Tsyganov Dmitry V, Samet Alexander V, Silyanova Eugenia A, Ushkarov Vladimir I, Varakutin Alexander E, Chernysheva Natalia B, Chuprov-Netochin Roman N, Khomutov Andrey A, Volkova Anna S, Leonov Sergey V, Semenova Marina N, Semenov Victor V
N.D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation.
School of Biological and Medical Physics, Moscow Institute of Physics and Technology, Institutskiy per. 9, Dolgoprudny, Moscow Region 141701, Russian Federation.
ACS Omega. 2022 Jan 24;7(4):3369-3383. doi: 10.1021/acsomega.1c05515. eCollection 2022 Feb 1.
Derivatives of natural allylpolyalkoxybenzenes conjugated to triphenylphosphonium (TPP) cations by aliphatic linkers of three, six, seven, and eight atoms were synthesized to examine the role of the polyalkoxybenzene pharmacophore, TPP fragment, and linker length in antiproliferative activities. The key synthetic procedures included (i) hydroboration-oxidation of apiol, dillapiol, myristicin, and allyltetramethoxybenzene; (ii) acylation of polyalkoxybenzyl alcohols or amines; and (iii) condensation of polyalkoxybenzaldehydes followed by hydrogenation and cyclopropyl-homoallyl rearrangement. The targeted TPP conjugates as well as the starting allylbenzenes, the corresponding alkylpolyalkoxybenzenes, and the respective alkyl-TPP salts were evaluated for cytotoxicity in a panel of human cancer cell lines using MTT and Click-iT-EdU assays and in a sea urchin embryo model. The linker of three carbon atoms was identified as favorable for selective cancer cell growth inhibition. Although the propyl-TPP salt was cytotoxic at low micromolar concentrations, the introduction of a polyalkoxybenzene moiety significantly potentiated inhibition of both cell growth and DNA synthesis in several human cancer cell lines, HST-116 colon cancer, A375 melanoma, PC-3 prostate cancer, and T-47D breast carcinoma cells, while it failed to produce any developmental abnormalities in the sea urchin embryos.
合成了通过三、六、七和八个原子的脂肪族连接体与三苯基鏻（TPP）阳离子共轭的天然烯丙基聚烷氧基苯衍生物，以研究聚烷氧基苯药效基团、TPP片段和连接体长度在抗增殖活性中的作用。关键的合成步骤包括：（i）芹菜脑、莳萝脑、肉豆蔻醚和烯丙基四甲氧基苯的硼氢化-氧化反应；（ii）聚烷氧基苄醇或胺的酰化反应；以及（iii）聚烷氧基苯甲醛的缩合反应，随后进行氢化反应和环丙基-高烯丙基重排反应。使用MTT和Click-iT-EdU测定法以及海胆胚胎模型，对目标TPP共轭物以及起始烯丙基苯、相应的烷基聚烷氧基苯和各自的烷基-TPP盐在一组人类癌细胞系中的细胞毒性进行了评估。已确定三个碳原子的连接体有利于选择性抑制癌细胞生长。尽管丙基-TPP盐在低微摩尔浓度下具有细胞毒性，但引入聚烷氧基苯部分显著增强了对几种人类癌细胞系（HST-116结肠癌、A375黑色素瘤、PC-3前列腺癌和T-47D乳腺癌细胞）的细胞生长和DNA合成的抑制作用，同时它在海胆胚胎中未产生任何发育异常。
