Synthetic study of novel antitumor agents

番荔枝内酯是具有通过长烃链与α，β-不饱和-γ-内酯环连接的一个至三个四氢呋喃环的聚酮化合物。由于抑制线粒体NADH泛醌氧化还原酶（复合物I），它们表现出抗肿瘤活性。我们对acetogeinns和针对复合物I的农药之间的结构和生物学相似性感兴趣，并设计了它们的杂交分子。目前，我们发现噻吩类化合物对人癌细胞株具有较强的抑制活性，并合成了三个茄素（solamin）的C35-氟代类似物。结果表明，γ-内酯部分上的氟原子数影响对人癌细胞系的生长抑制活性，表明乙酸配基中的γ-内酯部分可能在乙酸配基与靶分子之间的相互作用中起重要作用。

Annonaceous acetogenins are polyketides featuring one to three tetrahydrofuran ring(s) connected an alpha,beta-unsaturated-gamma-lactone ring via a long hydrocarbon chain. They exhibit an antitumor activity, owing to the inhibition of mitochondrial NADH ubiquinone oxidoreductase (complex I). We were interested in structural and biological similarities between acetogeinns and pesticides targeting complex I, and designed hybrid molecules of them. Now, we revealed that the thiophen analogue showed potent inhibitory activities against human cancer cell lines.The convergent synthesis of three C35-fluorinated analogues of solamin, a mono-THF acetogenin, has also been achieved. As a result, it was revealed that the number of fluorine atoms on the gamma-lactone moiety affects the growth inhibitory activity against human cancer cell lines, indicating that the gamma-lactone moiety in acetogenins may play an important role in the interaction between acetogenins and the target molecules.