavailable 6-unsubstituted 2-aminodihydropyridimidine 8 has been obtained from the 2-thioxo derivative 6 by a stepwise method involving a substitution reaction with the amine at the 2-position. These 6-unsubstituted compounds 6, 7, and some 6-methyl derivatives 16 were assessed for their antiproliferative effect on the human promyelocytic leukemia cell line, HL-60. The 4-propyl-6-methyl derivative 16b showed relatively strong activity with the IC50 value of 952 nM.



中文翻译:

6-未取代的2-氧代,2-硫代和2-氨基-3,4-二氢嘧啶的合成及其对HL-60细胞的抗增殖作用

已经开发了用于6-未取代的3,4-二氢嘧啶-2(1H)-硫酮6和-酮7的通用且有效的合成方法。在三组分反应中,比较了用作二氢嘧啶环的C5-C6片段的试剂的反应性。在催化量的AlCl 3存在下,通过加热使硫脲或尿素12,醛13和3-二甲基氨基丙烯酸乙酯9顺利进行反应,得到67高产。我们的方案的合成新颖性如下:1)路易斯酸介导的反应,2)良好至高收率,3)醛和脲的广泛应用。迄今为止,不连续的6-未取代的2-氨基二氢吡啶二甲酰亚胺8是通过逐步法从2-硫代肟衍生物6获得的,该方法涉及与胺在2-位的取代反应。这些6-未取代的化合物67,和一些6-甲基衍生物16被评定为在人早幼粒细胞白血病细胞系的抗增殖作用,HL-60。4-丙基-6-甲基衍生物16b具有相对较强的活性,IC 50值为952 nM。

更新日期:2020-06-23
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