Concise and flexible synthesis of the five-membered ring synthon of highly oxygenated jatrophane diterpenes

Die Wolfsmilchgewächse (Euphorbiaceae), sind seit jeher phytopharmakologisch von großer Bedeutung. Extrakte von Wolfsmilchgewächsen besitzen verschiedenste biologische Aktivitäten. Effluxpumpen, wie P-Glykoprotein, sind verantwortlich für multidrug resistance (MDR) Effekte, die zum Scheitern von Chemotherapie bei Krebserkrankungen führen. Nachdem in Untersuchungen von Jatrophan Diterpenen die Inhibierung solcher Effluxpumpen erreicht werden konnte ist es denkbar Jatrophan Diterpene in Chemotherapien zu verwenden um MDR Effekten vorzubeugen. Dass bereits einige Synthesearbeiten publiziert wurden lässt sich auf die faszinierenden Strukturen und vielversprechenden biologischen Aktivitäten von Jatrophanen zurückführen. Darüber hinaus wurden auch einige wenige Totalsynthesen, sowohl von natürlichen als auch unnatürlichen Jatrophan Diterpenen mit Jatrophan Struktur, veröffentlicht. In dieser Masterarbeit sind die synthetischen Arbeiten an höher oxygenierten fünfgliedrigen Syntheseintermediaten dokumentiert. Der gewählte Syntheseweg orientiert sich stark an vorhergehenden synthetischen Arbeiten an weniger oxygenierten fünfgliedrigen Ringfragmenten, die in unserer Arbeitsgruppe durchgeführt wurden. Geplante Schlüsselschritte der Synthese umfassen unter anderem eine asymmetrische Epoxidierung nach Sharpless, eine Aldol Reaktion, eine Ringschlussmetathese sowie einer Sequenz aus einer Hydroborierung und einer Oxidation

Syntheses, reactivity, and biological applications of coumarins

This comprehensive review, covering 2021–2023, explores the multifaceted chemical and pharmacological potential of coumarins, emphasizing their significance as versatile natural derivatives in medicinal chemistry. The synthesis and functionalization of coumarins have advanced with innovative strategies. This enabled the incorporation of diverse functional fragments or the construction of supplementary cyclic architectures, thereby the biological and physico-chemical properties of the compounds obtained were enhanced. The unique chemical structure of coumarine facilitates binding to various targets through hydrophobic interactions pi-stacking, hydrogen bonding, and dipole-dipole interactions. Therefore, this important scaffold exhibits promising applications in uncountable fields of medicinal chemistry (e.g., neurodegenerative diseases, cancer, inflammation)

Highly Selective PTK2 Proteolysis Targeting Chimeras to Probe Focal Adhesion Kinase Scaffolding Functions

Focal adhesion tyrosine kinase (PTK2) is often overexpressed in human hepatocellular carcinoma (HCC), and several reports have linked PTK2 depletion and/or pharmacological inhibition to reduced tumorigenicity. However, the clinical relevance of targeting PTK2 still remains to be proven. Here, we present two highly selective and functional PTK2 proteolysis-targeting chimeras utilizing von Hippel–Lindau and cereblon ligands to hijack E3 ligases for PTK2 degradation. BI-3663 (cereblon-based) degrades PTK2 with a median DC₅₀ of 30 nM to >80% across a panel of 11 HCC cell lines. Despite effective PTK2 degradation, these compounds did not phenocopy the reported antiproliferative effects of PTK2 depletion in any of the cell lines tested. By disclosing these compounds, we hope to provide valuable tools for the study of PTK2 degradation across different biological systems

Quality of life of palliative chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction treated with irinotecan combined with 5-fluorouracil and folinic acid: results of a randomised phase III trial

