We report structure-activity relationships for organometallic RuII complexes of the type [(eta6-arene)Ru(XY)Cl]Z, where XY is an N,N- (diamine), N,O- (e.g., amino acidate), or O,O- (e.g., beta-diketonate) chelating ligand, the arene ranges from benzene derivatives to fused polycyclic hydrocarbons, and Z is usually PF6. The X-ray structures of 13 complexes are reported. All have the characteristic "piano-stool" geometry. The complexes most active toward A2780 human ovarian cancer cells contained XY=ethylenediamine (en) and extended polycyclic arenes. Complexes with polar substituents on the arene or XY=bipyridyl derivatives exhibited reduced activity. The activity of the O,O-chelated complexes depended strongly on the substituents and on the arene. For arene=p-cymene, XY=amino acidate complexes were inactive. Complexes were not cross-resistant with cisplatin, and cross-resistance to Adriamycin was circumvented by replacing XY=en with 1,2-phenylenediamine. Some complexes were also active against colon, pancreatic, and lung cancer cells.

Organometallic compounds offer broad scope for the design of therapeutic agents, but this avenue has yet to be widely explored. A key concept in the design of anticancer complexes is optimization of chemical reactivity to allow facile attack on the target site (e.g., DNA) yet avoid attack on other sites associated with unwanted side effects. Here, we consider how this result can be achieved for monofunctional ''piano-stool'' ruthenium(II) arene complexes of the type [( 6 -arene)Ru(ethylenediamine)(X)] n؉ . A potentially important activation mechanism for reactions with biomolecules is hydrolysis. Density functional calculations suggested that aquation (substitution of X by H2O) occurs by means of a concerted ligand interchange mechanism. We studied the kinetics and equilibria for hydrolysis of 21 complexes, containing, as X, halides and pseudohalides, pyridine (py) derivatives, and a thiolate, together with benzene (bz) or a substituted bz as arene, using UV-visible spectroscopy, HPLC, and electrospray MS. The x-ray structures of six complexes are reported. In general, complexes that hydrolyze either rapidly {e.g., X ‫؍‬ halide [arene ‫؍‬ hexamethylbenzene (hmb)]} or moderately slowly [e.g., X ‫؍‬ azide, dichloropyridine (arene ‫؍‬ hmb)] are active toward A2780 human ovarian cancer cells, whereas complexes that do not aquate (e.g., X ‫؍‬ py) are inactive. An intriguing exception is the X ‫؍‬ thiophenolate complex, which undergoes little hydrolysis and appears to be activated by a different mechanism. The ability to tune the chemical reactivity of this class of organometallic ruthenium arene compounds should be useful in optimizing their design as anticancer agents.anticancer ͉ bioorganometallic ͉ hydrolysis ͉ kinetics ͉ ruthenium complexes O rganometallic chemistry has evolved rapidly during the last 50 years, notably in areas related to catalysis and materials (1). Applications in biology and medicine are in their infancy, but the potential for exciting developments is clear (2). In the field of cancer chemotherapy, the cyclopentadienyl complex [Cp 2 TiCl 2 ] has been in clinical trials (3, 4), and a ferrocene derivative of Tamoxifen is a candidate for trials for breast cancer therapy (5). The successful design of second-and thirdgeneration platinum anticancer drugs, now widely used in the clinic, has demonstrated that detailed knowledge of the factors that control ligand substitution and redox reactions is very valuable in drug design. The chemical reactivity of the complexes can be chosen so as to balance the inertness required for the drug to reach its target site (e.g., DNA) and minimize attack on other sites (side effects) yet allow activation necessary for binding to the target. Thus, cis-[PtCl 2 (NH 3 ) 2 ], cisplatin, is relatively unreactive in high-chloride media (e.g., blood plasma) and is activated by hydrolysis near DNA in the nucleus (6). In contrast, carboplatin and oxaliplatin are relatively inert to hydrolysis, have a milder spectrum of side effects, and probably attack DNA by means of chelate ...

