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.
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.
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.
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