Centre for Chemical Biology, Chemistry, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
Bioorg Med Chem. 2013 Jan 1;21(1):333-47. doi: 10.1016/j.bmc.2012.10.003. Epub 2012 Oct 23.
With our lead compound (E)-3-(4-chlorophenyl)-2-(1H-pyrrole-2-carbonyl)acrylonitrile (1) inducing 50% growth inhibition of 11 cancer cell lines at 27-61 μM, potency enhancements were rapidly established through the synthesis of a series of focused compound libraries. Six highly focused libraries (46 compounds in total) were synthesised. Each library allowed the identification of a new lead compound, viz Library A identified (E)-3-(pentafluorophenyl)-2-(1H-pyrrole-2-carbonyl)acrylonitrile (11) and (E)-3-(1H-indol-3-yl)-2-(1H-pyrrole-2-carbonyl)acrylonitrile (13) as inhibitors with improved cytotoxicity. Synthesis of discrete libraries of amidoacrylamide analogues (Ar-CC(CN)-Ar✠Ar-CC(CN)-C(O)NH)-Ar) resulted in a series of analogues significantly more potent that the lead, 1. Three furan three analogues: (E)-3-(5-chlorofuran-2-yl)-2-cyano-N-(4-methoxybenzyl)acrylamide (33), (E)-3-(5-bromofuran-2-yl)-2-cyano-N-(4-methoxybenzyl)acrylamide (34) and (E)-2-cyano-3-(furan-3-yl)-N-(4-methoxybenzyl)acrylamide (37) returned broad spectrum growth inhibition (GI(50) values of 5-16 μM). Replacement of the furan moiety with simple aromatics gave an additional three analogues: (E)-2-cyano-N-(4-methoxybenzyl)-3-phenylacrylamide (39), (E)-3-(4-chlorophenyl)-2-cyano-N-(4-methoxybenzyl)acrylamide (41) and (E)-2-cyano-N-(4-methoxyphenyl)-3-(naphthalen-1-yl)acrylamide (45) with GI(50) values of 7-24 μM. The final library retained the aromatic substituents but introduced a 3,4-dichlorbenzylamine moiety to afford the 1-naphthyl substituted 52, which was the most potent broad spectrum cytotoxic analogue produced here in with an average GI(50)=8.6 μM. This represents a fivefold potency enhancement relative to 1 and a new cytotoxic scaffold suitable for further development.
用我们的先导化合物 (E)-3-(4-氯苯基)-2-(1H-吡咯-2-羰基)丙烯腈 (1) 在 27-61 μM 时抑制 11 种癌细胞系的生长达到 50%，通过合成一系列聚焦化合物库迅速提高了活性。合成了六个高度聚焦的库（总共 46 个化合物）。每个库都能鉴定出一种新的先导化合物，即库 A 鉴定出 (E)-3-(五氟苯基)-2-(1H-吡咯-2-羰基)丙烯腈 (11) 和 (E)-3-(1H-吲哚-3-基)-2-(1H-吡咯-2-羰基)丙烯腈 (13)，它们具有改善的细胞毒性。酰胺丙烯酰胺类似物 (Ar-CC(CN)-Ar✠Ar-CC(CN)-C(O)NH)-Ar) 的离散库的合成导致一系列比先导化合物 1 更有效的类似物。三种呋喃三类似物：(E)-3-(5-氯呋喃-2-基)-2-氰基-N-(4-甲氧基苄基)丙烯酰胺 (33)、(E)-3-(5-溴呋喃-2-基)-2-氰基-N-(4-甲氧基苄基)丙烯酰胺 (34) 和 (E)-2-氰基-3-(呋喃-3-基)-N-(4-甲氧基苄基)丙烯酰胺 (37) 表现出广谱生长抑制作用（GI(50) 值为 5-16 μM）。用简单的芳烃取代呋喃部分得到另外三个类似物：(E)-2-氰基-N-(4-甲氧基苄基)-3-苯基丙烯酰胺 (39)、(E)-3-(4-氯苯基)-2-氰基-N-(4-甲氧基苄基)丙烯酰胺 (41) 和 (E)-2-氰基-N-(4-甲氧基苯基)-3-(萘-1-基)丙烯酰胺 (45)，GI(50) 值为 7-24 μM。最后一个库保留了芳基取代基，但引入了 3,4-二氯苯甲胺部分，得到 1-萘基取代的 52，这是目前产生的最有效广谱细胞毒性类似物之一，平均 GI(50)=8.6 μM。这相对于 1 提高了五倍的活性，是一种适合进一步开发的新细胞毒性支架。
