Motivation for drug development

At present, the major clinical use of gold complexes relates to RA (see later). Despite this, there seems to be a dearth of activity, at least as judged from open literature, devoted to generating new gold drugs for Chrysotherapy with improved efficacy and reduced toxic side effects.48 50 Most recent efforts in pharmaceutical gold chemistry are dedicated to developing anti-tumour agents of both Au(I) and Au(III). Basically, cancer develops when cells in a particular part or parts of the body begin to proliferate out of control as a result of the uncontrolled growth of abnormal cells with damaged DNA that are not repaired by the normal repair mechanisms of the body. Tumour cells can spread through the bloodstream or lymph vessels, via a process known as metastasis, to other parts of the body where they begin to grow and replace normal tissue. Motivations for investigating the anti-cancer activity of gold complexes are varied, but there is increasing evidence of a link between inflammatory disorders and cancer.

Screening for anti-tumour activity of anti-arthritic gold drugs could have been motivated by long-term studies showing that patients undergoing Chryso-therapy had reduced risk from also suffering from cancer.51 However, the first mention of a link between inflammation and cancer dates back to 1863 when Virchow observed leukocytes in neoplastic tissues as discussed in a review by Balkwill and Mantovani52 that goes on to discuss possible links between the two conditions. Further, drugs such as cyclophosphamide (7), 6-mercaptopur-ine (8) and methotrexate (9) are known to have both anti-cancer and antiinflammatory characteristics;52 54 Figure 26.2 for chemical structures. Other reasons for developing gold complexes as anti-tumour agents relate to chemical similarities as well as to drug delivery strategies.

In terms of a chemical motivation for examining Au(III) species, Au(III) is isoelectronic with cisplatin, containing the Pt(II) centre and which is, the most widely used anti-cancer drug, and adopts similar square-planar structures, indicating perhaps that Au(III) complexes may also target DNA as does cisplatin. In terms of a drug delivery strategy, given that Au(I) drugs are tolerated, to a greater or lesser extent, by patients, and what is known about the metabolism of Au(I) drugs, i.e. they are prodrugs, the use of Au(I) as a platform to deliver biologically active molecules for cancer treatment is another motivation for their study. Amongst the first gold complexes to be investigated for cytotoxicity and anti-tumour activity were the gold drugs used in Chryso-therapy. Generally, drugs such as disodium aurothiomalate (2) were inactive, most likely due to their inability to enter cells. By contrast, Auranofin (6)

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Figure 26.2 Chemical structures of cyclophosphamide (7), 6-mercaptopurine (8) and methotrexate (9)

demonstrated significant potential in this regard, sparking considerable interest in the study of the anti-cancer potential of phosphinegold(I) thiolates.54,55

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