Helicates and related metallofoldamers, synthesised by dynamic self-assembly, represent an area of chemical space inaccessible by traditional organic synthesis, and yet with potential for discovery of new classes of drug. Here we report that water-soluble, optically pure Fe(ii)- and even Zn(ii)-based triplex metallohelices are an excellent platform for post-assembly click reactions. By these means, the in vitro anticancer activity and most importantly the selectivity of a triplex metallohelix Fe(ii) system are dramatically improved. For one compound, a remarkable array of mechanistic and pharmacological behaviours is discovered: inhibition of Na+/K+ ATPase with potency comparable to the drug ouabain, antimetastatic properties (including inhibition of cell migration, re-adhesion and invasion), cancer stem cell targeting, and finally colonosphere inhibition competitive with the drug salinomycin.

• Publication type
• Journal Article MeSH

The cisplatin analogues cis-[PtCl2(3ClHaza)2] (1) and cis-[PtCl2(3IHaza)2] (2) (3ClHaza and 3IHaza are 3-chloro-7-azaindole and 3-iodo-7-azaindole, respectively) are quite toxic to ovarian tumor cells, with moderately better IC50 values than for cisplatin in the cisplatin-sensitive cell line A2780. We investigated potential factors which might be involved in the mechanism underlying the cytotoxic effects of 1 and 2 and compared these factors with those involved in the mechanism underlying the effects of conventional cisplatin. Our data indicate that the higher cytotoxicity of 1 and 2 originates mainly from their efficient cellular accumulation, different effects at the level of cell cycle regulation, and reduced propensity for DNA adduct repair. Studies of their reactivity toward cellular components reveal efficient binding to DNA, which is typically required for an active platinum drug. Further results suggest that 1 and 2 are capable of circumventing resistance to cisplatin induced by alterations in cellular accumulation and DNA repair. Hence, the latter two factors appear to be responsible for differences in the toxicity of 1 or 2, and cisplatin in tumor cells. The results of this work reinforce the idea that direct analogues of conventional cisplatin-containing halogeno-substituted 7-azaindoles offer much promise for the design of novel therapeutic agents.

• MeSH
• Apoptosis drug effects   MeSH
• Cell Cycle drug effects   MeSH
• Glutathione chemistry   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• DNA Repair MeSH
• Organoplatinum Compounds chemistry   toxicity   MeSH
• DNA Damage drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Glutathione MeSH
• Organoplatinum Compounds MeSH

Carboplatin, an analogue of "classical" cis-diamminedichloridoplatinum(II) (cisplatin), is a widely used second-generation platinum anticancer drug. Cytotoxicity of cisplatin and carboplatin is mediated by platinum-DNA adducts. Markedly higher concentrations of carboplatin are required, and the rate of adduct formation is considerably slower. The reduced toxic effects in tumor cells and a more acceptable side-effect profile are attributable to the lower reactivity of carboplatin with nucleophiles, since the cyclobutanedicarboxylate ligand is a poorer leaving group than the chlorides in cisplatin. Recently, platinum complexes were shown to be particularly attractive as potential photochemotherapeutic anticancer agents. Selective photoactivation of platinum complexes by irradiation of cancer cells may avoid enhancement of toxic side-effects, but may increase toxicity selectively in cancer cells and extend the application of photoactivatable platinum complexes to resistant cells and to a wider range of cancer types. Therefore, it was of interest to examine whether carboplatin can be affected by irradiation with light to the extent that its DNA binding and cytotoxic properties are altered. We have found that carboplatin is converted to species capable of enhanced DNA binding by UVA irradiation and consequently its toxicity in cancer cells is markedly enhanced. Recent advances in laser and fiber-optic technologies make it possible to irradiate also internal organs with light of highly defined intensity and wavelength. Thus, carboplatin is a candidate for use in photoactivated cancer chemotherapy.

• MeSH
• DNA chemistry   drug effects   MeSH
• Photochemical Processes radiation effects   MeSH
• Carboplatin chemistry   pharmacology   radiation effects   toxicity   MeSH
• Kinetics MeSH
• Humans MeSH
• Tumor Cells, Cultured MeSH
• Plasmids MeSH
• DNA Damage drug effects   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents chemistry   pharmacology   radiation effects   toxicity   MeSH
• Drug Screening Assays, Antitumor MeSH
• Cattle MeSH
• Ultraviolet Rays MeSH
• Binding Sites drug effects   MeSH
• Cell Survival drug effects   MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Cattle MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• DNA MeSH
• Carboplatin MeSH
• Antineoplastic Agents MeSH