Sulfated Dendritic Polyglycerol Is a Potent Complement Inhibitor.

The complement system is a powerful mechanism of the innate immune defense system. Dysregulation may contribute to several diseases. Heparin is a known regulator of the complement system, but its application is limited due to its anticoagulative activity. A promising alternative is the synthetic analogue dendritic polyglycerol sulfate (dPGS). Although dPGS-mediated inhibition of the classical and alternative pathway has been roughly described previously, here we analyzed the effects of dPGS regarding the three pathways at different levels of the proteolytic cascades for the first time. Regarding the final outcome (membrane attack complex formation), IC50 values for dPGS varied between the alternative (900 nM), the classical (300 nM), and the lectin pathway (60 nM). In a backward approach, processing of proteins C5 and C3 via the respective convertase was analyzed by ELISA to narrow down dPGS targets. A dose-dependent reduction of C5a and C3a levels was detected. Further, the analysis via surface plasmon resonance revealed novel dPGS binding proteins; the pro-inflammatory anaphylatoxins C3a and C5a and the classical pathway activator C1q showed down to nanomolar binding affinities. The fully synthetic multivalent polymer dPGS seems to be a promising candidate for the further development to counteract excessive complement activation in disease.

Reductively cleavable polymer-drug conjugates based on dendritic polyglycerol sulfate and monomethyl auristatin E as anticancer drugs.

Stimuli-responsive polymer-drug conjugates (PDCs) provide promising approaches in anticancer treatment. Here, we report the synthesis and biological evaluation of PDCs made of the highly potent antimitotic agent monomethyl auristatin E conjugated to dendritic polyglycerol and dendritic polyglycerol sulfate via a reductively cleavable, self-immolative disulfide linker. Cell viability assays with the human cancer cell lines A549 (lung carcinoma) and HeLa (cervix carcinoma) revealed that the drug's cytotoxicity was reduced by conjugation to the polymers, with the sulfated conjugates being more effective than the non-sulfated ones. Kinetic studies using real-time cell analysis indicated a retarded drug release from the polymers, with a much later cytotoxic response after treatment with the non-sulfated conjugates due to less cellular uptake, as confirmed by flow cytometry and confocal laser scanning microscopy. In contrast, the non-cleavable dPGS-MMAE conjugate that was synthesized for comparison was not cytotoxic under the same conditions. Overall, reductively cleavable dPGS-SS-MMAE conjugates showed promising results in vitro and good tolerability in vivo. Further in vivo studies are planned.

Dendritic Polyglycerol Sulfate for Therapy and Diagnostics.

Dendritic polyglycerol sulfate (dPGS) has originally been investigated as an anticoagulant to potentially substitute for the natural glycosaminoglycan heparin. Compared to unfractionated heparin, dPGS possesses lower anticoagulant activity but a much higher anticomplementary effect. Since coagulation, complement activation, and inflammation are often present in the pathophysiology of numerous diseases, dPGS polymers with both anticoagulant and anticomplementary activities represent promising candidates for the development of polymeric drugs of nanosized architecture. In this review, we describe the nanomedical applications of dPGS based on its anti-inflammatory activity. Furthermore, the application of dPGS as a carrier molecule for diagnostic molecules and therapeutic drugs is reviewed, based on the ability to target tumors and localize in tumor cells. Finally, the application of dPGS for inhibition of virus infections is described.

Efficient Self-Assembly of Di-, Tri-, Tetra-, and Hexavalent Hosts with Predefined Geometries for the Investigation of Multivalency.

Coordination-driven self-assembly of differently shaped di- to hexavalent crown-ether host molecules is described. A series of [21]crown-7- and [24]crown-8-substituted bipyridine and terpyridine ligands was synthetized in a "toolbox" approach. Subsequent coordination to 3d transition metal and ruthenium(II) ions provides an easy and fast access to host assemblies with variable valency and pre-defined orientations of the crown-ether moieties. Preliminary isothermal calorimetry (ITC) titrations provided promising results, which indicated the host complexes under study to be suitable for the future investigation of multivalent and cooperative binding. The hosts described herein will also be suitable for the construction of various multiply threaded mechanically interlocked molecules.

Pyridyl-functionalised 3H-1,2,3,4-triazaphospholes: synthesis, coordination chemistry and photophysical properties of low-coordinate phosphorus compounds.

Novel conjugated, pyridyl-functionalised triazaphospholes with either tBu or SiMe3 substituents at the 5-position of the N3 PC heterocycle have been prepared by a [3+2] cycloaddition reaction and compared with structurally related, triazole-based systems. Photoexcitation of the 2-pyridyl-substituted triazaphosphole gives rise to a significant fluorescence emission with a quantum yield of up to 12 %. In contrast, the all-nitrogen triazole analogue shows no emission at all. DFT calculations indicate that the 2-pyridyl substituted systems have a more rigid and planar structure than their 3- and 4-pyridyl isomers. Time-dependent (TD) DFT calculations show that only the 2-pyridyl-substituted triazaphosphole exhibits similar planar geometry, with matching conformational arrangements in the lowest energy excited state and the ground state; this helps to explain the enhanced emission intensity. The chelating P,N-hybrid ligand forms a Re(I) complex of the type [(N^N)Re(CO)3 Br] through the coordination of nitrogen atom N(2) to the metal centre rather than through the phosphorus donor. Both structural and spectroscopic data indicate substantial π-accepting character of the triazaphosphole, which is again in contrast to that of the all-nitrogen-containing triazoles. The synthesis and photophysical properties of a new class of phosphorus-containing extended π systems are described.