Helimeric porphyrinoids: Stereostructure and chiral resolution of meso -tetraarylmorpholinochlorins

The synthesis and chiral resolution of free-base and Ni(II) complexes of a number of derivatives of meso-tetraphenylmorpholinochlorins, with and without direct β-carbon-to-o-phenyl linkages to the flanking phenyl groups, is described. The morpholinochlorins, a class of stable chlorin analogues, were synthesized in two to three steps from meso-tetraphenylporphyrin. The conformations and the relative stereostructures of a variety of free-base and Ni(II) complexes of these morpholinochlorins were elucidated by X-ray diffractometry. Steric and stereoelectronic arguments explain the relative stereoarray of the morpholino-substituents, which differ in the free-base and Ni(II) complexes, and in the monoalkoxy, β-carbon-to-o-phenyl linked morpholinochlorins, and the dialkoxy derivatives. The Ni(II) complexes were all found to be severely ruffled whereas the free-base chromophores are more planar. As a result of the helimeric distortion of their porphyrinoid chromophores, the ruffled macrocycles possess a stable inherent element of chirality. Most significantly, resolution of the racemic mixtures was achieved, both by classical methods via diastereomers and by HPLC on a chiral phase. Full CD spectra were recorded and modeled using quantum-chemical computational methods, permitting, for the first time, an assignment of the absolute configurations of the chromophores. The report expands the range of known pyrrole-modified porphyrins. Beyond this, it introduces large chiral porphyrinoid π-systems that exist in the form of two enantiomeric, stereochemically stable helimers that can be resolved. This forms the basis for possible future applications, for example, in molecular-recognition systems or in materials with chiroptic properties. © 2011 American Chemical Society

Syntheses, reactivity, and functionalization of meso-substituted porphyrins

Titelblatt Inhaltsverzeichnis I Einleitung 1 1 Begriffserklärung und Nomenklatur 1 2 Synthetische Betrachtungen 2 II Motivation und Aufgabenstellung 17 III Mono-meso-subtituierte Porphyrine und ihre Folgederivate 19 1 Mono-meso-substituierte Porphyrine 19 2 Folgeumsetzungen mit Lithiumorganylen 25 3 Metalloporphyrine 47 4 Zusammenfassung 53 5 Literatur 55 IV Porphyrine des A2B2-Typs 62 1 Darstellung von Porphyrinen des A2B2-Typs durch Organolithiumverbindungen 62 2 A2B2-Porphyrine mit push-pull-Muster 65 3 Zusammenfassung 74 4 Literatur 76 V Dendritische Porphyrine 80 1 Einführung 80 2 Ergebnisse 82 3 Katalyseuntersuchungen 87 4 Zusammenfassung 90 5 Literatur 91 VI Zusammenfassung / Summary 96 VIII Experimenteller Teil 100 IX Abkürzungen 186 DankZiel dieser Arbeit war die Darstellung und Funktionalisierung meso- substituierter Porphyrine. Ein besonderer Schwerpunkt stellte die Synthese von ABCD-Porphyrinen dar. Für ihre Darstellung ging man von mono-meso- substituierten Porphyrinen aus. Diese konnten durch die Verwendung von Dipyrromethan, Pyrrol-2-carbaldehyd und verschiedenen Aldehyden in Ausbeuten von 2 bis 12 % synthetisiert werden. Als weiteres Produkt entstanden dabei meist die 5,15-disubstituierten Verbindungen. Anschließend wurde durch aromatische nukleophile Substitution mit Lithiumorganylen aryl- und alkylsubstituierte Reste in die meso-Position der mono-substituierten Porphyrine eingeführt. Mit dieser Methode gelang die Darstellung mehrerer 5,10- und 5,15-disubstituierter AB-Porphyrine, ABC-Porphyrine und ABCD- Porphyrine. Ausgesuchte mono- und 5,15-disubstituierte Porphyrine wurden zu verschiedenen Metallkomplexen umgesetzt und in Abhängigkeit des Substituenten sowie des Zentralions röntgenkristallopgraphisch untersucht.The aim of this thesis was the syntheses and functionalization of meso- substituted porphyrins. A main focus was on porphyrins of the ABCD-type. The starting point was the syntheses of mono-meso-substituted porphyrins. The use of dipyrromethane, pyrrole-2-carbaldehyde, and various aldehydes realized a simple and straightforward method to synthesize mono-meso-substituted porphyrins in yields of 2-12 %. In many cases the 5,15-disubstituted porphyrins were observed as a second product. The introduction of aryl and alkyl substituents into the meso position was realized via subsequent aromatic nucleophilic substitution with organolithium compounds. With this method we succeeded in the preparation of several porphyrins of the 5,10-AB-, 5,15-AB-, ABC- and ABCD-type. Individual mono- and 5,15-disubstituted porphyrins were metalated to the appropriate metal complexes. The crystal structure allowed an X-ray analysis and thus a comparison of properties depending on the substituents and central ion. Another main focus was the syntheses of porphyrins of the 5,10-A2-15,20-B2-type. Starting from porphyrins of the 5,10-A2-type the modification of the macrocycle using organolithium compounds was developed. The Heck reaction provided another possibility to introduce substituents into the meso position. The syntheses of 5,10-A2-15,20-B2-push-pull porphyrins depending on the nature of the substituents could be realized

