开发了在亲核膦催化剂的影响下,用氮和碳为中心的亲核试剂对抗癌天然产物arglabin进行化学和非对映选择性修饰的通用方法。arglabin的α-亚甲基-γ-丁内酯部分的锁定s-顺式几何结构有利于通过磷和烯醇化氧中心之间的静电相互作用来进一步稳定两性离子中间体,导致对该倍半萜内酯进行空前有效的膦催化的迈克尔加成。使用n-Bu3P作为催化剂,吡唑,邻苯二甲酰亚胺,2-恶唑烷酮,4-喹唑啉酮,尿嘧啶,胸腺嘧啶,胞嘧啶,获得了arglabin的腺嘌呤加合物。arglabin与活性亚甲基化合物的n-Bu3P催化反应导致主要形成带有新的季碳中心的双加合物。在体外评估了所有合成的Michael加合物和先前获得的磷酸化的arglabin衍生物对11种癌症和两种正常细胞系的作用,并将结果与目前用作抗癌药物的天然arglabin及其二甲基氨基盐酸盐的结果进行了比较。2-恶唑烷酮,尿嘧啶,丙二酸二乙酯,二苄基膦酸酯,与参考化合物相比,arglabin的氰甲基膦酸二乙酯衍生物对几种癌细胞系表现出更强的抗增殖活性,对正常细胞系的细胞毒性较低,表明所开发的方法用于设计具有更好治疗潜力的新型抗癌药物的可行性。
A general method for chemo- and diastereoselective modification of anticancer natural product arglabin with nitrogen- and carbon-centered pronucleophiles under the influence of nucleophilic phosphine catalysts was developed. The locked s-cis-geometry of α-methylene-γ-butyrolactone moiety of arglabin favors for the additional stabilization of the zwitterionic intermediate by electrostatic interaction between phosphonium and enolate oxygen centers, leading to the unprecedentedly high efficiency of the phosphine-catalyzed Michael additions to this sesquiterpene lactone. Using n-Bu3P as the catalyst, pyrazole, phthalimide, 2-oxazolidinone, 4-quinazolinone, uracil, thymine, cytosine, and adenine adducts of arglabin were obtained. The n-Bu3P-catalyzed reaction of arglabin with active methylene compounds resulted in the predominant formation of bisadducts bearing a new quaternary carbon center. All synthesized Michael adducts and previously obtained phosphorylated arglabin derivatives were evaluated in vitro against eleven cancer and two normal cell lines, and the results were compared to those of natural arglabin and its dimethylamino hydrochloride salt currently used as anticancer drugs. 2-Oxazolidinone, uracil, diethyl malonate, dibenzyl phosphonate, and diethyl cyanomethylphosphonate derivatives of arglabin exhibited more potent antiproliferative activity towards several cancer cell lines and lower cytotoxicity towards normal cell lines in comparison to the reference compounds, indicating the feasibility of the developed methodology for the design of novel anticancer drugs with better therapeutic potential.