Saito Yohei, Kobayashi Yukiko, Yoshida Nanami, Goto Masuo, Nakagawa-Goto Kyoko
School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7568, United States.
J Org Chem. 2021 May 21;86(10):7092-7106. doi: 10.1021/acs.joc.1c00348. Epub 2021 May 12.
The oxygen in the benzofuran (BF) of three antiproliferative natural neolignans, salvinal (), obovaten (), and 2-[7-methoxy-2-(4-methoxyphenyl)-3-methylbenzofuran-5-yl]ethanol (), was replaced with sulfur to form the new biological scaffold benzothiophene (BT) thio-lignans -. Compounds - and synthesized derivatives were evaluated for antiproliferative activity against five human cancer cell lines, including a multidrug-resistant cell line. Thio-salvinal () displayed significant antiproliferative effects with half-maximal inhibitory concentration (IC) values of 0.57-0.95 μM against all tested cell lines, except for the HER2 negative breast cancer cell line MCF-7. This thio-lignan was 6.5-9.4 times more potent than parent . However, the related thio-lignans, and , showed much weaker antiproliferative effects than and were less potent than the parent natural benzofuran lignans and . Newly synthesized thio-lignan affected cell cycle progression at 24 and 48 h in the G2/M transition and S phase, respectively, as well as promoted sub-G1 induction by stimulating microtubule depolymerization and nuclear fragmentation. Since a highly reactive aldehyde in salvinal is generally not appropriate for drug development, we have successfully found nonaldehyde derivative showing biological activity similar to salvinal by replacing BF with BT and an aldehyde with 1,3-dioxolane.
三种具有抗增殖活性的天然新木脂素（salvinal、倒卵叶五味子素和2-[7-甲氧基-2-(4-甲氧基苯基)-3-甲基苯并呋喃-5-基]乙醇）苯并呋喃（BF）结构中的氧原子被硫原子取代，形成了新的生物骨架苯并噻吩（BT）硫代木脂素。对化合物及合成衍生物针对包括一种多药耐药细胞系在内的五种人类癌细胞系的抗增殖活性进行了评估。硫代salvinal对除HER2阴性乳腺癌细胞系MCF-7外的所有测试细胞系均表现出显著的抗增殖作用，其半数最大抑制浓度（IC）值为0.57 - 0.95 μM。这种硫代木脂素的活性比母体化合物高6.5 - 9.4倍。然而，相关硫代木脂素和的抗增殖作用比弱得多，且比母体天然苯并呋喃木脂素和的活性低。新合成的硫代木脂素在24小时和48小时分别影响细胞周期进程，使细胞停滞在G2/M期转换和S期，还通过刺激微管解聚和核碎片化促进亚G1期诱导。由于salvinal中一种高反应性醛通常不适用于药物开发，我们通过用BT取代BF并用1,3 - 二氧戊环取代醛基，成功发现了具有与salvinal相似生物活性的非醛衍生物。
