8 research outputs found
Total synthesis of the cyclic monoterpenoid pyrano[3,2-a]carbazole alkaloids derived from 2-hydroxy-6-methylcarbazole
The synthesis of seven pyrano[3,2-a]carbazole alkaloids has been achieved using their putative biogenetic precursor 2-hydroxy-6-methylcarbazole as key intermediate
Fluor-18-markierte selektive Cyclooxygenase-2-Inhibitoren: Entwicklung von zwei potenten Tracern mit tricyclischer Kernstruktur und Beeinflussung der metabolischen StabilitÀt von Pyrazol-basierten Radiotracern
Die funktionelle Bildgebung der Expression der Cyclooxygenase-2 (COX-2) stellt aufgrund ihrer bedeutsamen Rolle bei pathophysiologischen Prozessen, insbesondere bei der Tumorprogression, einen wichtigen Forschungsansatz dar. Als nichtinvasive, bildgebende Methode bietet die PET (Positronen-Emissions-Tomographie) unter Ausnutzung von radiomarkierten MolekĂŒlen eine Möglichkeit, zeitlich und rĂ€umlich molekulare Prozesse abzubilden und zu verfolgen. Das Radionuklid Fluor-18 wird wegen seiner nahezu optimalen kernphysikalischen und chemischen Eigenschaften fĂŒr die PET verwendet. Aufgrund der hohen Anforderungen, die an einen Radiotracer fĂŒr die Bildgebung mittels PET gestellt werden, ist es bisher nicht gelungen, eine geeignete radiomarkierte Verbindung fĂŒr die Visualisierung der COX-2-Expression in vivo zu entwickeln. Insbesondere die SpezifitĂ€t, SelektivitĂ€t und AffinitĂ€t sowie die metabolische StabilitĂ€t eines Radiotracers sind wesentliche Parameter, die ĂŒber den Erfolg der Verbindung in vivo entscheiden. Basierend auf den bisherigen Erkenntnissen bei der Entwicklung radiomarkierter selektiver COX-2-Inhibitoren verfolgte diese Arbeit zwei Strategien der Radiotracerentwicklungen.
Als potente Zielverbindungen wurden aus der Stoffklasse mit tricyclischer Kernstruktur das Pyrrolo[3,2,1-hi]indol PI (1-(4-Fluorphenyl)-2-(4-methansulfonyl)phenyl-pyrrolo[3,2,1-hi]indol) und das 1,2-Dihydropyrrolo[3,2,1-hi]indol DHPI (5-Fluorphenyl-4-(4-methansulfonyl)phenyl-1,2-dihydropyrrolo[3,2,1-hi]indol) ausgewĂ€hlt. Die Radiosynthese von [18F]PI gelang in einer manuellen Cu(II)-vermittelten 18F-Fluorierung ausgehend vom entsprechenden ArylboronsĂ€urepinakolester. Die Radiosynthese von [18F]DHPI erfolgte automatisiert ĂŒber eine Zwei-Stufen/ Ein-Topf-Reaktion bestehend aus einer 18F-Fluorierung und anschlieĂender intramolekularer McMurry-Reaktion. Der Radiotracer [18F]DHPI wurde umfassend hinsichtlich seiner radiopharmakologischen Eigenschaften untersucht. Trotz seiner hohen StabilitĂ€t in vivo ist insbesondere die hohe Lipophilie von [18F]DHPI hinderlich fĂŒr eine spezifische Anreicherung im Tumorgewebe.
Im zweiten Teil der Arbeit wurde die chemische Struktur eines potenten, jedoch metabolisch unzureichend stabilen Radiotracers mit 1,5-Diaryl-substituierter Pyrazol-Kernstruktur und [18F]Fluormethylseitenkette (basierend auf Celecoxib) durch SeitenkettenverlĂ€ngerung und Deuterierung verĂ€ndert, sodass eine Beeinflussung der StabilitĂ€t erfolgen sollte. Es wurden die entsprechenden Referenzverbindungen und PrĂ€kursoren hergestellt. Die Radiosynthesen der drei Zielverbindungen erfolgten automatisiert in einer nucleophilen aliphatischen Substitutionsreaktion. Die drei Radiotracer wurden in vitro und in vivo hinsichtlich ihrer StabilitĂ€t und der zugrundeliegenden Metabolisierungsprozesse untersucht. Dabei zeigte insbesondere die Methode der Deuterierung ein hohes Potential fĂŒr die Verbesserung der metabolischen StabilitĂ€t unter Beibehaltung der AffinitĂ€t zum Zielenzym
Total synthesis of the cyclic monoterpenoid pyrano[3,2-a]carbazole alkaloids derived from 2-hydroxy-6-methylcarbazole
The synthesis of seven pyrano[3,2-a]carbazole alkaloids has been achieved using their putative biogenetic precursor 2-hydroxy-6-methylcarbazole as key intermediate
Total synthesis of the cyclic monoterpenoid pyrano[3,2-a]carbazole alkaloids derived from 2-hydroxy-6-methylcarbazole
The synthesis of seven pyrano[3,2-a]carbazole alkaloids has been achieved using their putative biogenetic precursor 2-hydroxy-6-methylcarbazole as key intermediate
Diaryl-Substituted (Dihydro)pyrrolo[3,2,1-<i>hi</i>]indoles, a Class of Potent COXâ2 Inhibitors with Tricyclic Core Structure
A new compound class of diaryl-substituted
heterocycles with tricyclic
dihydropyrroloÂ[3,2,1-<i>hi</i>]Âindole and pyrroloÂ[3,2,1-<i>hi</i>]Âindole core structures has been designed and was synthesized
by a modular sequence of FriedelâCrafts acylation, amide formation,
and McMurry cyclization. This synthesis route represents a novel and
versatile access toward dihydropyrroloÂ[3,2,1-<i>hi</i>]Âindoles
and is characterized by good chemical yields and high modularity.
