Background: One of the most significant limitations that therapeutic oligonucleotides present is the development of specific and efficient delivery vectors for the internalization of nucleic acids into cells. Therefore, there is a need for the development of new transfection agents that ensure a proper and efficient delivery into mammalian cells. Methods: We describe the synthesis of 1,3,5-tris[(4-oelyl-1-pyridinio)methyl]benzene tribromide (TROPY) and proceeded to the validation of its binding capacity toward oligonucleotides, the internalization of DNA into the cells, the effect on cell viability, apoptosis, and its capability to transfect plasmid DNA. Results: The synthesis and chemical characterization of TROPY, which can bind DNA and transfect oligonucleotides into mammalian cells through clathrin and caveolin-mediated endocytosis, are described. Using a PPRH against the antiapoptotic survivin gene as a model, we validated that the complex TROPY–PPRH decreased cell viability in human cancer cells, increased apoptosis, and reduced survivin mRNA and protein levels. TROPY was also able to stably transfect plasmid DNA, as demonstrated by the formation of viable colonies upon the transfection of a dhfr minigene into dhfr-negative cells and the subsequent metabolic selection. Conclusions: TROPY is an efficient transfecting agent that allows the delivery of therapeutic oligonucleotides, such as PPRHs and plasmid DNA, inside mammalian cells.
The solution structure of two intramolecular diesters (methylene and 1,3-propylidene) of mesobiliverdin-XIII was studied and compared with that of the corresponding dimethyl ester. The UV/Vis absorption spectra, chiral discrimination with ethyl (S)-(À)-lactate, and the 1 H NMR spectra (ROESY) show that the cyclization of the propionate substituents of biliverdins does not signi®cantly affect the helix structure or its (P) (M) interconversion. The internal methylene diester does not show conformational heterogeneity of the propionate substituents and probably exists only in one diastereomeric form. In this case, the results point to a simultaneous racemization of the tetrapyrrole helix and the bridge cycle. The methylene diester of mesoprotoporphyrin was also synthesized. In this case, the geometry of the propionate chains is probably similar to that present in some hemoproteins.
Zur Struktur des u È ber die Propionsa Èurereste u È berbru È ckten Mesobiliverdins XIII in Lo ÈsungZusammenfassung. Die Struktur zweier zyklischer Ester (Methylendioxy-und 1,3-Dipropylenoxy-) des Mesobiliverdin XIII in Lo Èsung wurde untersucht und mit der des entsprechenden Dimethylesters verglichen. Die UV/Vis-Spektren, die chirale Diskriminierung mit A È thyl-(S)-(À)-Laktat und die 1 H-NMR-Spektren (ROESY) zeigen, daû durch interne Zyklisierung u Èber die Propionsa Èure die Helixstruktur oder die (P) (M) Konvertierung kaum bein¯uût wird. Beim zyklischen Methylendioxyester weisen die Propionsa Èuresubstituenten verschiedene Konformationen auf. Wahrscheinlich existiert nur eine einzige diastereoisomere Form unter gleichzeitiger Racemisierung der Tetrapyrrolhelix und des Ringes der Bru Èckenester. Der Methylendioxyester des Mesoprotoporphyrins wurde ebenfalls dargestellt. Die Geometrie seiner Propionatreste entspricht wahrscheinlich derjenigen, die in einigen Ha Èmoproteinen gefunden wurde.
The effect of cyclization of the propionic acid residues in mesobilirubin XIII propan-1,3-diyl ester on the angle between the dipyrrinone halves has been studied. This compound is shown to dimerize in chloroform solutions, and a conformation is proposed which is similar to that of the corresponding dimethyl ester. The results point to the contribution of %±% interactions, besides hydrogen bonding, to the geometry of the dimer.
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