In vitro and in vivo evaluation of doxorubicin conjugates with the divalent peptide E-[c(RGDfK)2] that targets integrin alphavbeta3

Integrins, especially integrin alpha vbeta 3, are attractive receptors for vascular targeting strategies. Recently, a divalent RGD peptidomimetic, E-[c(RGDfK) 2], has been described that demonstrates increased uptake in human ovarian carcinoma OVCAR-3 xenograft tumors. Inspired by these results, we set out to develop doxorubicin conjugates with E-[c(RGDfK) 2] by binding two different maleimide derivatives of doxorubicin to E-[c(RGDfK) 2] that was thiolated with iminothiolane. In this way, two water-soluble derivatives were obtained, E-[c(RGDfK) 2]-DOXO-1 and E-[c(RGDfK) 2]-DOXO-2. In E-[c(RGDfK) 2]-DOXO-1, doxorubicin was bound to the peptide through a stable amide bond, and in E-[c(RGDfK) 2]-DOXO-2, a MMP-2/MMP-9 cleavable octapeptide was introduced between doxorubicin and the peptide. The rationale for a MMP-2/MMP-9-cleavable linker was that MMP-2 and MMP-9 bind to integrin alpha vbeta 3 and both are overexpressed in tumor vasculature. In addition, analogous control doxorubicin-containing peptides bearing c(RADfK) that does not bind to integrin alpha vbeta 3 were synthesized, i.e., c(RADfK)-DOXO-1 and c(RADfK)-DOXO-2. Whereas E-[c(RGDfK) 2]-DOXO-2 was cleaved effectively by MMP-2 and in OVCAR-3 tumor homogenates releasing a doxorubicin-tetrapeptide or doxorubicin as the final cleavage product, no release of doxorubicin was observed for E-[c(RGDfK) 2]-DOXO-1. Proliferation of HUVEC in the presence of MMP-2-cleavable doxorubicin-containing peptides exhibited 6- to 10-fold increased inhibition compared to the amide-linked doxorubicin-containing peptides. In addition, inhibition of HUVEC sprouting during a 24 h exposure was approximately 3-fold stronger for E-[c(RGDfK) 2]-DOXO-2 and 20-fold stronger for the reference peptide conjugate c(RADfK)-DOXO-2 than for doxorubicin alone. In vivo studies in an OVCAR-3 xenograft model demonstrated no or only moderate antitumor efficacy for either E-[c(RGDfK) 2], E-[c(RGDfK) 2]-DOXO-1, E-[c(RGDfK) 2]-DOXO-2, or c(RADfK)-DOXO-2, even at doses of 3 x 24 mg/kg doxorubicin equivalents, compared to an improved antitumor effect for doxorubicin at 2 x 8 mg/kg