Fuchun Xie, Shukun Li, Donglu Bai
2007
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0
Influential Citations
25
Citations
Journal
ACS Combinatorial Science
Abstract
ReceiVed September 8, 2006 Pyrimidine is found widely as a core structure in a large variety of compounds that exhibit important biological activity.1 It is convenient to synthesize substituted pyrimidines by reaction of amidines or guanidine with R,!unsaturated ketones, !-diketones, !-alkoxyand !-aminovinyl ketones, and N-aryl acetyleneic imines.2 The use of combinatorial approaches to the high-throughput synthesis of this druglike scaffold would be a powerful advance in helping to speed up drug discovery. Recently, Nie et al. have reported a new method for the preparation of a 2,4,6substituted pyrimidines library using a microwave-assisted reaction of 2!-hydroxychalcones with amidines or guanidine.3 To the best of our knowledge, no method was explored to generate the 2,4,5-substitued pyrimidines for combinatorial synthesis. Here, we report (1) a combinatorial synthesis of a 2,4,5-substituted pyrimidine library using a sequential threecomponent, one-pot reaction and (2) its antitumor activities. Chromone as a 1,3-diketone equivalent can be condensed with amidine to form o-hydroxyphenyl pyrimidine.5 Since substitution of pyrimidine at the 4-position will block Suzuki coupling of a 5-iodo-4-substituted pyrimidine, we thus designed a one-pot process to form 2,4,5-substitued pyrimidines by Suzuki coupling6 that applies diversified commercial available boronic acids to the chromone core, followed by condensation with a variety of amidines (Scheme 1). According to our reported method,4 a mixture of iodochromone (1.2 mmol) and aryl boronic acids (1.1 equiv) in the presence of 2% Pd(PPh3)4 and 2.0 equiv K2CO3 in 5 mL THF-H2O (4:1) was refluxed overnight and then split into six portions, to which was added 1.5 equiv of amidines f-k (0.3 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.3 mmol or 0.6 mmol) for each portion. The mixture was stirred at 50-60 °C for about 10 h, and the corresponding products were obtained by flash chromatography. Using five boronic acids and six amidines (Table 1), we successfully synthesized a small quantity of a pyrimidine library including 30 diversified compounds. The electronic variations on both the aryl group of the boronic acid and the substitution of amidine gave the desired product in moderate to good yield (Table 2). The compounds were assayed for the inhibition of human hepatocellular carcinoma cell line BEL-7402 (Table 2). Two compounds, ak and dh, exhibited a high degree of inhibition, more than 80% against BEL-7402 cell growth at 15 μM, with an IC50 value of 1.02 and 5.08 μM, respectively. In the process of preparation of a large amount of ak, we tested Felpin’s reported method,7 which applied catalytic 10% Pd/C as an inexpensive catalyst for Suzuki coupling in aqueous acetonitrile, followed by condensation with acetamidine in DMF separately. The compound ak was obtained in 77% yield over two steps. (Scheme 2). According to the bioassay result, we then kept the building blocks a, k and d, h to synthesize several derivatives of ak * To whom correspondence should be addressed. Phone/Fax: 86-02150805896. E-mail: yhhu@mail.shcnc.ac.cn. Scheme 1. Synthesis of Diversified 2,4,5-Substituted Pyrimidines via Suzuki Coupling and Condensation