Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, Uttar Pradesh, India.
Department of Chemistry, Howard University, Washington, DC 20059, USA.
Dalton Trans. 2024 Nov 26;53(46):18484-18493. doi: 10.1039/d4dt02337d.
The localized drug action in tumors to overcome the side effects of chemotherapy has become an impetus for the development of photoactivated chemotherapy (PACT). As potential PACT agents, ruthenium(II) polypyridyl complexes have emerged as efficient photocages for anticancer agents. Bioactive molecules possessing functional groups such as nitrile, thioether, pyridine, imidazole, . are often directly attached to the primary coordination sphere of Ru(II) polypyridyl complexes for this purpose. Herein, we propose an alternative design strategy to attach potential anticancer agents lacking these functional groups with Ru(II) polypyridyl complexes through a pyridyl linker moiety. The proposition is, however, a thoughtful extrapolation of a serendipitous crossed aldol reaction that took place between the Ru(II)-coordinated 4-Pyridinecarboxaldehyde (4-PyCHO) and acetone, discovered while the Ru(II)-complex [Ru(ttp)(dppz)(4-PyCHO)] {[1]} [ttp = -tolyl terpyridine, dppz = dipyrido[3,2-:2',3'-]phenazine, 4-PyCHO = 4-Pyridinecarboxaldehyde] was being purified by silica gel column chromatography with acetone/water/saturated aqueous KNO solution as the eluent. The resultant pure aldol product [Ru(ttp)(dppz)(4-PyCHAc)] {[1-Ac]} [4-PyCHAc = aldol modified 4-Pyridinecarboxaldehyde, , 4-hydroxy-4-(pyridin-4-yl)butan-2-one)], was unambiguously characterized by a variety of spectroscopic techniques and X-ray crystallography. Furthermore, a H NMR study after 470 nm light irradiation and subsequent ESI-MS analysis revealed that 4-PyCHO could be photo-released from [1-Ac] as its generated aldol adduct 4-PyCHAc. Therefore, this finding serves as a proof-of-concept that provides a simpler alternative design strategy for appending cancer-selective agents having carbonyl groups with α-hydrogens to ruthenium(II) polypyridyl complexes and their photorelease for selective and targeted anticancer chemotherapy.
肿瘤局部药物作用克服化疗副作用已成为光动力化疗（PACT）发展的动力。作为潜在的 PACT 试剂，钌（II）多吡啶配合物已成为有效的抗癌剂光笼。具有氰基、硫醚、吡啶、咪唑等功能基团的生物活性分子通常直接连接到 Ru(II) 多吡啶配合物的初级配位球中，以达到此目的。在此，我们提出了一种替代设计策略，通过吡啶连接基将缺乏这些功能团的潜在抗癌剂与 Ru(II) 多吡啶配合物连接。然而，这一建议是对 Ru(II) 配位的 4-吡啶甲醛（4-PyCHO）和丙酮之间发生的交叉羟醛反应的一种深思熟虑的推断，该反应是在 Ru(II)-配合物 [Ru(ttp)(dppz)(4-PyCHO)]{[1]} [ttp = -甲苯基三吡啶，dppz = 二吡啶并[3,2-a:2',3'-c]吩嗪，4-PyCHO = 4-吡啶甲醛]通过硅胶柱层析用丙酮/水/饱和硝酸钾溶液作为洗脱剂进行纯化时发现的。所得的纯羟醛产物 [Ru(ttp)(dppz)(4-PyCHAc)]{[1-Ac]}[4-PyCHAc = 羟醛修饰的 4-吡啶甲醛， ，4-羟基-4-(吡啶-4-基)丁-2-酮]），通过各种光谱技术和 X 射线晶体学得到了明确的表征。此外，470nm 光照射后的 1H NMR 研究和随后的 ESI-MS 分析表明，4-PyCHO 可以从[1-Ac]中光解出，作为其 生成的羟醛加合物 4-PyCHAc。因此，这一发现证明了一种概念验证，为将具有α-氢的羰基的癌症选择性试剂连接到钌（II）多吡啶配合物并进行光解以用于选择性和靶向抗癌化疗提供了一种更简单的替代设计策略。
