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Dalton Discussion 10: Applications of Metals in Medicine and Healthcare APPLICATIONS of PLATINUM GROUP METALS in CANCER and HIV TREATMENT

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Dalton Discussion 10: Applications of Metals in Medicine and Healthcare APPLICATIONS of PLATINUM GROUP METALS in CANCER and HIV TREATMENT DOI: 10.1595/147106708X298296 Dalton Discussion 10: Applications of Metals in Medicine and Healthcare APPLICATIONS OF PLATINUM GROUP METALS IN CANCER AND HIV TREATMENT Reviewed by Christian G. Hartinger Institut des Sciences et Ingénierie Chimiques, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland; and University of Vienna, Institute of Inorganic Chemistry, Währinger Str. 42, A-1090 Vienna, Austria; E-mail: [email protected] Dalton Discussion 10 on the topic Orvig and colleagues), which re-entered clinical tri- “Applications of Metals in Medicine and als in 2007 after several years with a lack of interest Healthcare” was held at the University of Durham, from drug development companies, was used to U.K., from 3rd to 5th September 2007 (1). Dalton underline the fact that patience is required, and Discussions represent a conference concept quite that nobody in the field can expect to develop different from the norm with a clear focus, as the drugs overnight. This is a long term process with name implies, on the discussion. Therefore the an average duration of about ten years, there are majority of the presentations were short five many failures and costs are high. minute talks on papers submitted for a Dalton Transactions special issue (2), distributed in advance Antitumour and Anti-HIV to all the participants, followed by a discussion of Applications of PGMs about twenty-five minutes. Additionally, five With regard to platinum group metals (pgms), Keynote lectures, given by experts in the field, and an overwhelming number of presentations at approximately sixty poster presentations were Dalton Discussion 10 focused on their application included. The conference was perfectly suited to as antineoplastic agents. Platinum complexes are initiate collaborations, develop ideas or simply dis- applied in half of all chemotherapeutic schemes cuss. The follow-up meeting “Dalton Discussion against a wide range of tumours, although they are 11: The Renaissance of Main Group Chemistry” effective against only a handful of tumourigenic was announced by Professor Robin Perutz, the diseases. Keynote presenter Chi-Ming Che President of the Dalton Division Council of the (University of Hong Kong, China) et al. reported Royal Society of Chemistry, and will take place in on their recent developments of platinum(II), 2008 at the University of California, Berkeley, ruthenium(II), ruthenium(III) and ruthenium(IV) U.S.A. (3). complexes alongside non-pgm compounds (gold, About 100 participants from both academia and iron and vanadium) as anticancer and anti-HIV industry, including chemists, biologists and clini- agents (4). Che presented Pt complexes which bind cians, discussed recent results obtained for non-covalently to biomolecules, and are capable of metal-based therapeutics and diagnostics. binding in an electrostatic or hydrophobic manner Currently, metal compounds are not the drugs of as well as via intercalation. Some of the complexes first choice in clinical application or for companies were found to be up to 100 times more potent in to develop. As several experts pointed out, there is vitro than cisplatin. Furthermore, amino- a need to initiate long-term discussion and interdis- alcohol-platinum complexes were proposed as ciplinary research, and to convince both clinicians protein-staining reagents in sodium dodecyl sulfate and society of the benefit of metal-based drugs. (SDS)-polyacrylamide gels, due to their high bind- The example of the vanadium compound bis(mal- ing affinities to proteins, and protein interaction is tolato)oxovanadium(IV) (BMOV), which has also accompanied by an enhancement of the emis- insulin mimetic properties (developed by Chris sion. In addition, Ru complexes with quinone- Platinum Metals Rev., 2008, 52, (2), 96–99 96 diimine as auxiliary ligands were shown to interca- from the presenter’s point of view was given late into DNA, but were found to exhibit mild (Figure 1). cytotoxicities of about 200 μM against epidermal KB-3-1 and KB-V-1 carcinoma cell lines. A ruthe- nium-oxo oxalato cluster was presented which exhibited promising anti-HIV properties, being about ten times more active than the common HIV-1 RT inhibitor 3'-azido-3'-deoxythymidine-5'- phosphate. Nicholas P. Farrell (Virginia Commonwealth University, U.S.A.) and coworkers, who developed the trinuclear Pt compound BBR3464 up to clinical trials, reported on BBR3464 analogues which are not capable of binding covalently to bio- molecules (5). They observed by mass spectrome- Fig. 1 A road-map for the development of drugs try, circular dichroism and fluorescence studies the (ADME = adsorption, distribution, metabolism and excretion) pre-association of these compounds with human serum albumin (HSA) at an initial stage. It is Fricker pointed out that the advantages of metal- thought that non-covalent interaction of these Pt based drugs are thought to derive from a precise 3D complexes with HSA might circumvent