Darren M. Griffith

A novel anti-cancer bifunctional platinum drug candidate with dual DNA binding and histone deacetylase inhibitory activity

The successful design and synthesis of a novel multifunctional platinum drug candidate with DNA binding, histone deacetylase inhibitory activity and enhanced selectivity for cancer cells are described.

Current and Potential Applications of Bismuth-Based Drugs

Bismuth compounds have been used extensively as medicines and in particular for the treatment of gastrointestinal ailments. In addition to bismuth’s well known gastroprotective effects and efficacy in treating H. pylori infection it also has broad anti-microbial, anti-leishmanial and anti-cancer properties. Aspects of the biological chemistry of bismuth are discussed and biomolecular targets associated with bismuth treatment are highlighted. This review strives to provide the reader with an up to date account of bismuth-based drugs currently used to treat patients and discuss potential medicinal applications of bismuth drugs with reference to recent developments in the literature. Ultimately this review aims to encourage original contributions to this exciting and important field.

Novel trans-platinum complexes of the histone deacetylase inhibitor valproic acid; synthesis, in vitro cytotoxicity and mutagenicity.

The first examples of Pt complexes of the well known anti-epilepsy drug and histone deacetylase inhibitor, valproic acid (VPA), are reported. Reaction of the Pt(II) am(m)ine precursors trans-[PtCl(2)(NH(3))(py)] and trans-[PtCl(2)(py)(2)] with silver nitrate and subsequently sodium valproate gave trans-[Pt(VPA(-1H))(2)(NH(3))(py)] and trans-[Pt(VPA(-1H))(2)(py)(2)], respectively. The valproato ligands in both complexes are bound to the Pt(II) centres via the carboxylato functionality and in a monodentate manner. The X-ray crystal structure of trans-[Pt(VPA(-1H))(2)(NH(3))(py)] is described. Replacement of the dichlorido ligands in trans-[PtCl(2)(py)(2)] and trans-[PtCl(2)(NH(3))(py)] by valproato ligands (VPA(-1H)) to yield trans-[Pt(VPA(-1H))(2)(py)(2)] and trans-[Pt(VPA(-1H))(2)(NH(3))(py)] respectively, significantly enhanced cytotoxicity against A2780 (parental) and A2780 cisR (cisplatin resistant) ovarian cancer cells. The mutagenicity of trans-[Pt(VPA(-1H))(2)(NH(3))(py)] and trans-[Pt(VPA(-1H))(2)(py)(2)] was determined using the Ames test and is also reported.

Enzyme Inhibition as a Key Target for the Development of Novel Metal-Based Anti-Cancer Therapeutics

Historically, DNA has been the target for many metal-based anti-cancer drugs, but drawbacks of prevailing therapies have stimulated the search for new molecular targets which may present unique opportunities for therapeutic exploitation. Enzyme inhibition has recently been identified as an alternative and significant target. The pursuit of novel metallodrug candidates that selectively target enzymes is now the subject of intense investigation in medicinal bioinorganic chemistry and chemical biology. In the field of drug design, it is recognised by many that exploiting the structural and chemical diversity of metal ions for the identification of potential hit and lead candidates can dramatically increase the number of possible drug candidates that may be added to the already abundant armoury of chemotherapeutic agents. This review will focus on recent key advancements in enzyme inhibition as a key target for the development of novel metal-based anti-cancer therapeutics. The enormous clinical success of classical platinum drugs, amongst others, coupled with the wealth of knowledge accumulated in recent years on enzyme structure and function, has undoubtedly been the impetus behind the development of new metallodrug candidates with enzyme inhibitory properties. Recent trends in this field will be reviewed with a particular emphasis on metal complexes that inhibit protein and lipid kinases, matrix metalloproteases, telomerases, topoisomerases, glutathione-S-transferases, and histone deacetylases.

