Rapid Assembly of Complex 3D Heterocycles from Simple Enamide Building Blocks

Professor Georg Manolikakes
RPTU Kaiserslautern-Landau, Germany

Description
The rapid construction of three-dimensional heterocycles containing multiple stereogenic centres represents a key challenge in modern synthetic and medicinal chemistry. Aliphatic heterocycles with a defined three-dimensional structure offer intriguing opportunities to improve the activity as well as the pharmacokinetic profile of potential drug candidates. Hence, there is a sustained interest in the development of novel approaches for an efficient synthesis of three-dimensional heterocyclic scaffolds. In the last years, enamides have emerged a versatile tools for the stereoselective synthesis of complex molecules containing multiple stereocenters. Herein, novel methods for a rapid and highly modular synthesis of structurally divers three-dimensional heterocyclic scaffolds from enamides as simple common building blocks will be presented:

i) a novel method for the diastereoselective construction pyrimido[2,1-a]isoindoles bearing three contíguos stereocenters, a so far difficult to access, heterocyclic scaffold, with three continuous stereocenters.
ii) novel apporaches for the diastereo- and enatioseletricve synthesis of densely susbtitued spiroisoindolinones.
iii) a diastereoselective synthesis of isoindoloquinolinones contaning three stereogenic centres.
iv) a novel domino reaction for the synthesis of tetrahydropyrans containing five continuous stereogenic centers with an exceptionally high degree of diastereoselectivity.

These methods enable the rapid assembly of structurally complex molecules bearing multiple continuous stereocenters in a very efficient and operationally simple manner.

Optimizing Microwave-Assisted Synthesis of a Novel FRET-Based Rhodamine Sensor for Hg(II) Ion Detection

Dr. Ana M.G. Silva
University of Porto, Portugal

Description
Rhodamines and their analogues, including rosamines, are an important class of fluorescent dyes known for their high molar absorptivity and intense fluorescence in the visible spectrum. Their successful applications as fluorescent sensors and bioimaging probes have led to the exploration of new strategies for creating high-performance molecules, primarily through structural modifications of the xanthene ring. In recent projects, we have designed fluorescent rhodamine chelators with specific responses to different metal ions in various types of matrices. We strategically couple analyte specific chelators to rhodamines to produce molecules that exhibit a fluorescent turn-off or turn-on response.

In this work, we are presenting the results obtained with a new fluorescence resonance energy transfer (FRET)-based sensor for the selective detection of Hg(II) ion. Through an optimized strategy under microwave-assisted protocols, three dansyl-rhodamine derivatives were prepared. The influence of the isothiocyanate in the formation of the thiosemicarbazide recognition site of the sensor was explored using different substituents. The most promising sensor, denoted as RD1, exhibited a two-stage response mechanism towards Hg(II), which was further corroborated by density functional theory (DFT) calculations.

Cytochrome P450 Compound I: Reactivity and Bonding

Professor Hajime Hirao
The Chinese University of Hong Kong, China

Description
Cytochrome P450 enzymes (P450s) are found in a wide range of organisms and form a superfamily of heme proteins with significant implications across various scientific fields, including biology, medicine, pharmaceutical sciences, and agriculture. The critical roles of human P450s in drug metabolism, in particular, underscore their broad relevance to human health. From a simulation perspective, P450s offer a wealth of fascinating scientific challenges that warrant in-depth investigation, with one prominent example being the mechanism of drug metabolism by human P450s. While substantial progress has been made in understanding P450-catalyzed oxidative substrate transformations over the past few decades, our microscopic insight into biocatalysis in human P450s, especially in relation to drug metabolism, remains limited. This is largely due to their flexible, sizable active-site pockets, the complex structures of substrate drug compounds, and the scarcity of crystal structures of P450–drug complexes. Additionally, the bonding nature of the reactive iron(IV)-oxo, known as Compound I (Cpd I), which drives these transformations, is a fundamental question that still requires exploration. In this presentation, I will discuss our recent findings in these areas.