546 Anorganische Chemie
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The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has called for an urgent need for dedicated antiviral therapeutics. Metal complexes are commonly underrepresented in compound libraries that are used for screening in drug discovery campaigns, however, there is growing evidence for their role in medicinal chemistry. Based on previous results, we have selected more than 100 structurally diverse metal complexes for profiling as inhibitors of two relevant SARS-CoV-2 replication mechanisms, namely the interaction of the spike (S) protein with the ACE2 receptor and the papain-like protease PLpro. In addition to many well-established types of mononuclear experimental metallodrugs, the pool of compounds tested was extended to approved metal-based therapeutics such as silver sulfadiazine and thiomersal, as well as polyoxometalates (POMs). Among the mononuclear metal complexes, only a small number of active inhibitors of the S/ACE2 interaction was identified, with titanocene dichloride as the only strong inhibitor. However, among the gold and silver containing complexes many turned out to be very potent inhibitors of PLpro activity. Highly promising activity against both targets was noted for many POMs. Selected complexes were evaluated in antiviral SARS-CoV-2 assays confirming activity for gold complexes with N-heterocyclic carbene (NHC) or dithiocarbamato ligands, a silver NHC complex, titanocene dichloride as well as a POM compound. These studies might provide starting points for the design of metal-based SARS-CoV-2 antiviral agents.
Die vorliegende Arbeit gliedert sich in drei Teile. Der erste Teil beschäftigt sich mit der Synthese und Reaktivität von Rhodium-η\(^4\)-1,2-azaboretkomplexen. Im darauffolgenden Abschnitt werden die Synthese und Charakterisierung von 1,2-Azaborininen näher betrachtet. Der letzte Teil dieser Thesis befasst sich mit der Reaktivität von 1-Rhoda-3,2-azaborolen gegenüber Iminoboranen.
In the present thesis, the potential of functionalized Re(CO)3 complexes as thiol-specific probes, luminescent markers for microscopy, and non-radioactive congeners for 99mTc and 186/188Re radiopharmaceuticals was explored.
In the first section, three different routes to alkyne-based thiol probes were investigated. Initially, a mixed 2-picolyl/triazole ligand (pictz), with the aim of directly introducing the required peripheral thiol-specific alkyne group to the ligand periphery, was prepared from 2 (azidomethyl)pyridine and 1,4-Bis(ethinyl)benzene. However, the resulting complexes showed likely due to the significant flexibility introduced by the methylene linker connecting the triazole and pyridyl groups, unfavorable luminescence properties. A second attempt was based on a mixed pyridyl/NHC ligand, for which the non-functionalized parent compound was synthesized, but also shows a low emission, which led to the route being abandoned. In the end, a Sonogashira coupling of 4-brom-2,2’-bipyridine with trimethylsilylacetylene gave the desired complex [ReBr(bpyCCH)(CO)3], which showed the desired bright orange luminescence centered around 570–590 nm upon excitation at 380 nm. NMR studies in the presence of L cysteine under different conditions (no additive, addition of morpholine as base, and 2,2 dimethoxy-2-phenylacetophenone as a radical initiator) showed that the cysteine thiol group has to be either deprotonated or oxidized to the thiyl state for a reaction to take place. Only in the latter two cases, the typical spectral signature of a trans-alkene moiety from sulfur addition to the CC triple bond was observed in the 1H NMR spectra of the respective reaction mixtures.