Ruthenium(III) dimethyl sulfoxide pyridinehydroxamic acid complexes as potential antimetastatic agents: synthesis, characterisation and in vitro pharmacological evaluation

Reaction of 3-pyridinehydroxamic acid and 4-pyridinehydroxamic acid (3-pyha and 4-pyha) with either [NBu4][RuCl4(dmso-S)2] or [(dmso)2H][RuCl4(dmso-S)2] (dmso is dimethyl sulfoxide) in acetone afforded three new ruthenium(III) dimethyl sulfoxide pyridinehydroxamic acid complexes: [NBu4][trans-RuCl4(dmso-S)(4-pyha)]·CH3COCH3 (1), [3-pyhaH][trans-RuCl4(dmso-S)(3-pyha)] (2) and [4-pyhaH][trans-RuCl4(dmso-S)(4-pyha)] (3). The solid-state structure of [NBu4][trans-RuCl4(dmso-S)(4-pyha)]·CH3COCH3 (1) was determined by X-ray crystallography. 2 and 3 were pharmacologically evaluated for their in vitro cytotoxicity, their ability to inhibit cell invasion and their gelatinase activity. 2 and 3 were devoid of cytotoxicity against the cell lines tested. 2 inhibited invasion of the highly invasive MDA-MB-231 cells to a much greater extent than 3. Contrary to expectations, neither 2 nor 3 had any inhibitory effect on matrix metalloproteinase (MMP) production and/or activity and in fact 3 was found to enhance the production and/or activity of both MMP-2 and MMP-9.

Valuable insight into the anticancer activity of the platinum-histone deacetylase inhibitor conjugate, cis-[Pt(NH3)2malSAHA-2H)].

cis-[Pt(II)(NH3)2(malSAHA-2H)], a cisplatin adduct conjugated to a potent histone deacetylase inhibitor (HDACi), suberoylanilide hydroxamic acid (SAHA), was previously developed as a potential anticancer agent. This Pt-HDACi conjugate was demonstrated to have comparable cytotoxicity to cisplatin against A2780 ovarian cancer cells but significantly reduced cytotoxicity against a representative normal cell line, NHDF. Thus, with a view to (i) understanding more deeply the effects that may play an important role in the biological (pharmacological) properties of this new conjugate against cancer cells and (ii) developing the next generation of Pt-HDACi conjugates, the cytotoxicity, DNA binding, cellular accumulation and HDAC inhibitory activity of cis-[Pt(II)(NH3)2(malSAHA-2H)] were investigated and are reported herein. cis-[Pt(II)(NH3)2(malSAHA-2H)] was found to have marginally lower cytotoxicity against a panel of cancer cell lines as compared to cisplatin and SAHA. cis-[Pt(II)(NH3)2(malSAHA-2H)] was also found to accumulate better in cancer cells but bind DNA less readily as compared to cisplatin. DNA binding experiments indicated that cis-[Pt(II)(NH3)2(malSAHA-2H)] bound DNA more effectively in cellulo as compared to in cell-free media. Activation of the Pt-HDACi conjugate was therefore investigated. The binding of cis-[Pt(II)(NH3)2(malSAHA-2H)] to DNA was found to be enhanced by the presence of thiol-containing molecules such as glutathione and thiourea, and activation occurred in cytosolic but not nuclear extract of human cancer cells. The activity of cis-[Pt(NH3)2(malSAHA-2H)] as a HDAC inhibitor was also examined; the conjugate exhibited no inhibition of HDAC activity in CH1 cells. In light of these results, novel Pt-HDACi conjugates are currently being developed, with particular emphasis, through subtle structural modifications, on enhancing the rate of DNA binding and enhancing HDAC inhibitory activity.

Monohydroxamic acids and bridging dihydroxamic acids as chelators to ruthenium(III) and as nitric oxide donors: syntheses, speciation studies and nitric oxide releasing investigation