The Os(II) arene ethylenediamine (en) complexes [(eta(6)-biphenyl)Os(en)Cl][Z], Z = BPh(4) (4) and BF(4) (5), are inactive toward A2780 ovarian cancer cells despite 4 being isostructural with an active Ru(II) analogue, 4R. Hydrolysis of 5 occurred 40 times more slowly than 4R. The aqua adduct 5A has a low pK(a) (6.3) compared to that of [(eta(6)-biphenyl)Ru(en)(OH(2))](2+) (7.7) and is therefore largely in the hydroxo form at physiological pH. The rate and extent of reaction of 5 with 9-ethylguanine were also less than those of 4R. We replaced the neutral en ligand by anionic acetylacetonate (acac). The complexes [(eta(6)-arene)Os(acac)Cl], arene = biphenyl (6), benzene (7), and p-cymene (8), adopt piano-stool structures similar to those of the Ru(II) analogues and form weak dimers through intermolecular (arene)C-H...O(acac) H-bonds. Remarkably, these Os(II) acac complexes undergo rapid hydrolysis to produce not only the aqua adduct, [(eta(6)-arene)Os(acac)(OH(2))](+), but also the hydroxo-bridged dimer, [(eta(6)-arene)Os(mu(2)-OH)(3)Os(eta(6)-arene)](+). The pK(a) values for the aqua adducts 6A, 7A, and 8A (7.1, 7.3, and 7.6, respectively) are lower than that for [(eta(6)-p-cymene)Ru(acac)(OH(2))](+) (9.4). Complex 8A rapidly forms adducts with 9-ethylguanine and adenosine, but not with cytidine or thymidine. Despite their reactivity toward nucleobases, complexes 6-8 were inactive toward A549 lung cancer cells. This is attributable to rapid hydrolysis and formation of unreactive hydroxo-bridged dimers which, surprisingly, were the only species present in aqueous solution at biologically relevant concentrations. Hence, the choice of chelating ligand in Os(II) (and Ru(II)) arene complexes can have a dramatic effect on hydrolysis behavior and nucleobase binding and provides a means of tuning the reactivity and the potential for discovery of anticancer complexes.

Organic molecules, such as pharmaceuticals, agro-chemicals and pigments, frequently form several crystal polymorphs with different physicochemical properties. Finding polymorphs has long been a purely experimental game of trial-and-error. Here we utilize in silico polymorph screening in combination with rationally planned crystallization experiments to study the polymorphism of the pharmaceutical compound Dalcetrapib, with 10 torsional degrees of freedom one of the most flexible molecules ever studied computationally. The experimental crystal polymorphs are found at the bottom of the calculated lattice energy landscape, and two predicted structures are identified as candidates for a missing, thermodynamically more stable polymorph. Pressure-dependent stability calculations suggested high pressure as a means to bring these polymorphs into existence. Subsequently, one of them could indeed be crystallized in the 0.02 to 0.50 GPa pressure range and was found to be metastable at ambient pressure, effectively derisking the appearance of a more stable polymorph during late-stage development of Dalcetrapib.

The effects of high pressure on pharmaceutical compounds and energetic materials can have important implications for both the properties and performance of these important classes of material. Pharmaceutical compounds are frequently subjected to pressure during processing and formulation, causing interconversion between solid forms that may affect properties such as solubility and bio-availability. Energetic materials experience extremes of both pressure and temperature under conditions of detonation and deflagration, causing changes in properties such as sensitivity to shock and chemical reactivity. This tutorial review outlines the various methods used to study these materials at high pressure, describes how pressure can be used to explore polymorphism, and provides examples of compounds that have been studied at high pressure.

Graphical tools based on Hirshfeld surfaces and two-dimensional (2D) fingerprint plots are shown to be valuable for visualizing and analyzing intermolecular interactions in polymorphs of molecular crystals and make the task of polymorph comparison easier and considerably faster. This is the direct result of the underlying principle behind the Hirshfeld surface, which embraces a “whole of structure” view of intermolecular interactions, rather than concentrating exclusively on assumed important (i.e., short) interactions. The subtle relationships between polymorphs of tetrathiafulvalene and p-dichlorobenzene are more easily discernible through comparison of Hirshfeld surfaces and fingerprint plots, rather than solely through conventional structure viewing, and differences and similarities among clearly distinct polymorphs of oxalic acid, terephthalic acid, and p-dichlorobenzene more readily emerge and can be easily catalogued in terms of specific atom···atom interaction types. Conformational polymorphism makes the comparisons more challenging, and Hirshfeld surfaces provide sufficient information for piracetam, while for ROY (5-methyl-2-((2-nitrophenyl)amino)-3-thiophenecarbonitrile, nicknamed ROY due to its red, orange, and yellow crystal forms) fingerprint plots are preferred, summarizing the major features of each crystal structure in a single, colored 2D plot. In addition to the successful applications to polymorph discrimination, improvements to the Hirshfeld surface approach are identified, the most notable being the breakdown of 2D fingerprint plots into specific atom···atom contacts in the crystal.

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The structural response of the nootropic drug piracetam (2-oxo-pyrrolidineacetamide) to both direct compression and high-pressure recrystallization from aqueous solution is reported. Crystals obtained by these methods have been characterized in situ by single-crystal X-ray diffraction. Compression of form II between pressures of 0.45-0.70 GPa caused a reversible, singlecrystal to single-crystal transition to give a new polymorph, form V. Crystallization from a dilute aqueous solution of piracetam at a pressure of 0.6 GPa via crystallization of high-pressure ice-VI resulted in the formation of a previously unreported dihydrate. The molecular packing arrangements of these new structures are compared with the known polymorphs and hydrates of piracetam. This study highlights how the systematic variation of pressure is a powerful method for the exploration of polymorphism and solvate formation and has the potential to add a further dimension to polymorph screening of pharmaceuticals.