Conformational control of anticancer activity: the application of arene-linked dinuclear ruthenium(II) organometallics

Dinuclear metal complexes have emerged as a promising class of biologically active compounds which possess unique anticancer activity. Here, we describe a novel series of arene-linked dinuclear organometallic Ru(II) complexes, where the relative conformation of the ruthenium centres is controlled by the stereochemical configuration of 1,2-diphenylethylenediamine linker moieties, as confirmed by X-ray crystallography. The reactivity and cytotoxicity of these compounds is compared to flexible dinuclear and mononuclear analogues, demonstrating in all cases the complexes can undergo aquation, coordinate to typical biological donor ligands and importantly, in the case of dinuclear analogues, crosslink oligonucleotide and peptide sequences. Differences in the conformation of the isomeric dinuclear compounds lead to significantly different levels of cytotoxicity against A2780, A2780cisR and HEK-293 cell lines; isomers with a closed conformation are significantly more cytotoxic than isomers with a more open conformation and they are also significantly less susceptible to acquired resistance mechanisms operating in the A2780cisR cell line. These rigid dinuclear compounds possess markedly increased cytotoxicity relative to the non-cytotoxic mononuclear analogues that does not appear to be related to differences in complex lipophilicity or cellular uptake, which, in general, remain similar in magnitude across the series. Thus, the molecular conformation of such dinuclear species may be crucial in determining the nature of the adducts formed on coordination to biological targets in a cellular environment, and opens up a novel route toward the development of more active metal-based anticancer agents

Potential of cycloaddition reactions to generate cytotoxic metal drugs in vitro

Severe general toxicity issues blight many chemotherapeutics utilized in the treatment of cancers, resulting in the need for more selective drugs able to exert their biological activity at only the required location(s). Toward this aim, we report the development of an organometallic ruthenium compound, functionalized through a η6-bound arene ligand with a bicyclononyne derivative, able to participate in strain-promoted cycloaddition reactions with tetrazines. We show that combination of the ruthenium compound with a ditetrazine in biological media results in the in situ formation of a dinuclear molecule that is more cytotoxic toward cancer cells than the starting mononuclear ruthenium compound and tetrazine components. Such an approach may be extended to in vivo applications to construct a cytotoxic metallodrug at a tumor site, providing a novel approach toward the turn-on cytotoxicity of metallodrugs in the treatment of cancer

Recent progress in the development of organometallics for the treatment of cancer

From their early successes in medicine, organometallic compounds continue to attract interest as potential chemotherapeutics to treat a range of diseases. Here, we show from recent literature selected largely from the last two years that organometallics offer unique opportunities in medicine and, increasingly, a mechanistic-based approach is applied to their development, which has not always been the case

Chandra and Hubble Study of a New Transient X-ray Source in M31

We present X-ray and optical observations of a new transient X-ray source in M31 first detected 23-May-2004 at R.A.=00:43:09.940 +/- 0.65'', Dec.=41:23:32.49 +/- 0.66''. The X-ray lightcurve shows two peaks separated by several months, reminiscent of many Galactic X-ray novae. The location and X-ray spectrum of the source suggest it is a low mass X-ray binary (LMXB). Follow-up HST ACS observations of the location both during and after the outburst provide a high-confidence detection of variability for one star within the X-ray position error ellipse. This star has $\Delta$B ~ 1 mag, and there is only a ~1% chance of finding such a variable in the error ellipse. We consider this star a good candidate for the optical counterpart of the X-ray source. The luminosity of this candidate provides a prediction for the orbital period of the system of 2.3$^{+3.7}_{-1.2}$ days.Comment: 17 pages, 3 figures, 4 tables, accepted for publication in Ap

pH-dependent modulation of reactivity in Ruthenium(II) organometallics

The pH-dependent intramolecular chelation of a tethered sulfonamide ligand in ruthenium(II) arene complexes is demonstrated, a process shown to modulate metal-centered reactivity toward the model ligand guanosine 5′-monophosphate within the physiologically relevant pH region