From a set of 19 derivatives, 11 candidates were selected for determination
of their COX inhibition potency and were found to be selective inhibitors
with high affinity to COX-2 (IC<sub>50</sub> ranging from 20â2500
nM and negligible inhibition of COX-1). The binding mode of the novel
inhibitors in the active side of COX-2 was calculated <i>in silico</i> using the proteinâligand docking program GOLD by application
of the molecular structures of two compounds derived from X-ray crystallography.
Two novel compounds with high affinity to COX-2 (<b>6k</b> =
70 nM, <b>8e</b> = 60 nM) have a fluoro substituent, making
them promising candidates for the development of <sup>18</sup>F-radiolabeled
COX-2 inhibitors for imaging purposes with positron emission tomography
(PET)
Diaryl-Substituted (Dihydro)pyrrolo[3,2,1-<i>hi</i>]indoles, a Class of Potent COXâ2 Inhibitors with Tricyclic Core Structure
A new compound class of diaryl-substituted
heterocycles with tricyclic
dihydropyrroloÂ[3,2,1-<i>hi</i>]Âindole and pyrroloÂ[3,2,1-<i>hi</i>]Âindole core structures has been designed and was synthesized
by a modular sequence of FriedelâCrafts acylation, amide formation,
and McMurry cyclization. This synthesis route represents a novel and
versatile access toward dihydropyrroloÂ[3,2,1-<i>hi</i>]Âindoles
and is characterized by good chemical yields and high modularity.
From a set of 19 derivatives, 11 candidates were selected for determination
of their COX inhibition potency and were found to be selective inhibitors
with high affinity to COX-2 (IC<sub>50</sub> ranging from 20â2500
nM and negligible inhibition of COX-1). The binding mode of the novel
inhibitors in the active side of COX-2 was calculated <i>in silico</i> using the proteinâligand docking program GOLD by application
of the molecular structures of two compounds derived from X-ray crystallography.
Two novel compounds with high affinity to COX-2 (<b>6k</b> =
70 nM, <b>8e</b> = 60 nM) have a fluoro substituent, making
them promising candidates for the development of <sup>18</sup>F-radiolabeled
COX-2 inhibitors for imaging purposes with positron emission tomography
(PET)
Diaryl-Substituted (Dihydro)pyrrolo[3,2,1-<i>hi</i>]indoles, a Class of Potent COXâ2 Inhibitors with Tricyclic Core Structure
A new compound class of diaryl-substituted
heterocycles with tricyclic
dihydropyrroloÂ[3,2,1-<i>hi</i>]Âindole and pyrroloÂ[3,2,1-<i>hi</i>]Âindole core structures has been designed and was synthesized
by a modular sequence of FriedelâCrafts acylation, amide formation,
and McMurry cyclization. This synthesis route represents a novel and
versatile access toward dihydropyrroloÂ[3,2,1-<i>hi</i>]Âindoles
and is characterized by good chemical yields and high modularity.
From a set of 19 derivatives, 11 candidates were selected for determination
of their COX inhibition potency and were found to be selective inhibitors
with high affinity to COX-2 (IC<sub>50</sub> ranging from 20â2500
nM and negligible inhibition of COX-1). The binding mode of the novel
inhibitors in the active side of COX-2 was calculated <i>in silico</i> using the proteinâligand docking program GOLD by application
of the molecular structures of two compounds derived from X-ray crystallography.
Two novel compounds with high affinity to COX-2 (<b>6k</b> =
70 nM, <b>8e</b> = 60 nM) have a fluoro substituent, making
them promising candidates for the development of <sup>18</sup>F-radiolabeled
COX-2 inhibitors for imaging purposes with positron emission tomography
(PET)