Despite very promising research, to date, no synthetic organoselenium compounds are in clinical use as anti-cancer agents. Early research generally involved the substitution of sulfur for selenium in sulfur-containing compounds of known activity, often resulting in little improvement in activity or toxicity.1 However, many organoselenium compounds showing potent anti-cancer activity have been developed, such as triphenylselenonium ion 12,49 selenocyanates 13,1,49
selenazofurin 14a,1,15,96 1,3-selenazine derivative 151,97 and selenocysteine conjugates 16 and 17.
OH OH 18
OH OH 18
Selenazofurin 14a is a c-nucleoside that is an inosine monophosphate dehydrogenase (IMPDH) inhibitor.96 IMPDH catalyzes the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP), which is a key step in the synthesis of purines. In rapidly multiplying cells IMPDH activity is increased; thus IMPDH inhibition is the target of some potential anti-cancer agents. Due to increased IMPDH inhibition, selenazofurin 14a has 5-10-fold higher activity than the sulfur analogue.1,96 Analogues of selenazofurin have also been prepared including the monophosphate derivative 14b and seleno-phenfurin 18 which also shows IMPDH inhibition.102
As discussed earlier (section 'selenium metabolites') methylselenocysteine (MSeC) undergoes ^-elimination by ^-lyases to generate methylselenol, a critical metabolite in the anti-cancer activity of dietary selenium. Unnatural selenocysteine conjugates have been prepared, which are also metabolized by ^-lyase to selenols, ammonia and pyruvate99,100 (Figure 17.5).
Ip found that Se-allyl-DL-selenocysteine 16 displayed excellent anti-tumor activity against mammary tumors in rats.101 Research has shown that the selenocysteine conjugates are much better substrates for ^-lyase than the corresponding sulfur analogue, showing rates of ^-elimination up to two orders of magnitude higher.100,101 Selenocysteine (Se-Cys) conjugates, particularly those containing phenyl substituents such as 17, show promise as prodrugs able to deliver selenols selectively to kidneys, as ^-lyase is present in high concentrations in the kidneys and liver.99 An additional use for Se-Cys conjugates is to ameliorate the toxic effects of cisplatin.98 Cisplatin is severely nephrotoxic and there are currently no compounds used clinically to protect against its toxicity. Rooseboom and co-workers found that Se-Cys conjugates improved viability of cisplatin-treated cells having normal ^-lyase activity whereas the corresponding cells having very low ^-lyase activity showed no improvement in cell viability.98 Owing to the selective delivery of selenol by Se-Cys conjugates it is thought that these compounds may provide protection against the toxic effects of cisplatin without adversely affecting its efficacy against cancer. Excessive production of ROS has been implicated in the toxicity of cisplatin; thus one possible mechanism for the protective effect of Se-Cys conjugates involves the induction of anti-oxidant enzymes.98 An alternative hypothesis is that selenol binds to the platinum contained in cisplatin, deactivating it. There is evidence that methylselenol is capable of binding to platinum, giving credence to this hypothesis.103
Selenocyanates such as 13, particularly bis-selenocyanates, exhibit anti-cancer activity in a number of different models.1 Rao found evidence that bis-selenocyanate inhibits protein kinase C (PKC) activity, which is intimately involved with tumor development.104 It is believed that selenocyanates are metabolized to the corresponding selenol (in the same manner as are thio-cyanates), by glutathione and glutathione transferases.49 Indeed, selenols appear to be a frequently seen metabolite of organoselenium compounds with anti-cancer activity.
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