Sensor/Effector Drug Design with Potential Relevance to Cancer

Abstract

Many cancer cells exhibit a disturbed intracellular redox balance, making them distinctively different from their 'healthy' counterparts. Some tumors, such as solid lung carcinoma, are hypoxic, and its cells are therefore more reducing than normal, while others, such as the ones of breast and prostate cancer, proliferate under oxidative stress (OS). These biochemical differences between normal and tumor tissue are significant, and can be used to design effective, yet selective redox drugs. The resulting drug design can follow different avenues. The bioreductive approach is perhaps the most advanced, and uses changes in intracellular redox enzyme concentrations to activate otherwise inactive pro-drug molecules inside cancer cells by a reductive step, often followed by further chemical transformations, such as hydrolysis. Related anti-cancer compounds, such as varacin, employ an intricate combination of reduction and oxidation processes to develop their therapeutic potential inside cells. Another, just emerging approach considers the use of pro-oxidants and catalysts, taking advantage of the inherent efficiency and selectivity associated with OS-induced cell death. Even more complex tactics, such as chelator-assisted photodynamic therapy, exploit the intracellular metal homeostasis to target cancer cells. Together, all of these avenues try to endow molecules with a combination of sensor and effector properties, which might allow them to single out and selectively kill cancer cells without the need for cell-selective drug delivery systems. In the long term, such agents could be associated with high efficiency, good selectivity and dramatically reduced drug side effects.

Oncocalyxone A: electrochemical, spectroscopic investigation and studies of its interaction with DNA, nucleobases and N-acetylcysteine

“…[36][37][38][39][40][41][42] As already described, oxidative stress leading to DNA damage and alkylation of nuclear cellular nucleophiles are the two major mechanisms of quinone cytotoxicity. 9,12,16,43 Concerning the results in the present study, a typical electrochemical behavior (in aprotic medium) is observed for oncocalyxone A, represented by diffusional two quasi-reversible reduction systems, with a well-stabilized anion radical as evidenced by ESR analysis. Oncocalyxone A has shown significant DNA activity, represented by the decrease and shift of oxidation peaks of guanosine/guanine and adenosine/adenine.…”

“…10 Oncocalyxone A, a para-benzoquinone with an extended conjugated dienone scaffold, may possibly function as a reactive Michael acceptor toward nucleophilic sites on proteins, for example, cysteinyl thiol groups, or on DNA. 11 In this case, its pro-oxidant activity (enhancer of oxidative stress) 12 might increase once thiols are recognized as the main class of biologically important antioxidants, behaving as reducing agents.…”

“…14 In protic medium, electrochemical studies on DNA and also in the presence of biologically important thiols like N-acetylcysteine (NAC) can be performed 15 to test the Michael acceptor nature of this quinone, 10,11 which would favour its pro-oxidant nature, with relevance in antitumor activity. 12,16,17 More specifically, the use of NAC is relevant once it has been used as tools for investigating the role of ROS (reactive oxygen species) in numerous biological and pathological processes. 16,17 NAC inhibits the activation of c-Jun N-terminal kinase, p38 MAP kinase, redox-sensitive activating protein-1 and nuclear factor kappa B transcription factor activities, regulating expression of numerous genes.…”

The Organotelluride Catalyst (PHTE)2NQ Prevents HOCl-Induced Systemic Sclerosis in Mouse

“…Interestingly, some catalytic agents called ''sensor/effector'' multifunctional redox catalysts can modulate the intracellular redox balance by generating more reactive oxidants or by targeting cysteine residues in proteins. These molecules seem to be particularly effective and selective (Fry and Jacob, 2006). Among the ''sensor/effector'' multifunctional redox catalyst agents, quinone-and chalcogen (selenium, tellurium)-containing agents have shown an in vitro cytotoxic activity against various types of tumor cells Coriat et al, 2011;Lilienthal et al, 2011).…”

Probing the redox activity of T-lymphocytes deposited at electrode surfaces with voltammetric methods

“…(2). Interestingly, many cancer cells have an increased redox activity (12,13). Hence, detection of the redox state of any given cell population may be a valuable diagnostic procedure.…”