Bunch Research Group
Organic chemistry and medicinal chemistry. Design and synthesis of neuroactive ligands, SAR studies, target-oriented synthesis, new synthetic methodology to access sp3-rich molecules, new planarheterocycles, new techniques in medicinal chemistry
New methodology in organic chemistry
Novel Planar Heterocycles
Chemical space is enormous! It is estimated to comprise some 10(200) distinct molecules with a molecular weight below 500. Every single molecule displays a unique biological activity. Planar heterocycles may be regarded as key fragments of a molecule (drug), as each heterocycle will engage in unique interactions with a protein target, inducing selectivity, higher potency and/or fine-tuning pharmacokinetic properties. Interestingly, only a limited number of heterocycles have been prepared (~1800) in comparison to the estimated total number possible (~30.000)! We are motivated to explore this huge potential by synthesis of novel planar heterocycles and subsequently to incorporate them in advanced medicinal chemistry studies. Recently we have disclosed the first synthesis of oxazolo[4,5-b]pyrazines by a new palladium-catalyzed domino reaction with an intramolecular ring closure of an N-(2-chloro-3-heteroaryl)arylamide:
TBAF Cleaves Boroxazolidones to Corresponding Free Amino Acids
Protection of α-amino acids with 9-borabicyclo[3.3.1]nonane (9-BBN) to give their corresponding boroxazolidones is highly attractive as it concurrently masks both the amino and the carboxylic acid functionalities. However, the required harsh methods for their deprotection have limited its use. In this work we report that tetrabutylammonium fluoride (TBAF) is a mild and versatile reagent for cleaving boroxazolidones to their corresponding free α-amino acids, in high yields.
Design and Synthesis of Neuroactive Ligands
We work on the design and synthesis of novel ligands for the ionotropic glutamate receptors (iGluRs), the metabotropic glutamate receptors (mGluRs) and the excitatory amino acid transports (EAATs). We are creative in our approach and take advantage of state-of-the-art methodology within the core disciplines organic chemistry, medicinal chemistry, and computational chemistry. All synthesized ligands are characterized pharmacologically by our close collaborators in Denmark, Europe and Abroad. It is our objective to discover new pharmacological tool compounds which can be used to elucidate the role and functional of the glutamatergic neurotransmitter system in the brain.
Our latest work within the mGluR field comprises the design and stereoselective synthesis of four carboxylate substituted cyclopropyl glutamate analogs. In summary, LBG-30100 is a fully selective mGluR2 agonist, while LBG-30102 and LBG-30103 are selective mGluR group III agonists. Published in J. Med. Chem. 2016, 59, 914-924
We are working on different scaffolds for structure-based design of subtype selective agonists and antagonists. We have ongoing projects within all of three groups of iGluRs, the AMPA, Kainate and NMDA receptors. A key scaffold which we designed and synthesized and are exploring the potential is LBG-10100, ACS Chem. Neurosci 2011, 2, 107-114. First SAR studies of this class of iGluR antagonists have shown interesting receptor group and subunit selectivity from subtle chemical modifications, J. Med. Chem. 2015, 58, 6131-6150.
Redesign of antagonist LBG-10100 led to 4-substituted pyrolidine, the LBG-10200 series - as a new scaffold for selective iGluR antagonists. SAR studies revealed interesting group and subtype selectivity jumps after only subtle structural changes. Published in J. Med. Chem. 2017, 60, 441-457.
The excitatory amino acid transporters (EAATs) comprise five subtypes named EAAT1-5. We focus on discovering subtype selective inhibitors as well as positive allosteric modulators (PAMs). The efforts have led to the discovery of the first selective EAAT1 inhibitor UCPH-101, J. Med. Chem. 2009, 52, 912-915 and J. Med. Chem. 2010, 53, 7180–7191, and the blood-brain-barrier penetrable analog UCPH-102, ChemMedChem 2016, 11, 403-419. Extensive SAR studies and assignment of absolute stereochemical configuration by infrared and vibrational circular dichroism spectroscopy in combination with ab initio hartree-fock calculations, has been carried out, J. Med. Chem. 2012, 55, 5403-5412.
By screening of a compound library, followed by SAR studies, compound 41003 was disclosed as a new class of selective EAAT1 inhibitors and a SAR study carried out. Published in J. Med. Chem. 2016, 59, 8757-8770.
Rational design of novel beta-phenylsulfonamido asparte analogs gave a new lead structure for subsequent SAR studies and interesting subtype selectivity profiles. While LBG-41503B is nonselective inhibitor of EAAT1-3, analog LBG-41520 is selective for EAAT1, LBG-41514 is selective for EAAT2 and LBG-41530 displays a preference for EAAT3. Published in J. Med. Chem. 2016, 59, 8771-8786
We are motivated to discover new chemical scaffolds which display unprecedented GABA receptor subtype selectivity. Our work focuses on novel PAMs designed from scaffold jumps and merging of known PAMS. We apply state-of-the-art in silico strategies to achieve our objectives.
MAO LIGANDS (SUBSTRATES)
We are interested in exploring the substrate specificity of the MAO-A and MAO-B enzymes. This work has led to a detailed structure-structure-activity relationship study of a number alkyl amines. Illustration shows MAO-B with N-methyl phenethyl amine in turquoise. Published in Org. & Biomol. Chem. 2014, 12, 8689-8695
We have open MSc projects within all our research fields. Project duration can be from 45-60 ECTS points, with flexible starting date. You can find available master projects here.
When doing you MSc thesis work in the group you will be affiliated with a PhD student or Postdoc who will supervise you on a daily basis. In addition to this, biweekly project meetings are held with me (LB), where we discuss recent problems, and project goals.If you are interested in doing your thesis work in the group, please send me an email with the following information:
- Words of motivation
- List of relevant course taken and grades optained
- Preferred start date and duration (ECTS point)
All correspondence should be directed to Lennart Bunch
We welcome letter of interests from MSc students or MSc graduates who are interested in doing a PhD in organic chemistry or medicinal chemistry. A PhD fellowship can be funded in a number of ways:
- Joint application to a public or private foundation
- University of Copenhagen, Faculty fellowships (next time January 2016)
- Self funded
To learn more about the PhD study program at University of Copenhagen, Faculty of Health and Medical Sciences, click here. Express you interest by sending as PDF:
- Letter of motivation (1 page)
- Your CV (1 page)
- List of publications
All correspondence should be directed to Lennart Bunch.
We welcome applicants who are interested in a Postdoc position. Projects of the highest international standard are available within all our research topics.The Postdoc position can be funded in a number of ways:
- Joint application
- Bring your own funding
If you would like to learn more about how to become a Postdoc in the group, please send as PDF:
- Letter of motivation (1 page)
- Your CV (1 page)
- List of publications
- Plan for raising funding from your own country
All correspondence should be directed to Group leader Lennart Bunch
I established my research group in 2007 and has a strong international profile comprising students and co-workers from several countries. The working environment is vibrant and ambitious, and the language of daily communication is English - both spoken and written.
I hold biweekly project meetings with every group member, where we discuss recent progress, challenges, and goals. Aside from this, I run an open door policy everyday after 13:00. You are welcome to drop by.
We engage in scientific and social activities with the other chemistry groups at the department as well as with our collaborating partners.
Organic chemistry and medicinal chemistry at the highest level. Our research objectives are:
- New synthetic methodology to easily access structurally complex molecules
- New reagents with relevance for medicinal chemistry
- Design and synthesis of novel tool compounds for use by our collaborators in the studying of neurological mechanisms in the healthy and diseased brain