Al Otaibi Ahmed, Deane Fiona M, Russell Cecilia C, Hizartzidis Lacey, McCluskey Siobhann N, Sakoff Jennette A, McCluskey Adam
Chemistry, School of Environmental & Life Sciences, The University of Newcastle University Drive, Callaghan NSW 2308 Australia
Department of Medical Oncology, Calvary Mater Newcastle Hospital Edith Street Waratah 2298 Australia.
RSC Adv. 2019 Mar 8;9(14):7652-7663. doi: 10.1039/c9ra00118b. eCollection 2019 Mar 6.
The Ugi four component reaction of an aldehyde, amine, isocyanide and an ethanoic acid was effected smoothly in protic ionic liquids ethylammonium nitrate (EAN) and propylammonium nitrate (PAN) to afford analogues of α-phenylacetamido amides in good to excellent isolated yields. The corresponding reactions in [BMIM][PF] and the protic ionic liquid ethanolammonium nitrate (ETAN) failed. Microwave irradiation in EAN facilitated rapid access to three focused libraries, based on the parent isocyanide: cyclohexyl isocyanide, benzyl isocyanide and ethyl isocyanoacetate. Analysis of the structure activity relationship data suggested the presence of a bulky moiety originating from the isocyanide (cyclohexyl and benzyl) enhanced cytotoxicity. Removal of the acetylenic H-atom from the ethanoic acid moiety was detrimental to cytotoxicity. The most active analogues produced, -(2-cyclohexylamino)-1-(4-methoxyphenyl)-2-oxoethyl--(3,5-dimethoxyphenyl)propiolamide, returned average GI values of ≤1 μM across the cancer cell lines evaluated. Combined, these data suggest that analogues of this nature are interesting potential anti-cancer development leads.
醛、胺、异腈和乙酸的Ugi四组分反应在质子离子液体硝酸乙铵（EAN）和硝酸丙铵（PAN）中顺利进行，以良好至优异的分离产率得到α-苯基乙酰胺类似物。在[BMIM][PF]和质子离子液体硝酸乙醇铵（ETAN）中进行的相应反应失败。在EAN中进行微波辐射有助于快速获得基于母体异腈的三个聚焦库：环己基异腈、苄基异腈和异氰基乙酸乙酯。结构活性关系数据分析表明，源自异腈（环己基和苄基）的庞大基团的存在增强了细胞毒性。从乙酸部分去除乙炔氢原子对细胞毒性不利。所产生的活性最高的类似物，即-(2-环己基氨基)-1-(4-甲氧基苯基)-2-氧代乙基-(3,5-二甲氧基苯基)丙炔酰胺，在所评估的癌细胞系中返回的平均GI值≤1μM。综合这些数据表明，这种性质的类似物是有趣的潜在抗癌开发先导物。