In the second chapter, axial ligand modification in [Re(N3)(bpy)(CO)3] by iClick reaction with different alkynes was explored. In addition to dimethyl acetylene dicarboxylate (DMAD), a number of other terminal and internal alkynes was also investigated and the iClick reaction also extended to strained and “masked” alkynes in the form of cyclooctyne and oxanorbornadiene derivatives. While bulky phenyl groups in internal alkynes of the general formula C6H5CCR with R = COCH3 or COOCH3 did, likely due to steric hinderance, not lead to formation of any triazolato product, other internal and terminal alkynes showed iClick reactions to proceed with reaction rate constants in the range of 10 5 to 101 M-1 s-1, with two strongly electron-withdrawing groups like ester or trifluoromethyl generally leading to the fastest reactions and strained or masked alkynes in the 10-4 to 10-2 M-1 s-1 range. Some of the title complexes were internalized by bacterial cells, as demonstrated by luminescence microscopy, but overall the quantum yields were too low for general suitability as emissive markers and the compounds will require further optimization of their photophysical properties for future and more universal use.
In the last section, a one-pot synthesis of [Re(triazolatoCOOCH3,COOCH3)(bpy)(CO)3] by sequential addition of 2,2’-bipyridine (bpy), sodium azide, and DMAD to [ReBr3(CO)3]2- was based on HPLC detection, developed. By careful optimization of the HPLC gradient and reaction times after each of the consecutive additions, the title compound could indeed be isolated and authenticated by matching of retention time and UV/Vis spectral signature to that of an authentic sample separately synthesized on a preparative scale, paving the way to transfer the method to radioactive 99mTc complexes.
Overall, this work shows the great utility of the [ReX(N^N)(CO)3] moiety for both, small molecule reporters and biological molecules such as thiols, in luminescence spectroscopy, as well as models for radioactive Tc analogues.
Fully aromatic, luminescent, and highly robust BNB-doped phenalenyls have been prepared, which are isoelectronic to the phenalenyl cation. B-Fluoromesityl-substitution leads to fluorescence in an extremely narrow range and significant increase in the reduction potential. Detailed theoretical investigations revealed an intramolecular aromaticity switch upon one-electron reduction.
Platinum-Templated Coupling of B=N Units: Synthesis of BNBN Analogues of 1,3-Dienes and a Butatriene
(2021)
The 1:2 reaction of [μ-(dmpm)Pt(nbe)]2 (dmpm=bis(dimethylphosphino)methane, nbe=norbornene) with Cl2BNR(SiMe3) (R=tBu, SiMe3) yields unsymmetrical (N-aminoboryl)aminoboryl PtI2 complexes by B−N coupling via ClSiMe3 elimination. A subsequent intramolecular ClSiMe3 elimination from the tBu-derivative leads to cyclization of the BNBN unit, forming a unique 1,3,2,4-diazadiboretidin-2-yl ligand. In contrast, the analogous reaction with Br2BN(SiMe3)2 leads, via a twofold BrSiMe3 elimination, to a PtII2 A-frame complex bridged by a linear BNBN isostere of butatriene. Structural and computational data confirm π electron delocalization over the entire BNBN unit.
The development of "click" reactions, including copper-catalyzed azide-alkyne
cycloaddition (CuAAC) and its strain promoted variant has been essentially
contributed to the synthesis of small molecules and bio(macro)molecule conjugates.
In contrast, the inorganic click reaction ("iClick") as a catalyst-free cycloaddition
reaction occurring within the inner coordination sphere of a metal-azido complex with
dipolarophiles such as alkynes, gained significantly less attention.
The objective of the present thesis was to utilize the iClick reaction to create a
diverse array of biomolecule-functionalized transition metal complexes and to identify
patterns in the reactivity and structure preference of the resulting triazolate products.
While existing studies have predominantly explored the influence of various ligands
on the reactivity and structure of triazolate products, the first part of this work focused
on the influence of different metal centers on the speed of the iClick reaction. An
isostructural series of Ni(II), Pd(II), Pt(II), and Au(III) azido complexes with a N^C^N
pincer ligand was studied to discern trends in the iClick reaction kinetics with different
electron-poor alkynes and the structural parameters of their triazolato products.
Building from this knowledge, the attachment of functionalized alkynes was used to
install biorelevant small molecules such as carbohydrates, coumarin and biotin.
Through this approach, the resulting triazolato complexes were tested for the
improvement of their photophysical properties, protein binding, and modulation of
biological activity.
