3-芳基-6-甲酰胺吡唑并[1,5-a]嘧啶类化合物的合成及其抗癌活性研究
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摘要
以乙酰乙酸乙酯和N,N-二甲基甲酰胺二甲缩醛为原料,通过缩合、环合、水解和酰胺化4步反应合成了一系列新的2,7-二甲基-3-芳基-6-甲酰胺吡唑并[1,5-a]嘧啶类化合物(6a～6f),其结构经~1H NMR、~(13)C NMR、IR、MS和元素分析。采用MTT法,以索拉菲尼(sorafenib)为阳性对照药,测定了化合物对人肝癌细胞株(HepG2)的体外抗增殖活性。结果表明:6a～6f具有一定的抗癌活性,其中化合物6a对人肝癌细胞株(HepG2)的抗增殖活性(IC50=10. 2μmol·L~(-1))和阳性对照药索拉菲尼(IC_(50)=7. 9μmol·L~(-1))相当。
Six novel 3-( 2,4-dichlorophenyl)-2,7-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxamides( 6a ～ 6f) were synthesized by condension,cyclization,hydrolysis and amidation reaction using acetacetic ester and N,N-dimethylformamide dimethyl acetal as the starting materials. The structures were characterized by ~1H NMR,~(13)C NMR,IR,MS and elemental analysis. The antiproliferative activities against HepG2 cancer cell lines were tested by MTT assay with sorafenib as the positive control. In particular,compound 6a showed the most potent activity with IC50 of 10. 2 μmol·L~(-1),which was equivalent to that of the positive control sorafenib( IC_(50)= 7. 9 μmol·L~(-1)).
Six novel 3-( 2,4-dichlorophenyl)-2,7-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxamides( 6a ～ 6f) were synthesized by condension,cyclization,hydrolysis and amidation reaction using acetacetic ester and N,N-dimethylformamide dimethyl acetal as the starting materials. The structures were characterized by ~1H NMR,~(13)C NMR,IR,MS and elemental analysis. The antiproliferative activities against HepG2 cancer cell lines were tested by MTT assay with sorafenib as the positive control. In particular,compound 6a showed the most potent activity with IC50 of 10. 2 μmol·L~(-1),which was equivalent to that of the positive control sorafenib( IC_(50)= 7. 9 μmol·L~(-1)).
引文
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[14] BECK J R,LYNCH M P. Synthesis of 1-(1,1-dimethylethyl)-1H-pyrazole-4-carboxylate ester derivatives[J]. J Hetero Chem,2010,24(3):693-695.
[2] QUIROGA J,PORTILLA J,ABONIA R,et al. Regioselective synthesis of novel substituted pyrazolo[1,5-a]. pyrimidines under solvent-free conditions[J]. Tetra Lett,2008,48(36):6352-6355.
[3] HASSAN A S,MASOUD D M,SROOR F M,et al.Synthesis and biological evaluation of pyrazolo[1,5-a]. pyrimidine-3-carboxamide as antimicrobial agents[J]. Med Chem Res,2017:1-11.
[4] LU X,TANG J,LIU Z,et al. Discovery of new chemical entities as potential leads against Mycobacterium tuberculosis[J]. Bioor Med Chem Lett,2016,26(24):5916-5919.
[5] ZHAO M,REN H,CHANG J,et al. Design and synthesis of novel pyrazolo[1,5-a]. pyrimidine derivatives bearing nitrogen mustard moiety and evaluation of their antitumor activity in vitro and in vivo[J]. Euro J Med Chem,2016,119:183-196.
[6] AL-ADIWISH W M,TAHIR M I M,SITI-NOOR-ADNALIZAWATI A,et al. Synthesis,antibacterial activity and cytotoxicity of new fused pyrazolo[1,5-a]. pyrimidine and pyrazolo[5,1-c].[1,2,4]. triazine derivatives from new 5-aminopyrazoles[J]. Euro J Med Chem,2013,64(43):464-476.
[7] DESHMUKH S,DINGORE K,GAIKWAD V,et al.An efficient synthesis of pyrazolo[1,5-a]. pyrimidines and evaluation of their antimicrobial activity[J]. J Chem Sci,2016,128(9):1459-1468.
[8] AZEREDO L F,COUTINHO J P,JABOR V A,et al.Evaluation of 7-arylaminopyrazolo[1,5-a]. pyrimidines as anti-Plasmodium falciparum,antimalarial,and Pf-dihydroorotate dehydrogenase inhibitors[J]. Euro J Med Chem,2017,126:72-83.
[9] LIU Y,LAUFER R,PATEL N K,et al. Discovery of pyrazolo[1,5-a]. pyrimidine TTK Inhibitors:CFI-402257 is a potent,selective,bioavailable anticancer agent[J]. ACS Med Chem Lett,2016,7(7):671-675.
[10] GREGG B T,TYMOSHENKO D O,RAZZANO D A,et al. Pyrazolo[1,5-a]pyrimidines. Identification of the privileged structure and combinatorial synthesis of 3-(hetero)arylpyrazolo[1,5-a]pyrimidine-6-carboxamides[J]. J Comb Chem,2007,9(3):507-512.
[11] SHEN H C,TAGGART A K P,WILSIE L C,et al.Discovery of pyrazolopyrimidines as the first class of allosteric agonists for the high affinity nicotinic acid receptor GPR109A[J]. Bioorg Med Chem Lett,2008,18(18):4948-4951.
[12] BLAD C C,VELDHOVEN J P D,KLOPMAN C,et al. Novel 3,6,7-substituted pyrazolopyrimidines as positive allosteric modulators for the hydroxycarboxylic acid receptor 2(GPR109A)[J]. J Med Chem,2012,55(7):3563-3567.
[13] GILLIGAN P J,BALDAUF C,COCUZZA A,et al.The discovery of 4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine:A corticotropin-releasing factor(h CRF 1)antagonist[J]. Bioorg Med Chem,2000,8(1):181-189.
[14] BECK J R,LYNCH M P. Synthesis of 1-(1,1-dimethylethyl)-1H-pyrazole-4-carboxylate ester derivatives[J]. J Hetero Chem,2010,24(3):693-695.