Research group

Marc Nazaré

Medicinal Chemistry

Portrait

Our group is focused on developing new chemical tools to answer fundamental biological questions. These tools cover a broad range of applications from modulation of protein-ligand and protein-protein interactions to structure-activity relationship studies.

Profile

Design and synthesis of chemical probes for their pharmacological investigation of biological systems
Small molecules can be used as research tools to investigate protein functions and elucidate molecular mechanisms or to influence signal transduction pathways. They can also be employed to validate hypotheses from genetic studies such as knock-down- and loss-of-function approaches. Moreover, these substances can serve as starting points for new therapeutic approaches and new drugs.
Goal of our research is the discovery and development of highly active, selective chemical tools for the specific modulation of protein-ligand or protein-protein interactions. Taking advantage on these optimized tools, we are in a further step, also investigating the tailored development of fluorescently labeled probes as well as DOTAM-based sensors for imaging and proximity labeling for chemical biology and biomarker applications.

 

Research Interests

Our group is focused on developing new chemical tools to answer fundamental biological questions. These tools cover a broad range of applications from modulation of protein-ligand and protein-protein interactions, SAR studies, in order to allow for a deeper understanding of signal transduction pathways, molecular recognition phenomena of particular drug targets and other cellular events. Together with our collaboration partners, the medicinal chemistry group optimizes small molecule hits emerging from screening or from rational drug design approaches. These efforts are strongly connected to the activities of the screening unit and the drug design group of the chemical biology platform at the FMP.
Each research project is guided by at least one of the following principles:

  • New chemical structures of the small molecule modulator
  • New unexplored mechanisms of action for a given biological protein target
  • New unexplored biological targets or pharmacological applications/therapeutic concept

As well as applying the principles of classical medicinal chemistry, other state-of-the art methodologies can be utilized and applied as required. These include parallel synthesis techniques, structure based design, compound management, computer modeling and X-ray crystallography.
In this context we are interested in developing and advancing enabling methodologies for the investigation of unexplored biological targets such as library design, synthetic methodology and fluorescent labeling.
This work embraces the following further areas/fields of interest:

SAR studies and the molecular recognition phenomena underlying protein ligand interactions
We are in particular interested in the role and impact of higher halogens in protein-ligand interactions. Very recently the general relevance of halogen π-interactions in lipophilic protein environments was described as an important and critical protein-ligand interaction which can contribute significantly to the overall affinity. However, in most cases this interaction has been discovered by random variations of substitution patterns and not by a directed rational approach. We intend to rationally exploit this interaction using available structural biology information as well as small, directed halogen biased libraries.

Synthetic methods to access privileged or novel scaffolds useful in drug discovery
The early selection of the appropriate central scaffold for a drug molecule is conceptually a challenging and decisive task in the design of new small molecule modulators. Whereas the peripheral side-chain decoration of a given hit structure is the first and obvious variation starting point, the exchange of the scaffold is inherently more difficult. As well as the underlying complex recognition phenomena, the availability i.e. ease of synthetic accessibility is an important and often underestimated factor for the successful optimization of a lead compound. Therefore we will investigate and develop new synthetic procedures for the synthesis of biologically relevant privileged or novel scaffolds. 

Contact

Dr. Marc Nazaré

Head, Nazaré Group

Contact Office

Dajana Baudach

Secretary, Sun Group,
Secretary Nazaré Group


Research Section

Chemical Biology

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Equipment


Agilent 1200 LC/DAD/TOF-MS (6220A)

This analytical LCMS/TOF system is equipped with a binary pump (up to 5mL/min), a high performance wellplate sampler (0.1 - 100µL), a column oven (up to 100°C) and a diode array detector (80Hz) allowing for simultaneous measurement at wavelengths between 190 and 950nm. The backend is an Agilent G6220A accurate mass time-of-flight mass spectrometer (100-3000m/z) enabling the user to determine the molecular composition of the analytes.

Agilent 1260 LC/DAD/SQ-MS (6120)

The analytical LCMS is equipped with a binary pump (up to 5mL/min), a high performance well plate sampler (0.1 - 40µL), a column oven and a new Agilent 1260 DAD (80 Hz) allowing for simultaneous measurement at wavelengths between 190 and 450nm. The backend is a robust single quadrupole mass spectrometer (up to 2000m/z). The system is used to analyze chemical reaction mixtures.

Agilent 1200 HPLC/DAD/ELSD

Our Agilent 1200 analytical HPLC is equipped with an autosampler, a column oven, a diode array detector (190-950nm) and an evaporative light scattering detector (ELSD) allowing for detection of non-UV absorbing analytes.

Picture of Agilent 1200 LC/DAD/TOF-MS (6220A)
Picture of Agilent 1260 LC/DAD/SQ-MS (6120)
Picture of Agilent 1200 HPLC/DAD/ELSD

Agilent 1200 LC/DAD/TOF-MS (6220A)

This analytical LCMS/TOF system is equipped with a binary pump (up to 5mL/min), a high performance wellplate sampler (0.1 - 100µL), a column oven (up to 100°C) and a diode array detector (80Hz) allowing for simultaneous measurement at wavelengths between 190 and 950nm. The backend is an Agilent G6220A accurate mass time-of-flight mass spectrometer (100-3000m/z) enabling the user to determine the molecular composition of the analytes.