Based on the clinical success of cisplatin for example in the treatment of testicular cancer, there is an ongoing interest in exploring the potential of other transition metal complexes as drug candidates for anticancer chemotherapy. A key objective in this field is the improvement of the selectivity of drug candidates, which can be achieved by addressing novel target sites beyond the traditional DNA interaction mechanism. Another promising strategy to achieve a high spatiotemporal control over the biological activity and thus minimize off-target side-effects is the use of light-activated metallodrugs. In that context, this thesis focuses on metal complexes and their ability to undergo ligand exchange reactions with specific biological ligands and respond to external stimuli such as light to improve their selectivity towards cancer cells. Besides their impact in medicinal chemistry, metal complexes are also highly attractive as luminescent probes to study biological systems. To enhance their cellular uptake and address specific intracellular target structures, the iClick (inorganic click) reaction serves as a very promising synthetic tool to prepare biofunctional metal complexes in a modular way.
As the treatment of effluents containing the antibiotic drug sulfadiazine (SZ) is one of the challenging problems in the field of environmental chemistry, it is essential to determine the concentration of SZ by a rapid and accurate method and then find a suitable method to degrade the assayed products into harmless chemicals. The color of the charge transfer (CT) complexes developed from the reaction of SZ with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), chloranilic acid (CHL) and picric acid (PA) was used to determine the concentration of SZ at 528, 510 and 410 nm, respectively. The Lambert–Beer's law is obeyed in the ranges of 6.80–68.06, 13.61–136.12 and 6.80–27.22 μg mL\(^{−1}\) for DDQ, CHL and PA complexes. The photolysis of SZ → DDQ in presence of sodium nitrite at 256 nm leads to faster degradation of SZ compared with the control experiments. This was simply spectrophotometrically followed by a decrease in the intensity of the CT band. The effect of some additives such as oxalic acid, and hematite nano particles was studied. For comparison, other π-acceptor reagents such as CHL and PA were used. About 80% of SZ is degraded in 45 min upon the illumination of SZ → DDQ at 256 nm, whereas 90 min is required in the case of CHL and PA to attain the same degradation limit.
A new series of [Pd2(L)4] cages based on photochromic dithienylethene (DTE) ligands allowed us to gain insight into the successive photoswitching of multiple DTE moieties in a confined metallo-supramolecular assembly. Three new X-ray structures of [Pd2(o-L4)4], [Pd2(o-L1)2(c-L1)2] and [Pd2(c-L1)4] (o-L and c-L = open and closed forms of DTE ligands, respectively) were obtained. The structures deliver snapshots of three different combinations of DTE photoisomeric states within the cage, facilitating a comparison of the all-open with the all-closed, and most notably, an intermediate form where open and closed switches co-exist in the same cage. Moreover, a series of spherical anionic borate clusters was introduced in order to study their roles in the light-controllable host–guest chemistry. The binding guests show higher affinities with the flexible open cage [Pd2(o-L1)4] than with the rigid closed cage [Pd2(c-L1)4]. For the [B12F12]2− guest, thermodynamic data obtained from NMR experiments was compared to results from isothermal titration calorimetry (ITC).
The rhodium(I) complex [Rh(κ3-P,O,P-Xantphos)(η2-PhC≡CPh)][BArF4] (ArF = 3,5-(CF3)2C6H4) is an effective catalyst for the cis-selective hydroboration of the alkyne diphenylacetylene using the amine-borane H3B·NMe3. Detailed mechanistic studies, that include initial rate measurements, full simulation of temporal profiles for a variety of catalyst and substrate concentrations, and speciation experiments, suggest a mechanism that involves initial coordination of alkyne and a saturation kinetics regime for amine-borane binding. The solid-state molecular structure of a model complex that probes the proposed resting state is also reported, [Rh(κ3-P,O,P-Xantphos)(NCMe)(η2-PhC≡CPh)][BArF4].