41st Annual Meeting of the American-Society-of-Clinical-Oncology -- MAY 13-17, 2005 -- Orlando, FLWOS: 000268881000007PubMed ID: 19568958The quality of life (QL) of advanced gastric cancer patients receiving irinotecan, folinic acid and 5-fluorouracil (5-FU) (IF arm) or cisplatin with 5-FU (CF arm) is presented. Patients with measurable or evaluable advanced gastric cancer received IF weekly for 6/7 weeks or CF q4 weeks. QL was assessed using the EORTC QLQ-C30 at baseline, subsequently every 8 weeks until progression and thereafter every 3 months until death. The QL data were analysed using several statistical methods including summary measures and pattern-mixture modelling. A total of 333 patients were randomised and treated (IF 170, CF 163). The time-to-progression for IF and CF was 5.0 and 4.2 months (P = 0.088), respectively. The overall compliance rates for QL questionnaire completion were 60 and 56% in the IF and CF arms, respectively. Significant treatment differences were observed for the physical functioning scale (P = 0.024), nausea\vomiting (P = 0.001) and EQ-5D thermometer (P = 0.020) in favour of the IF treatment arm. There was a trend in favour of IF over CF in time-to-progression. The IF group also demonstrated a better safety profile than CF and a better QL on a number of multi-item scales, suggesting that IF offers an alternative first-line platinum-free treatment option for advanced gastric cancer.Amer Soc Clin Onco

A Many-Faced Alkaloid: Polymorphism of (–)-Monophyllidin

The synthesis of the alkaloid (–)-monophyllidin is described. The molecule is a hybrid of xanthoxyline and (S)-proline, accessible in one-step through a Mannich reaction. In the solid-state, defined structural arrangements with different physical properties are formed. Single crystal X-ray diffraction revealed structures of six distinct polymorphs. In the crystalline state, the alkaloid can host small polar molecules (preferably water), while the (S)-proline moiety is present in the zwitterionic state. Combined with the chelate, which is already present in the xanthoxyline substructure, an ideal disposition for multiple hydrogen bond networks evolve. Therefore, highly water-soluble polymorphs of monophyllidin can form. This structural flexibility explains the many faces of the molecule in terms of structure as well as analytical data. Furthermore, speculations about the biological role of the molecule, with regard to the manifold interactions with water, are presented

The cross-over fermentation concept and its application in a novel food product : The dairy miso case study

Cross-over fermentations are processes in which a microorganism from one traditional fermentation process is introduced onto a new substrate and/or to a new partner. Here we show that Aspergillus oryzae normally used for the production of miso, a fermented soybean paste from Asia, can be applied to a traditional European fermented dairy product quark cheese, produced by fermenting milk with Lactococcus lactis. This cross-over fermentation resulted in a product with intense aroma properties, mainly due to high amounts of volatile fatty acids, ethyl esters, higher alcohols and ketones. Active metabolism of A. oryzae was required for alcohol production, whereas fat degradation occurred mainly due to enzymatic activities. Traditionally used practices in miso production, like mixing, addition of various amounts of salt and variations in fat content of the substrate altered metabolic and enzymatic properties of A. oryzae resulting in differences in final product characteristics. Aroma intensity of the product was shown by comparing volatile organic compounds with blue and white mould cheese. This study showed the potential of cross-over fermentation for novel food products. The enormous diversity of microorganisms used in traditional fermentation processes and the vast number of alternative substrates offer numerous opportunities for further novel fermented product development

Synthetic Ionizable Colloidal Drug Aggregates Enable Endosomal Disruption

Colloidal drug aggregates enable the design of drug-rich nanoparticles; however, the efficacy of stabilized colloidal drug aggregates is limited by entrapment in the endo-lysosomal pathway. Although ionizable drugs are used to elicit lysosomal escape, this approach is hindered by toxicity associated with phospholipidosis. It is hypothesized that tuning the pKa of the drug would enable endosomal disruption while avoiding phospholipidosis and minimizing toxicity. To test this idea, 12 analogs of the nonionizable colloidal drug fulvestrant are synthesized with ionizable groups to enable pH-dependent endosomal disruption while maintaining bioactivity. Lipid-stabilized fulvestrant analog colloids are endocytosed by cancer cells, and the pKa of these ionizable colloids influenced the mechanism of endosomal and lysosomal disruption. Four fulvestrant analogs-those with pKa values between 5.1 and 5.7-disrupted endo-lysosomes without measurable phospholipidosis. Thus, by manipulating the pKa of colloid-forming drugs, a tunable and generalizable strategy for endosomal disruption is established