The bpy (IC₅₀, 7 nM) and 5,6-dmp (IC₅₀,13.57 nM) Cu(ii) complexes exhibit phenomenal cytotoxicity.

A series of mixed-ligand Cu(II) complexes of the type: (i) [Cu(l-pro)(diimine)(H₂O)_n](ClO₄) (n = 0 or 1), where l-pro is l-proline and diimine is 2,2′-bipyridine (bpy; 1), (ii) 4,4′-dimethyl-2,2′-bipyridine (dmbpy; 2), (iii) 1,10-phenanthroline (phen; 3), (iv) 5,6-dimethyl-1,10-phenanthroline (5,6-dmp; 4), (v) 3,4,7,8-tetramethyl-1,10-phenanthroline (3,4,7,8-tmp; 5), (vi) dipyrido-[3,2-f:2′,3′-h]-quinoxaline (dpq; 6), and (vii) dipyrido[3,2-a:2′,3′-c]phenazine (dppz; 7) have been synthesized and characterized systematically. Complexes 2 and 3 have been structurally characterized. DNA- and protein-binding and cleavage studies revealed that 7 possesses stronger DNA- and protein-binding efficiency and also exhibits self-activating DNA-cleavage in the absence of an activating agent. The hydrophobic complexes 4 and 5 induced self-activated protein cleavage and yielded a single-cleaved fragment each. The cytotoxic property of all the seven complexes was examined by incubation with the human small cell lung carcinoma cell line A549. Complexes 4 and 6 exhibited almost similar cytotoxic properties [IC₅₀ = 1.4 µM (4) and 1.3 µM (6)], which was 9.3 and 10 times, respectively, more efficient than cisplatin (IC₅₀ = 13 µM). Complex 4 induced generation of the highest level of intracellular ROS which correlates with its efficient cytotoxic activity and provides scope for further investigation as a potential anticancer agent.

The higher DNA binding ability, lipophilicity, reversible Cu^II/Cu^I redox behavior, and ability to oxidatively cleave DNA and to produce ROS confers on the 5,6-dmp complex remarkable cytotoxicity (IC₅₀, 1.26 μM) against HeLa cervical cancer cells.

This research was aimed at finding the cytotoxic potential of the mixed ligand copper(II) complex [Cu(tdp)(phen)](ClO₄)—where H(tdp) is the tetradentate ligand 2-[(2-(2-hydroxyethylamino)-ethylimino)methyl]phenol, and phen is 1,10-phenanthroline—to two genotypically different breast cancer cells, MCF-7 (p53⁺ and ER⁺) and MDA-MB-231 (p53^- and ER^-). The complex has been already shown to be cytotoxic to ME180 cervical carcinoma cells. The special focus in this study was the induction of cell death by apoptosis and necrosis, and its link with ROS. The treatment brought about nuclear fragmentation, phosphatidylserine externalization, disruption of mitochondrial trans-membrane potential, DNA damage, cell cycle arrest at sub-G1 phase, and increase of ROS generation, followed by apoptotic death of cells during early hours and a late onset of necrosis in the cells surviving the apoptosis. The efficacy of the complex against genotypically different breast cancer cells is attributed to a strong association through p53-mitochondrial redox—cell cycle junction. The ADMET properties and docking of the complex at the active site of Top1 are desirable attributes of a lead molecule for development into a therapeutic. Thus, it is shown that the copper(II)–phenolate complex[Cu(tdp)(phen)]⁺ offers potential to be developed into a therapeutic for breast cancers in general and ER-negative ones in particular.

Mesotetra(4-carboxyphenyl)porphyrin (mTCPP) is a commercially available small molecule fluorophore and photosensitizer with four free carboxylic acid groups. mTCPP can readily be conjugated with amines for facile attachment of functional groups. In this work, we synthesized and assessed tetravalent, lysine-conjugated mTCPP, for its potential applications in targeted imaging and photodynamic therapy. Fmoc-protected d-lysine or l-lysine was conjugated to mTCPP via amide coupling with the epsilon amine group of lysine, followed by Fmoc deprotection. The resulting compounds did not dissolve well in aqueous solvent, but could be solubilized with the assistance of surfactants, including cholic acid. The l-amino acid transporter (LAT1) can uptake diverse neutral l-amino acids. In vitro studies with U87 cells revealed a non-specific uptake of the hydrophobic Fmoc-protected lysine-conjugated mTCPP precursors, but not d- or l-lysine mTCPP. Likewise, only the Fmoc-protected compounds induced substantial phototoxicty in cells following incubation and irradiation with blue light. These experimental results do not provide evidence to suggest that lysine-mTCPP is able to specifically target cancer cells. However, they do highlight mTCPP as a convenient and accessible framework for assessing molecular targeting of photosensitizers.