A serendipitous crossed aldol reaction in the ligand periphery of a Ru(ii) polypyridyl complex in silica bed: prospects for delivering anticancer agents for photoactivated chemotherapy

Abstract

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, etc. 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)]²⁺ {[1]} [ttp = p-tolyl terpyridine, dppz = dipyrido[3,2-a:2′,3′-c]phenazine, 4-PyCHO = 4-Pyridinecarboxaldehyde] was being purified by silica gel column chromatography with acetone/water/saturated aqueous KNO₃ solution as the eluent. The resultant pure aldol product [Ru(ttp)(dppz)(4-PyCHAc)]²⁺ {[1-Ac]} [4-PyCHAc = aldol modified 4-Pyridinecarboxaldehyde, i.e., 4-hydroxy-4-(pyridin-4-yl)butan-2-one)], was unambiguously characterized by a variety of spectroscopic techniques and X-ray crystallography. Furthermore, a ¹H 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 in situ 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.