Hoang Hung, LaBarbera Daniel V, Mohammed Kaleem A, Ireland Chris M, Skibo Edward B
Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287-1604, USA.
J Med Chem. 2007 Sep 20;50(19):4561-71. doi: 10.1021/jm0700870. Epub 2007 Aug 18.
This report describes the synthesis and biological activity of imidazoquinoxalines, benzimidazole-based analogues of indole-based pyrroloiminoquinone marine natural products. Our analogues consist of series 1, which possesses the ethylene tether and extended amidine feature found in the pyrroloiminoquinone natural products, and series 2, which also has the ethylene tether but with an electrostatically stabilized iminoquinone rather than a resonance stabilized iminoquinone (i.e., extended amidine). The biological properties of series 1 analogues, bearing electron-rich side chain rings (indole and phenol), display cytostatic and cytotoxic properties similar to that of the pyrroloiminoquinone natural products. In contrast, COMPARE analysis suggests that analogues bearing benzyl and phenethyl side chains possess a different cytotoxicity mechanism. Hollow fiber assays of analogs of 1 indicate promising antitumor activity and acceptable levels of toxicity. One analogue of 2 is active only against breast cancer cell lines, but the cellular target is as yet unknown.
本报告描述了咪唑并喹喔啉类化合物的合成及其生物活性，这类化合物是基于苯并咪唑的吲哚基吡咯并亚氨基醌海洋天然产物的类似物。我们的类似物包括系列1，其具有在吡咯并亚氨基醌天然产物中发现的乙烯连接基和延伸的脒特征；以及系列2，其同样具有乙烯连接基，但带有静电稳定的亚氨基醌而非共振稳定的亚氨基醌（即延伸的脒）。带有富电子侧链环（吲哚和苯酚）的系列1类似物的生物学特性显示出与吡咯并亚氨基醌天然产物相似的细胞生长抑制和细胞毒性特性。相比之下，COMPARE分析表明，带有苄基和苯乙基侧链的类似物具有不同的细胞毒性机制。对系列1类似物的中空纤维试验表明其具有有前景的抗肿瘤活性和可接受的毒性水平。系列2的一种类似物仅对乳腺癌细胞系有活性，但其细胞靶点尚不清楚。
