設計與合成苯偶氮駢和考布他汀A4的新穎抗癌衍生物

我們近年來的研究中證實Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) 與具有活性的小分子結合而得的混成試劑(Hybrid agents)可以提供更佳的抗癌選擇活性，並且嘗試著利用夾子化學(CuAAC, copper catalyzed alkyne azide cycloaddition)去修飾PBD的架構來合成Triazolo[4,5-d]quinoline/chromene/thiochromene衍生物，藉以縮短全合成的步驟並提升抗癌活性。另一方面，同樣在近年來也相當受到矚目的抗癌衍生物Combretastatin A-4 (CA4)，我們利用較符合原子經濟性、環境保護性、產率及位向選擇性高的PivOH以及TFA做為反應試劑藉由one-pot的方式去進行Combretastatin A-4抗癌新穎混成衍生物(CA4-quinoxaline、CA4-imidazole、CA4-spiroimidazole、CA4-oxazole)的合成，取代傳統合成路徑，藉此解決產率過低、位向選擇性太差，以及藉由昂貴且對環境具有高傷害的過渡金屬去進行催化…等的缺點，將合成得到的Triazolo[4,5-d]quinoline/chromene/thiochromene衍生物及PBDs與修飾後取得的Combretastatin A-4衍生物進行初步的體外細胞活性篩選(in vitro)，期望這類衍生物可以提供較佳的抗癌選擇活性。

關鍵字

抗癌衍生物；苯偶氮駢；考布他汀A4

並列摘要

The Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) conjugate agents with active moieties of known antitumor and antiviral agents are being designed and synthesized to provide highly sequence-selective DNA-interactive properties and antitumor activity. Based on above reason, a series of hybrid agents PBD-indole, PBD-Gallic, PBD-triazole and PBD-enediyne was designed and synthesized to provide highly sequence-selective DNA-interactive properties and antitumor activity, which was reported by our groups. With the background in mind, we hereby intend to propose the design and synthesis of novel triazolo[4,5-d]quinoline/chromene/thiochromene derivatives via CuAAC reaction (Copper catalyzed alkyne azide cycloaddition). In view of this reason, the new approach to construct the new series activity motif with the simple, efficient, and eco-friendly methodology, which could be overcome the previously drawback such as laborious and complex work-up and purification procedure, generation of significant amounts of waste materials, strong acidic conditions, occurrence of side reactions, low yields, use of expensive transition metal as a catalysts. On the other hand, the Combretastatin A-4 derivatives are known of its anticancer activity via inhibitor of tubulin assembly. Based on the above facts, a variety of synthetic routes have been devised for the synthesis of CA4 analogues. However, most of previous methods suffer from one or more limitations such as harsh reaction conditions, unsatisfactory product yields, tedious isolation procedures, expensive and detrimental metal precursors, which limit their use under the aspect of environmentally benign processes. Futhermore, the Structure activity relationship demonstrated CA4 derivatives, which cis-form is more effective anticancer activity than trans-form. Based on above reason, we have described a simple, efficient, and eco-friendly methodology for the synthesis of the Combretastatin A-4 with quinoxalines, imidazole, spiroimidazole, and oxzole as restrict to construct CA4-quinoxaline, CA4-imidazole, CA4-spiroimidazole, CA4-oxazole derivatives as novel anticancer agents. Finally, the MTT assay was screened against human cancer cell line, that the promising antitumor activity was reported.