环戊烯酮类前列腺素的合成新方法及其靶向白血病干细胞活性研究

The cyclopentenone prostaglandins (cycPG) are a kind of prostaglandins with particular bioactivities. Recently, a novel and natural cycPG named Δ12-PGJ3 has been reported to exhibit antileukemic activity targeting leukemia stem cells (LSC) at nanomolar concentrations. This study offered hope for the establishment of a new class of drugs with antileukemic activity. However, this compound has never been isolated and also difficult to be synthesized. Thus, it is the primary task to obtain enough samples of Δ12-PGJ3 and analogs for further R&D. Recently, we have high efficiently synthesized the cycPG Epoxyisoprostane through organocatalytic and one-pot reactions. On this basis, herein we proposed that the chiral cyclopentenone core of Δ12-PGJ3 could be accessed from α, β-unsaturated aldehyde, acetoacetate and wittig reagents through organocatalytic Michael/Wittig/Aldol reaction. Then a series of cycPG such as Δ12-PGJ2, 15d-Δ12,14-PGJ2 and particularly Δ12-PGJ3 and analogs could be efficiently synthesized. With the library of cycPG, the antileukemic activity targeting LSC will be evaluated and the SAR will be obtained, which will open the way for further R&D of cycPG as antileukemic drugs.

环戊烯酮前列腺素(cycPG)是一类具有特异生物活性的前列腺素。近期发现cycPG类新化合物Δ12-PGJ3，能靶向杀死小鼠体内白血病干细胞(LSC)，有望被用于治疗白血病，极具开发前景。但该化合物来源稀缺，合成路线冗长繁琐（仅一例合成报道），为深入活性研究和药物开发带来了困难。前期我们通过有机催化和一锅法反应，完成了具有相同母核的前列腺素Epoxyisoprostane的高效合成。在此基础上，本项目首次提出以α,β-不饱和醛、乙酰乙酸酯和Wittig试剂为原料，通过有机催化Michael/Wittig/Aldol反应来构建手性环戊烯酮母核，再经简单转化，可实现包括Δ12-PGJ3在内的多个cycPG类化合物的高效合成。进一步通过共同中间体策略，拟首次合成一系列的Δ12-PGJ3类似物，并考察其靶向LSC的活性，初步揭示构效关系，为进一步开发新型LSC靶向药物奠定基础。

环戊烯酮前列腺素(cycPG)是一类具有特异生物活性的前列腺素。近期发现cycPG类新化合物Δ12-PGJ3，能靶向杀死小鼠体内白血病干细胞(LSC)，有望被用于治疗白血病，极具开发前景。但该化合物来源稀缺，合成路线冗长繁琐（仅一例合成报道），为深入活性研究和药物开发带来了困难。我们通过有机催化和一锅法反应，完成了具有相同母核的前列腺素Epoxyisoprostane的高效合成。进一步地，本项目实现了以α,β-不饱和醛、乙酰乙酸酯和Wittig试剂为原料，通过有机催化Michael/Wittig/Aldol反应来构建手性环戊烯酮母核，并以此为关键方法学，完成了包括15-d-Δ12,14-PGJ2、Δ12-PGJ3和Δ12-PGJ2d等在内的多个cycPG类化合物的高效全合成。进一步通过共同中间体策略，合成了一系列的Δ12-PGJ3类似物，并考察其靶向LSC的活性，为进一步开发新型LSC靶向药物奠定了基础。