Taxanes, including paclitaxel, are widely used in cancer therapy. In an attempt to overcome some of the disadvantages entailed with taxane chemotherapy, we devised the synthesis of ferrocenyl-functionalized paclitaxel derivatives and studied their biological properties. The cytotoxic activity was measured with a panel of human cancer cell lines of various tissue origin, including multidrug-resistant lines. A structure-activity study of paclitaxel ferrocenylation revealed the N-benzoyl-ferrocenyl-substituted derivative to be the most cytotoxic. In contrast, substitution of the 3'-phenyl group of paclitaxel with a ferrocenyl moiety led to less potent antiproliferative compounds. However, these agents were able to overcome multidrug resistance, as they were virtually unrecognized by ABCB1, a major cellular exporter of taxanes. Interestingly, the redox properties of these ferrocenyl derivatives appear to play a less important role in their mode of action, as there was no correlation between intracellular redox activity and cytotoxicity/cell-cycle distribution. The antiproliferative activity of ferrocenyl taxanes strongly depends on the substitution position, and good tubulin polymerization inducers, as confirmed by molecular docking, were usually more cytotoxic, whereas compounds with stronger pro-oxidative properties exhibited lower antiproliferative activity.
The influenceo ft he chemical substitution, crystal packing, and aurophilic interactions of the gold(I) acetylide complexes of the type (ArCOCC) n AuPEt 3 (n = 1,2) on their luminescent propertiesw ere examined. All described complexes undergo ligand scrambling in solution,w hich results in the formation of stable, easily isolated crystals that contain [ArCO(CC) n ] 2 Au À (Et 3 P) 2 Au + homoleptic species. In particular,w eobserved that the (benzoylacetylide)gold(I) complex yields three crystal forms with strikingly differentl uminescence properties. We monitored the conversion pathway for these forms:a no range luminescentf orm of homoleptic complex upon dryingu ndergoes spontaneous transformation to bright greenf luorescent form and finally to the weakly blue emissive one. In addition, we report ar are exampleo fah elical arrangement of Au·Au·Au chains that are observed for the first time in acetylide gold(I)c omplexes in the case of heteroleptic (benzoylacetylide)gold(I) complex. This is av ery rare case in which crystal structures and ensuing electronicp roperties of the heteroleptica nd Au I complexesc ould be directly compared.
The main goal of this study is the validation of relativistic Hirshfeld atom refinement (HAR) as implemented in Tonto for high-resolution X-ray diffraction datasets of an organo-gold(I) compound. The influence of the relativistic effects on statistical parameters, geometries and electron density properties was analyzed and compared with the influence of electron correlation and anharmonic atomic motions. Recent work in this field has indicated the importance of relativistic effects in the static electron density distribution of organo-mercury compounds. This study confirms that differences in electron density due to relativistic effects are also of significant magnitude for organo-gold compounds. Relativistic effects dominate not only the core region of the gold atom, but also influence the electron density in the valence and bonding region, which has measurable consequences for the HAR refinement model parameters. To study the effects of anharmonic motion on the electron density distribution, dynamic electron density difference maps were constructed. Unlike relativistic and electron correlation effects, the effects of anharmonic nuclear motion are mostly observed in the core area of the gold atom.
Hirshfeld atom refinement (HAR) is one of the most effective methods for obtaining accurate structural parameters for hydrogen atoms from X-ray diffraction data. Unfortunately, it is also relatively computationally expensive, especially for larger molecules due to wavefunction calculations. Here, a fragmentation approach has been tested as a remedy for this problem. It gives an order of magnitude improvement in computation time for larger organic systems and is a few times faster for metal–organic systems at the cost of only minor differences in the calculated structural parameters when compared with the original HAR calculations. Fragmentation was also applied to polymeric and disordered systems where it provides a natural solution to problems that arise when HAR is applied. The concept of fragmentation is closely related to the transferable aspherical atom model (TAAM) and allows insight into possible ways to improve TAAM. Hybrid approaches combining fragmentation with the transfer of atomic densities between chemically similar atoms have been tested. An efficient handling of intermolecular interactions was also introduced for calculations involving fragmentation. When applied in fragHAR (a fragmentation approach for polypeptides) as a replacement for the original approach, it allowed for more efficient calculations. All of the calculations were performed with a locally modified version of Olex2 combined with a development version of discamb2tsc and ORCA. Care was taken to efficiently use the power of multicore processors by simple implementation of load-balancing, which was found to be very important for lowering computational time.
The crystal and molecular structures of the popular anti-inflammatory drug ketoprophen were examined. The centrosymmetric form of ketoprophen (β-ket) that has been reported so far, was structurally, geometrically and energetically compared with the non-centrosymmetric form (S-enantiomer) of ketoprophen (α-ket). The molecules in both crystal structures are in similar arrangements, with antiparallel-oriented benzophenone moieties.
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