Synthesis and Cytotoxicity of Ring C‐Functionalized Derivatives of the Marine Natural Product (–)‐Dibromophakellstatin

Abstract

Keywords: Natural products / Alkaloids / Nitrogen heterocycles / Synthetic methods / Cytotoxicity / Structure-activity relationshipsA structure-activity relationship study of ring C-functionalized derivatives of the cytotoxic marine natural product (-)-dibromophakellstatin from the sponge Phakellia mauritiana is reported. Functionalization of the pyrrolidine ring was achieved starting from the hydroxy derivative by conversion to the triflate followed by etherification by epimerizing nucleophilic substitution. We identified (12R)-dibromo-12-hy-

Indolo‐Phakellins as β5‐Specific Noncovalent Proteasome Inhibitors

“…Furthermore, the presented data are in line with a previous study of N-hydroxyureas (HUs) as reversible noncovalent CP inhibitors, which describes the optimization of a low-affinity b5 ligand (IC 50 = 230 mm) to an inhibitor with an IC 50 of 0.34 mm (HU10, Figure 2 c) through precise targeting of both the S1 and the S3-sub pockets. [24,25] Only the (À)enantiomer displayed antitumor activity, which is in accordance with the herein presented binding mode of 4. Importantly, removal of the adamantyloxy group from HU10 resulted in complete loss of potency, thus highlighing once more the strong influence of the P3 site on ligand stabilization in the substrate binding channel.…”

“…Importantly, removal of the adamantyloxy group from HU10 resulted in complete loss of potency, thus highlighing once more the strong influence of the P3 site on ligand stabilization in the substrate binding channel. [25] The yCP:4 complex structure clearly demonstrates that larger substituents at this position clash with the protein and thus have vastly decreased cytotoxic capabilities. [24,25] Only the (À)enantiomer displayed antitumor activity, which is in accordance with the herein presented binding mode of 4.…”

Indolo‐Phakelline als β5‐spezifische nichtkovalente Proteasom‐Inhibitoren

“…Frühere Studien der Arbeitsgruppe um Lindel zu synthetischen Phakellstatin‐Derivaten haben gezeigt, dass das (+)‐Enantiomer von Dibromphakellstatin und dessen Abkömmlinge keinen zytotoxischen Effekt auf diverse Krebszelllinien aufweisen 24. 25 Im Einklang mit dem dargelegten Bindemodus von 4 verfügt lediglich das (−)‐Enantiomer über Antitumoraktivität. Dieselbe Enantiospezifität wurde auch im Fall von Palau'amin beobachtet, das in der Natur nur als (−)‐Enantiomer vorkommt 26…”

“…Ferner belegen frühere Ansätze bezüglich synthetischer C‐Ring‐funktionalisierter Derivate von Dibromphakellstatin, dass ausschließlich (−)‐(12 R )‐Dibrom‐12‐hydroxyphakellstatin eine stärkere zytotoxische Wirkung gegen verschiedene Tumorzelllinien gegenüber aufweist als der Naturstoff 25. Aus der yCP: 4 ‐Komplexstruktur ist ersichtlich, dass größere Substituenten am C‐Ring mit der Proteinwand kollidieren und somit die zytotoxischen Eigenschaften erheblich reduzieren.…”

Coumarin–triazole Hybrids and Their Biological Activities

“…Various hydrazone 34 , [1,2,4‐triazolo][3,4‐ b ]thiadiazinyl 35 , pyrazole 36 , alkyl and aryl 37 , pyridine 38 , chalcone 39 , 3‐oxo‐2,3‐dihydrofuran 40 , pyrrole , dithiocarbamate , benzimidazole , dialkynylcarbinol , steroidal , costunolide , colchicines , (−)‐Dibromophakellstatin fused coumarin–triazole hybrids and cyclized coumarin–triazole hybrids , the 1,2,4‐triazole‐5‐one hybrids 41 , as well as triazole tethered bis‐coumarin 42 (Fig. ) were screened for their anticancer activities, in spite of the majority of them showed weak to moderate activity against the tested cancer cell lines, the enriched SAR paved the way to the further rational design.…”