Picture of Agilent 1200 LC/DAD/TOF-MS (6220A)

Agilent 1260 LC/DAD/SQ-MS (6120)

The analytical LCMS is equipped with a binary pump (up to 5mL/min), a high performance well plate sampler (0.1 - 40µL), a column oven and a new Agilent 1260 DAD (80 Hz) allowing for simultaneous measurement at wavelengths between 190 and 450nm. The backend is a robust single quadrupole mass spectrometer (up to 2000m/z). The system is used to analyze chemical reaction mixtures.

Picture of Agilent 1260 LC/DAD/SQ-MS (6120)

Agilent 1200 HPLC/DAD/ELSD

Our Agilent 1200 analytical HPLC is equipped with an autosampler, a column oven, a diode array detector (190-950nm) and an evaporative light scattering detector (ELSD) allowing for detection of non-UV absorbing analytes.

Picture of Agilent 1200 HPLC/DAD/ELSD

Preparative RP-HPLCs

For the separation of chemical reaction mixtures that are soluble in water/acetonitrile we use one of our prep RP-HPLC systems: a "Waters Prep 150 LC" or " Shimadzu LC-20A Prominenc", respectively. Both are equipped with manual injection valves, multi wavelength detectors and fraction collection systems. 

Flash Chromatography

Our group has a total of four automated flash chromatography systems in use: a Biotage "Isolera One" and "Selekt" as well as two CombiFlash "Nextgen 300+". All are equipped with a binary pump systems, UV/Vis detection and automatic fraction collection, allowing for the automated separation and purification of UV active compounds in the milligram to multi gram scale. Additionally, the CombiFlash systems are equipped with ELS detection, allowing the convenient separation o

Lyophilizer Christ ALPHA 2-4 LSC

Our lyophilizer has 24 slots for the attachment of flasks. Sample solutions in suitable solvents like water or tert-butanol are frozen and the solvents are removed by vacuum sublimation.

Picture of Preparative RP-HPLCs
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Preparative RP-HPLCs

For the separation of chemical reaction mixtures that are soluble in water/acetonitrile we use one of our prep RP-HPLC systems: a "Waters Prep 150 LC" or " Shimadzu LC-20A Prominenc", respectively. Both are equipped with manual injection valves, multi wavelength detectors and fraction collection systems. 

Picture of Preparative RP-HPLCs

Flash Chromatography

Our group has a total of four automated flash chromatography systems in use: a Biotage "Isolera One" and "Selekt" as well as two CombiFlash "Nextgen 300+". All are equipped with a binary pump systems, UV/Vis detection and automatic fraction collection, allowing for the automated separation and purification of UV active compounds in the milligram to multi gram scale. Additionally, the CombiFlash systems are equipped with ELS detection, allowing the convenient separation o

Bild

Lyophilizer Christ ALPHA 2-4 LSC

Our lyophilizer has 24 slots for the attachment of flasks. Sample solutions in suitable solvents like water or tert-butanol are frozen and the solvents are removed by vacuum sublimation.

Picture

Biotage Initiator+ Microwave with Robot Sixty Autosampler

For microwave syntheses we have two Biotage Initiator+ reactors available. They are equipped with a Robot Sixty autosampler systems which can take up to sixty samples each, with volumes between 0.2 mL to 20 mL.

Picture

Biotage Initiator+ Microwave with Robot Sixty Autosampler

For microwave syntheses we have two Biotage Initiator+ reactors available. They are equipped with a Robot Sixty autosampler systems which can take up to sixty samples each, with volumes between 0.2 mL to 20 mL.

Picture

Patents

Fluorescent probes for monoacylglycerol lipase (MAGL)
WO2021058443; Benz, J.; Gazzi, T.; Gobbi, L.; Grether, U.; Hornsperger, B.; Kroll, C.; Kuhn, B.; Mostinski, Y.; Nazaré, M.; O'Hara, F.; Richter, H.

Preparation of fused pyrimidinones as class II phosphoinositide 3-kinase inhibitors useful in treatment of diseases
WO2019234237A1; Lo, W.-T.; Belabed, H.; Haucke, V.; Nazare, M.; Kuecuekdisli, M.

1,2,4-Triazole derivatives as tankyrase inhibitors and their preparation
WO2019243822A1; Krauss, S.; Nazare, M.; Anumala, U. R.; Lehtio, L.; Waaler, J.; Wegert, A.; Leenders, R. G. G.

Preparation of triazole derivatives as tankyrase inhibitors useful in treatment and prevention of diseases
WO 2018118868; Krauss, S.; Nazare, M.; Anumala, U. R.; Lehtio, L.; Waaler, J.; Holsworth, D.; Wegert, A.; Leenders, R. G. G.