A Drug of Such Damned Nature.1 Challenges and Opportunities in Translational Platinum Drug Research

Abstract

The platinum-based anticancer agents cisplatin, carboplatin, and oxaliplatin represent a spectacular translational science achievement. The basic research observations that led to the discovery of Pt complexes as DNA-binding agents that elicit cell arrest, the preclinical tumor regression studies, and the inorganic medicinal chemistry that led to clinical implementation of effective platinum complexes in the clinic have fueled multidisciplinary research into platinum-based drugs. While the successes are clear and the research activity continues, a significant window of time has passed since a new Pt drug has been approved for clinical use. Here we assess the current Pt drug landscape and challenges for future Pt development and discuss opportunities for improving our understanding of Pt drugs that utilize contemporary translational science tools such as chemical biology and real-time imaging. The underexplored spaces may reveal new opportunities for Pt drug development.

Modulating In Vitro Photodynamic Activities of Copper(II) Complexes

“…The complexes (1)(2)(3)(4) were prepared from a methanolic solution of Cu(NO 3 ) 2 ·3H 2 O by the slow addition of N,N,O (L 1 ) or N,N,S (L 2 ) donor ligands followed by the addition of N,N-diiminebased ligands (L 3 , L 4 ). The complexes were isolated or precipitated as perchlorate salts in about 70 % yield, and the complexes were dried in vacuo with P 4 O 10 after washing.…”

“…The complexes were characterized analytically and spectroscopically (Table S1). [24] Electronic spectra of the ligands and complexes (1)(2)(3)(4) were recorded in aqueous DMF (10 % DMF v/v) ( Figure 1, Table 1, Table S1, Figure S6). Molar conductance values of all the complexes in aqueous DMF (10 % DMF v/v) were typically in the range of 110-125 mS mol -1 , indicating 1:1 electrolyte and corresponding to the complex salt [M]ClO 4 where M is the complex cation.…”

“…[1][2][3][4][5] Systemic side effects in chemotherapy due to highdose requirements and tumor nonspecificity have caused serious concerns, leading to a search for a cost-effective, more tolerable, and tumor-specific treatment modality for cancer. [1][2][3][4][5] Systemic side effects in chemotherapy due to highdose requirements and tumor nonspecificity have caused serious concerns, leading to a search for a cost-effective, more tolerable, and tumor-specific treatment modality for cancer.…”

“…Recently, complexes of biocompatible first-row transition metals with low-energy charge transfer (CT) or dd bands were extensively explored for (visible light)-induced cytotoxicity. Herein, we report the synthesis, analytical characterization, photophysical studies and theoretical evaluation of singlet-oxygen generation on photoactivation, cellular localization, photocytotoxicity studies in human cervical cancer (HeLa) cells, and the photoactivated ROS generation of several new ternary copper(II) complexes [Cu(L 1 )B]ClO 4 (1,2) and [Cu(L 2 )B]ClO 4 (3,4), where L 1 = 2-[(pyridin-2-yl)methyleneamino]phenol, L 2 = 2-[(pyridin-2-yl)methyleneamino]benzenethiol and B are 1H-imidazo [4,5-f ] [1,10]phenanthroline (L 3 ) and 1-(pyren-2-yl)-1H-imidazo [4,5-f ] [1,10]phenanthroline (L 4 ), to explore the role of sulfur and oxygen coordination to Cu II in photocytotoxicity (Scheme 1). Several copper(II) complexes were explored for [singlet oxygen ( 1 O 2 )]-mediated photobiological investigations.…”

“…[18][19][20] Copper is one of the nontoxic, bioessential elements, and therefore, photochemotherapeutic application of copper-based complexes is an interesting and attractive option. Schematic representation of the complexes (1)(2)(3)(4). [21,22] However, the toxicity of the copper(II) complexes in the dark have limited their applications as ideal photosensitizers in photodynamic therapy.…”