The synthesis and spectroscopic characterisation of novel mononuclear Ru(III)(edta)(hydroxamato) complexes of general formula [Ru(H2edta)(monoha)] (where monoha = 3- or 4-NH2, 2-, 3- or 4-C1 and 3-Me-phenylhydroxamato), as well as the first example of a Ru(III)-N-aryl aromatic hydroxamate, [Ru(H2edta)(N-Me-bha)].H2O (N-Me-bha = N-methylbenzohydroxamato) are reported. Three dinuclear Ru(III) complexes with bridging dihydroxamato ligands of general formula [{Ru(H2edta)}2(mu-diha)] where diha = 2,6-pyridinedihydroxamato and 1,3- or 1,4-benzodihydroxamato, the first of their kind with Ru(III), are also described. The speciation of all of these systems (with the exception of the Ru-1,4-benzodihydroxamic acid and Ru-N-methylbenzohydroxamic systems) in aqueous solution was investigated. We previously proposed that nitrosyl abstraction from hydroxamic acids by Ru(III) involves initial formation of Ru(III)-hydroxamates. Yet, until now, no data on the rate of nitric oxide (NO) release from hydroxamic acids has been published. We now describe a UV-VIS spectroscopic study, where we monitored the decrease in the ligand-to-metal charge-transfer band of a series of Ru(III)-monohydroxamates with time, with a view to gaining an insight into the NO-releasing properties of hydroxamic acids.

A novel platinum complex of the histone deacetylase inhibitor belinostat: Rational design, development and in vitro cytotoxicity

The successful design and synthesis of a novel Pt complex of the histone deacteylase inhibitor belinostat are reported. Molecular modelling assisted in the identification of a suitable malonate derivative of belinostat (mal-p-Bel) for complexation to platinum. Reaction of [Pt(NH3)2(H2O)2](NO3)2 with the disodium salt of mal-p-Bel gave cis-[Pt(NH3)2(mal-p-Bel-2H)] (where -2H indicates that mal-p-Bel is doubly deprotonated) in excellent yield. An in vitro cytotoxicity study revealed that cis-[Pt(NH3)2(mal-p-Bel-2H)] possesses (i) considerable cytotoxicity against reported ovarian cancer cell lines, (ii) enhanced cytotoxicity relative to the previously reported Pt histone deacetylase inhibitor conjugate, cis-[Pt(II)(NH3)2(malSAHA-2H)] and (iii) favourable cyto-selective properties as compared to cisplatin and belinostat.

Novel Improved Synthesis of HSP70 Inhibitor, Pifithrin-μ. In Vitro Synergy Quantification of Pifithrin-μ Combined with Pt Drugs in Prostate and Colorectal Cancer Cells

We describe a novel improved approach to the synthesis of the important and well-known heat shock protein 70 inhibitor (HSP70), pifithrin-μ, with corresponding and previously unreported characterisation. The first example of a combination study comprising HSP70 inhibitor pifithrin-μ and cisplatin or oxaliplatin is reported. We have determined, using the Chou-Talalay method, (i) moderate synergistic and synergistic effects in co-treating PC-3 prostate cancer cells with pifithrin-μ and cisplatin and (ii) significant synergistic effects including strong synergism in cotreating HT29 colorectal cancer cells with oxaliplatin and pifithrin-μ.

The reduction of platinum(IV) and palladium(IV) ions by 2,6-pyridinedihydroxamic acid

Reaction of K(2)[Pt(IV)Cl(6)] and K(2)[Pd(IV)Cl(6)] with 2,6-pyridinedihydroxamic acid (2,6-pyha) and its disodium salt, 2,6-pyhaNa(2), yielded not the desired Pt(IV) and Pd(IV) 2,6-pyridinedihydroxamato complexes, but rather the Pt(II) and Pd(II) 2,6-pyridinedicarboxylato complexes, trans-[Pt(II)(2,6-pyca(H-1))(2)].2H(2)O and trans-[Pd(II)(2,6-pyca(H-1))(2)].2H(2)O respectively (2,6-pyca = 2,6-pyridinedicarboxylic acid). Thus in the presence of Pt(IV) and Pd(IV), the dihydroxamic acid was adventitiously hydrolysed to the corresponding dicarboxylic acid and Pt(IV) and Pd(IV) reduced to Pt(II) and Pd(II) in situ. The X-ray crystal structures of 2,6-pyha, 2,6-pyhaNa(2).8H(2)O, trans-[Pt(II)(2,6-pyca(H-1))(2)].2H(2)O and trans-[Pd(II)(2,6-pyca(H-1))(2)].2H(2)O are reported, together with a possible mechanism for the metal-assisted hydrolysis of the dihydroxamic acid and reduction of Pt(IV) and Pd(IV) to Pt(II) and Pd(II) respectively.