the deacti- configuration, leading to precise target/drug interac- vation of Pt drugs by binding to serum proteins, and tion; a capacity to coordinate to biomolecules, which this suggests a new mode of action for this com- is also tuneable by modification of the ligand sphere; pound class. and capacities to participate in biological redox The contribution from Peter J. Sadler’s group, processes and to undergo ligand exchange reactions. presented by Abraha Habtemariam (University of The speaker reviewed progress in the field of non-Pt Warwick, U.K.), was the 106Ru-radiolabelled putative anticancer drug candidates, notably Ru anticancer antitumour organometallic compound [(η6-fluo- agents including the two Ru compounds in clinical rene)RuCl(en)]PF6 (6). Synthesised with the trials, indazolium trans-[tetrachlorobis(1H- purpose of following and locating the Ru species in indazole)ruthenate(III)] (KP1019) and imidazolium vivo, the compound was administered to a non- trans-[tetrachloro(imidazole)(dimethyl sulfoxide)- tumour bearing male albino rat. The compound was ruthenate(III)] (NAMI-A) (8). found to be distributed over the whole animal, with In his Keynote lecture, Trevor W. Hambley the highest level in liver and kidneys, which illus- (University of Sydney, Australia) described recent trates the difficulty in finding drugs that do not developments in metal-based pharmaceuticals (9) accumulate in these organs. and classified metallodrugs into seven classes (see The Keynote talk of Simon P. Fricker Figure 2). Several pgm compounds are represented (AnorMED Inc., Canada), entitled ‘Metal based in classes (i) and (iii). In particular, the Ru-based drugs: from serendipity to design’, was focused on glycogen synthase kinase 3β (GSK3β) inhibitor established Pt anticancer agents but also reported DW1/2, developed in Eric Meggers’s group on new developments in the field, including com- (Philipps-Universität Marburg, Germany) (10), was pounds such as picoplatin, iproplatin and the orally mentioned as an example of a class (i) metallodrug. administerable satraplatin, as well as non-Pt com- Since most of the known anticancer Pt complexes plexes (7). The advantages of second and third are believed to exhibit their activity in other than generation compounds in comparison to cisplatin their administered forms, cisplatin and carboplatin as were highlighted: carboplatin has lower toxicity, well as Ru(III), Ru–arene and other Pt(II) and Pt(IV) satraplatin is orally bioavailable and picoplatin over- complexes can be considered as representatives comes resistance. Notably, an interesting road-map of class (iii). Platinum Metals Rev., 2008, 52, (2) 97 Other Metals Besides the talks mentioned above, there were numerous fascinating presentations and posters on applications of other metal compounds for medici- nal purposes. These include gold, titanium, rhenium and iron complexes for cancer chemotherapy, CO- releasing molecules, radio-metallodrugs for diagnosis and therapy (for example, copper com- plexes for positron emission tomography (PET) imaging and technetium binding to peptides), gadolinium complex-based contrast agents, zinc and copper complexes as probes for in vitro fluorescence imaging and α-emitters such as 213bismuth, 211asta- tine and 225actinium as therapeutics. Fig. 2 Classification of metallodrugs Concluding Remarks Janice R. Aldrich-Wright (University of In summary, a broad variety of applications in Western Sydney, Australia) et al. reported on a metals in medicine and healthcare was presented, targeted approach exploiting molecular hosts as with Pt, Ru and other metal-based drugs demon- drug delivery vehicles (11). Notably, some Pt strating the potential to become the major complexes containing the (1S,2S)-cyclohexane- treatments for some common diseases. Dalton diamine (chxn) moiety were found to be more Discussion 10 was a very interesting conference at a active in vitro than oxaliplatin analogues with the pleasant venue in the old city of Durham, and had (1R,2R)-chxn ligand. Loading such Pt(II) com- an appropriate size to benefit from the special con- plexes onto cucurbit[n]urils resulted in only ference mode with its focus on discussion. All the small modifications of the cytotoxicity of the contributions can be read in the special issue of complexes, indicating only minor influence of Dalton Transactions, published in autumn 2007 (2). the drug delivery system on the activity of the complexes. However, the application of these compounds is limited by their low solubility, References therefore other molecular hosts such as 1 Dalton Discussion 10: Applications of Metals in cyclodextrins, calix[n]arenes and dendrimers are Medicine and Healthcare, 3rd–5th September, 2007, being evaluated. Durham University, U.K.: http://www.rsc.org/DD10 Finally, the contribution from Paul J. Dyson’s 2 Dalton Trans., 2007, (43), 4873–5092 (École Polytechnique Fédérale de Lausanne 3 Dalton Discussion 11: The Renaissance of Main (EPFL), Switzerland) group dealt with the design Group Chemistry, 23rd–25th June, 2008, University of Ru organometallics, the tuning of lipophilicity, of California, Berkeley, U.S.A.: http://www.rsc.org/DD11 which influences the cellular uptake, and altering 4 R. W.-Y. Sun, D.-L. Ma, E. L.-M. Wong and C.-M.
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