Some secreted proteins undergo redox reactions, that is, transfer or shuffling of hydrogens and electrons between amino acids. The amino acid most often involved is cysteine, the redox reaction involving in particular, the cysteine thiol. Redox changes in cysteine residues can lead to net reduction, net formation or net interchange of disulfide bonds.
Recent evidence suggests that cell surface proteins are under redox control, not unlike that of intracellular proteins. The reducing nature of the intracellular environment facilitates interchange between the reduced and oxidised form of closely spaced dithiols (for review see Huppa and Ploegh, 1998). In contrast, the oxidising nature of the extracellular environment is generally considered to preclude the existence of closely spaced dithiols, which are thought to exist instead as disulfide bonds or as mixed disulfides with other thiol compounds. Closely spaced thiols have the capability to interchange between the reduced dithiol and oxidised disulfide bond and are therefore likely to be important for the function of redox active proteins.
Trivalent arsenicals form high affinity ring structures with closely spaced thiols. Closely spaced dithiols include thiols that are chemically vicinal, as in 2,3-dimercaptopropanol (DMP), for example, as well as thiols brought into spatial apposition by folding (Jauhianinen et al., 1988). Due to entropic factors, the resultant cyclic dithioarsinites are markedly more stable than the noncyclic products formed from trivalent arsenicals and monothiols (Stockten and Thompson, 1946). Arsenical derivatives have been used in the past as therapeutic agents for the treatment of disease. However, the inherent toxicities of arsenical compounds and their generally unfavourable therapeutic index have essentially precluded their use as pharmaceutical agents.
Consequently, there is a need for the development of therapeutically active arsenical compounds that are relatively non-toxic and which are effective in the treatment of mammalian disease, particularly those diseases related to rapidly proliferating cells.
The present invention provides compounds wherein a chemical moiety having the ability to disrupt cell function by inhibition of redox active proteins, such as a trivalent arsenical, is linked to a substantially cell membrane impermeable pendant group. The present invention further provides for pharmaceutical compositions comprising these compounds and to methods of treatment of inflammatory disorders, autoimmune diseases, blood vessel diseases, thrombosis, viral infections, and haematological and solid tumours.