RESEARCH

Our studies are truly multidisciplinary and involve a seamless integration of:
      • Catalysis
      • Enantioselective organic synthesis
      • Synthesis of heterocyclic compounds
      • Chemical Biology, Medicinal Chemistry, Enzymology
      • Structural Research
(e.g. crystallography, NMR, DSF).
These studies provides an excellent training ground for students interested in pursuing an academic or industrial career in organic chemistry, or in pharmaceutical/biomedical sciences. Select examples from each topic are provided below


CATALYSIS / ENANTIOSELECTIVE ORGANIC SYNTHESIS
The following are few representative examples from recently published work:

1. Enantioselective synthesis of phosphorus-containing peptidomimetics and α- aminophosphonate, α-aminophosphinate and α-aminophosphine oxide ligands
Asymmetric synthesis of various α-aminophosphonate, α-aminophosphinate and α- aminophosphine oxide building blocks for preparation of bioactive compounds and as ligands for asymmetric catalysis.

For the first asymmetric Suzuki-Miyaura coupling reaction refer to:
Fandrick, K.R. et al. Angew. Chem. Int. Ed. 2015, 54, 7144-7148.


2. Metal-Free Cycloetherification by in Situ Generated P-Stereogenic α-Diazonium Intermediates: A Convergent Synthesis of Enantiomerically Pure Dihydrobenzooxaphospholes

Li, S. et al Org. Lett. 2017, ASAP
These are collaborative projects with the Chemical Development Division of at Boehringer Ingelheim Pharmaceuticals, Inc. USA (http://us.boehringer-ingelheim.com/)

SYNTHESIS OF HETEROCYCLIC COMPOUNDS

1. Parallel Synthesis of Thienopyrimidine-Based (A) and Pyridopyrimidine- Based (B) Bioactive Heterocyclic compounds

Examples:
      • Lin, Y.-S. et al. J. Med. Chem. 2012, 55, 3201-3215
      • Leung, C.-Y. et al J. Med. Chem. 2013, 56, 7939-7950
      • Lacbay, C.M et al. J. Med. Chem. 2014, 57, 7435-7449
      • Pack et al. J. Med. Chem. 2017, ASAP


2. Total Synthesis of Thienopyrimidine-Based Cyclic Phostones

Example:
      • A. N. Matralis and Y. S. Tsantrizos Eur. J. of Org. Chem. 2016, 22, 3728-3736


CHEMICAL BIOLOGY, MEDICINAL CHEMISTRY, ENZYMOLOGY, STRUCTURAL RESEARCH

Chemical Biology, Medicinal Chemistry, Enzymology, Structural
Our studies in these fields are truly multidisciplinary and involve a seamless integration of organic synthesis, biochemistry and structural research. We have active collaborations with medical/clinical researchers within the McGill teaching hospitals that conduct in vivo studies in animal models and in vitro studies in diseased human tissues. This part of our program provides an excellent training ground for students interested in pursuing an academic or industrial career in a biomedical or pharmaceutical sciences.


1. Design and synthesis of active site and allosteric inhibitors of the human farnesyl pyrophosphate synthase (hFPPS) as potential antitumor agents. This is a collaborative project with the group of Prof. Albert Berghuis (Tier 1 Canada Research Chair in Structural Biology, Biochemistry Department, McGill University; http://www.mcgill.ca/berghuis-lab/) and Dr. Michael Sebag (MD/PhD in haematology, clinical research scientist and co-director of the McGill University Health Center Multiple Myeloma Treatment and Research Centre; https://www.youtube.com/watch?v=7GWZbUXdMzs)

Human FPPS plays a key role in the prenylation of small GTPases, which are intimately involved in oncogenesis. An allosteric pocket of the enzyme has been of particular interest as a therapeutic target, however, its natural biological function has been (until now) unknown. We identified that the catalytic product of hFPPS, farnesyl pyrophosphate (FPP), bind to this pocket and locks the enzyme in a conformationally inactive state. Therefore, this allosteric binding site offers an exquisite mechanism for controlling the intracellular levels of isoprenoid biosynthesis in vivo (Nature Communications 2017).

Literature Examples:
      • De Schutter, J.W., J. et al J. Med. Chem. 2014, 57, 5764-5770
      • Park et al. Frontiers in Chemistry 2014, 2, Article 50
      • Gritzalis, D. et al. Bioorg. Med. Chem. Lett. 2015, 25, 1117-1123.
      • Park, J et al. Nat. Commun. 2017, 8, 14132.


2. Design and synthesis of inhibitors of the human geranylgeranyl pyrophosphate synthase (hGGPPS) as potential therapeutics for the prevention of Alzheimer’s disease. This is a collaborative project with the group of Prof. Judes Poirier (Professor of Medicine and Psychiatry, McGill University, Director, Research Program on Aging, Cognition and Alzheimer’s Disease, and Associate Director, Centre for the Studies on the Prevention of Alzheimer’s disease, Douglas Mental Health University Institute; http://aging.mcgill.ca/poirier.htm)

Recent studies (unpublished work from our group) suggest that the expression of key enzymes in the mevalonate pathway is dysregulated in the brains of humans suffering from Alzheimer’s diseases (AD). An increase in the expression of the human enzyme geranylgeranyl pyrophosphate synthase (hGGPPS) has been observed with genetic variations (unpublished data). High intracellular levels of GGPP (the metabolic product of hGGPPS) is known to induce accumulation of phospho-Tau protein in the brain, leading to the formation of neurofibrillary tangles (NFTs), neuronal death and possibly the progression of Alzheimer’s diseases.


3. Development of antiviral agents with a novel mechanism of action targeting the HIV RT
This is a collaborative project with Prof. Matthias Götte (Chair, Department of Medical Microbiology and Immunology, University of Alberta; http://www.mmi.med.ualberta.ca/about/)

Literature example:
Lacbay, C.M. et al. J. Med. Chem. 2014, 57, 7335-7449


4. Design and synthesis of ZMPSTE24 inhibitors that block maturation of the nuclear lamin A as potential therapeutics for the treatment of cancer

(A) Catalytic Role of the Zinc Metalloprotease ZMPSET24.
(B) Immunofluorescence for lamin A of cancer cells expressing a vector control or a prelamin A mutant, which prevents its conversion to lamin A. Immunofluorescence defines the cell nucleus (blue DAPI staining) and the cytoskeleton (red-Tubulin) in the indicated cell lines expressing vector or the prelamin A mutant (magnification = 10 μm). The prelamin A mutant, triggers inhibition of cell proliferation and the formation of multinucleated tumor cells characteristic of cell senescence.
(C) Inhibition of tumor progression is clearly observed in 5-week old BALB/c nude mice expressing either the vector control or the prelamin A mutant (S22Aprog).

This is a multidisciplinary project involving collaborations with the groups of Prof Gerardo Ferbeyre (Biochemistry Department, University of Montreal; http://www.biochimie.umontreal.ca/activites-de-recherche/themes-de-recherche-et-professeurs/gerardo-ferbeyre/), Prof. Albert Berghuis (Tier 1 Canada Research Chair in Structural Biology, Biochemistry Department, McGill University; http://www.mcgill.ca/berghuis-lab/) and Dr. Michael Sebag (MD/PhD in haematology, clinical research scientist and co-director of the McGill University Health Center Multiple Myeloma Treatment and Research Centre; https://www.youtube.com/watch?v=7GWZbUXdMzs)

For a recent example refer to:
Moiseeva, O. et al. Cell Cycle 2015, 14, 2408-2421.