Mechanism of Cytotoxicity of Copper(I) Complexes of 1,2-Bis(diphenylphosphino)ethane

Abstract

The cytotoxic properties of arylphosphines are regulated by metals. We have synthesized a series of copper(I) complexes of 1,2-bis(diphenylphosphino)ethane (DPPE) and tested their in vitro cytotoxicity in a human lung carcinoma cell line H460. One of the complexes [Cu(2)(DPPE)(3)(CH(3)CN)(2)](ClO(4))(2) (C1), showed maximum cytotoxicity comparable to that of adriamycin. Treatment of cells with C1 caused DNA damage in vitro and activated the p53 pathway. Flow cytometry revealed that growth inhibition by C1 was due to a combination of cell cycle arrest and apoptosis. Simultaneous addition of C1 and adriamycin increased the cytotoxicity of either compound, suggesting the potential use of adriamycin in combination with C1. DNA binding and simulation studies suggest that adriamycin binds to DNA synergistically in the presence of C1. Thus, we have identified C1, a copper(I) complex of DPPE, as a potential chemotherapeutic drug for further testing, which could be used either alone or in combination with other chemotherapeutic drugs.

Copper in diseases and treatments, and copper‐based anticancer strategies

“…228 The authors also showed that simultaneous addition of (12) and of the DNA intercalating agent adriamycin increased the cytotoxicity of either compounds, suggesting the potential use of adriamycin with (12) in combination therapy (Scheme 12). 228 Following a similar mixed-ligand approach, several scorpionate ligands have been attached to a ''CuP 2 '' moiety. The use of dihydrobis(3-nitro-1,2,4-triazolyl)borate scorpionate co-ligands, [H 2 B(tz NO2 ) 2 ] À , had the double aim at increasing the water solubility and the kinetic inertness of the resulting mixed-complex.…”

“…Despite considerable efforts carried out in this field, the presence of several phenyl groups appended to the phosphorus donors in bisaryldiphosphine copper and gold compounds caused undesired nephrotoxicity 223 and cardiovascular toxicity 226 in animal models, respectively, thus precluding clinical trials in humans. 223,226 Consequently, efforts have been devoted to the design of more hydrophilic copper derivatives, as in the case of the partial substitution of the ''CuP 4 '' arylphosphine coordination sphere with heterocyclic thiones, 227 acetonitrile, 228 and N-heterocycles such as carbazole and benzotriazole producing mixed-ligand type compounds. 227 228 Mechanistic studies revealed that (12) damaged DNA in vitro and activated the p53 pathway eventually inhibiting the growth of cancer cells by inducing cell cycle arrest and apoptosis.…”

“…223,226 Consequently, efforts have been devoted to the design of more hydrophilic copper derivatives, as in the case of the partial substitution of the ''CuP 4 '' arylphosphine coordination sphere with heterocyclic thiones, 227 acetonitrile, 228 and N-heterocycles such as carbazole and benzotriazole producing mixed-ligand type compounds. 227 228 Mechanistic studies revealed that (12) damaged DNA in vitro and activated the p53 pathway eventually inhibiting the growth of cancer cells by inducing cell cycle arrest and apoptosis. 228 The authors also showed that simultaneous addition of (12) and of the DNA intercalating agent adriamycin increased the cytotoxicity of either compounds, suggesting the potential use of adriamycin with (12) in combination therapy (Scheme 12).…”

“…227 228 Mechanistic studies revealed that (12) damaged DNA in vitro and activated the p53 pathway eventually inhibiting the growth of cancer cells by inducing cell cycle arrest and apoptosis. 228 The authors also showed that simultaneous addition of (12) and of the DNA intercalating agent adriamycin increased the cytotoxicity of either compounds, suggesting the potential use of adriamycin with (12) in combination therapy (Scheme 12). 228 Following a similar mixed-ligand approach, several scorpionate ligands have been attached to a ''CuP 2 '' moiety.…”

Role of chelates in treatment of cancer

“…Cytotoxic effects are shown by copper(I) phosphane complexes of dihydridobis(3-nitro-1,2,4-triazolyl)borate, [25] copper(II) complex of N-Nicotinoyl-N′-o-hydroxythiobenzhydrazide, [26] copper(II)-doxorubicin chelate [27] and copper(I) complexes of 1,2-bis(diphenylphosphino) ethane (DPPE). [28] Copper(II) chelate of transbis(salicylaldoximato) showed cytotoxicity comparable to that of adriamycin by inducing cell cycle arrest and apoptosis. [29] Zinc-based chelates 1.…”