The development of RAPTA compounds for the treatment of tumors

© 2015 Elsevier B.V. Ruthenium(II)-arene RAPTA-type compounds have been extensively explored for their medicinal properties. Herein a comprehensive review of this class of compounds is provided. A discussion of the basic RAPTA structure is given together with the ways it has been modified to elucidate the key role of each part and to afford targeted derivatives. The various mechanistic studies conducted on RAPTA compounds are described and these are linked to the observed macroscopic biological properties. Ultimately, the review shows that certain RAPTA compounds display quite unique properties that point towards a clinical investigation

Optical Constraints on an X-ray Transient Source in M31

We have detected a transient X-ray source in the M31 bulge through a continuing monitoring campaign with the Chandra ACIS-I camera. The source was detected at R.A.=00:42:33.428 +/- 0.11'', Dec.=+41:17:03.37 +/- 0.11'' in only a single observation taken 2004 May 23. Fortuitous optical HST/ACS imaging of the transient location prior to the X-ray outburst, along with follow-up HST/ACS imaging during and after the outburst, reveals no transient optical source brighter than B (equivalent) = 25.5. The location of the source and its X-ray properties suggest it is a low mass X-ray binary (LMXB). Assuming the transient is similar to many Galactic X-ray novae, the X-ray luminosity of (3.9 +/- 0.5) X 10$^{37}$ erg s$^{-1}$ and the upper-limit on the optical luminosity provide a prediction of <1.6 days for the orbital period of the binary system.Comment: 15 pages, 3 figures, accepted for publication in Ap

A Soft X-ray Transient in the M31 Bulge

We have examined a probable soft X-ray transient source in the M31 bulge at R.A.=0:42:41.814 +/- 0.08", Dec. = 41:16:35.86 +/- 0.07". On the three occasions we observed the source, its spectrum was soft (kT_{in} ~1 keV). The brightest detection of the source was 2004 July 17 with a 0.3-7 keV luminosity of ~5 X 10^{37} erg/s. The only previous detection of the source was in 1979 by the Einstein observatory. The multiple detections over 25 years suggest the duty cycle of the source is in the range 0.02-0.06. Coordinated HST/ACS imaging before, during, and after the outburst revealed no variable optical source within the position errors of the X-ray source. The optical data place a firm upper limit on the brightness of the counterpart of the X-ray outburst of B>24.7, suggesting the binary has a period <5.2 days. The X-ray spectrum and lack of bright stars at the source location indicate the source was a soft transient event occurring in a low-mass X-ray binary, making this source a good black hole candidate in M31.Comment: 18 pages, 4 tables, 3 figures, accepted for publication in Ap

The Application of Reversible Intramolecular Sulfonamide Ligation to Modulate Reactivity in Organometallic Ruthenium(II) Diamine Complexes

Metallation of biomacromolecular species forms the basis for the anticancer activity of many metallodrugs. A major limitation of these compounds is that their reactivity is indiscriminate and can, in principle, occur in healthy tissue as well as cancerous tissue, potentially leading to side effects in vivo. Here we present pH-dependent intramolecular coordination of an arene-tethered sulfonamide functionality in organometallic ruthenium(II) ethylenediamine complexes as a route to controlling the coordination environment about the central metal atom. Through variation of the sulfonamide R group and the length of the tether linking it to the arene ligand the acidity of the sulfonamide NH group, and hence the pH-region over which regulation of metal coordination occurs, can be modulated. Intramolecular sulfonamide ligation controlled the reactivity of complex 4 within the physiologically relevant pH-region, rendering it more reactive towards 5?-GMP in mildly acidic pH-conditions typical of tumour tissue compared to the mildly alkaline pH-conditions typical of healthy tissue. However, the activation of 4 by ring-opening of the chelate was found to be a slow process relative to the timescale of typical cell culture assays and members of this series of complexes were found not to be cytotoxic towards the HT-29 cell line. These complexes provide the basis for the development of analogues of increased potency where intramolecular sulfonamide ligation regulates reactivity and therefore cytotoxicity in a pH-dependent, and potentially, tissue-dependent manner