Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal.
Dalton Trans. 2020 May 14;49(18):5974-5987. doi: 10.1039/d0dt00955e. Epub 2020 Apr 21.
In this work we explored the possibility of improving the selectivity of a cytotoxic Ru complex [RuCp(PPh)(2,2'-bipy)][CFSO] (where Cp = η-cyclopentadienyl) TM34 towards FGFR(+) breast cancer cells. Molecular dynamics (MD) simulations of TM34 in a phosphatidylcholine membrane model pinpointed the cyclopentadienyl group as a favorable derivatization position for the peptide conjugation approach. Three new Ru(ii) complexes presenting a functionalized η-cyclopentadienyl were synthesized, namely [Ru(η-CHCOOH)(2,2'-bipy)(PPh)][CFSO] (TM281) and its precursors, [Ru(η-CHCOOCHCH)(η-2,2'-bipy)(PPh)][CFSO] (3) and [Ru(η-CHCOOCHCH)(PPh)Cl] (2). Complex TM281 was prepared by the hydrolysis of the ethyl ester group appended to the η-cyclopentadienyl ligand of complex 3 with KCO in water/acetonitrile, followed by mild protonation using an ion exchange resin. The newly synthesized complexes were fully characterized by NMR, FTIR and UV-vis spectroscopic techniques. Also, electrochemical studies were carried out by means of cyclic voltammetry in order to evaluate the stability of the compounds. Single crystal X-ray diffraction studies were carried out for compounds 3 and TM281 which crystallized in the monoclinic system, space group P21/n. The unprecedented synthesis and characterization of three half-sandwich ruthenium(ii)-cyclopentadienyl peptide conjugates and their preliminary biological evaluation against human FGFR(+) and FGFR(-) breast cancer cells are also reported.
在这项工作中，我们探索了提高细胞毒性 Ru 配合物[RuCp(PPh)(2,2'-bipy)][CFSO](其中 Cp=η-环戊二烯基)TM34 对 FGFR(+)乳腺癌细胞选择性的可能性。在磷脂膜模型中对 TM34 的分子动力学(MD)模拟指出，环戊二烯基是肽键合方法的有利衍生化位置。合成了三个呈现官能化η-环戊二烯基的新 Ru(ii)配合物，即[Ru(η-CHCOOH)(2,2'-bipy)(PPh)]CFSO及其前体[Ru(η-CHCOOCHCH)(η-2,2'-bipy)(PPh)]CFSO和Ru(η-CHCOOCHCH)(PPh)Cl。通过 KCO 在水/乙腈中的水解，将 3 中η-环戊二烯基配体上的乙酯基团水解，然后用离子交换树脂温和质子化，制备配合物 TM281。新合成的配合物通过 NMR、FTIR 和 UV-vis 光谱技术进行了充分的表征。还通过循环伏安法进行了电化学研究，以评估化合物的稳定性。化合物 3 和 TM281 进行了单晶 X 射线衍射研究，它们结晶于单斜晶系，空间群 P21/n。还报道了三种半夹心钌(ii)-环戊二烯基肽缀合物的前所未有的合成和表征及其对人 FGFR(+)和 FGFR(-)乳腺癌细胞的初步生物学评价。
