Research in synthetic organic, bioorganic, and medicinal chemistry with relevance to life processes​

​Research in the Hanessian group exploits the power of modern synthetic organic chemistry to address timely objectives in a wide cross-section of areas with relevance to life processes. Among these are the total synthesis of biologically important natural products such as antibiotics, and anticancer agents, the design and  synthesis of drug prototypes based on structural information, aspects of drug delivery, the chemistry and biology of carbohydrates, peptides as well as their mimetics, asymmetric synthesis and catalysis, molecular recognition leading to self-assembly, the chemistry of small molecules that interact with RNA, DNA with relevance to antisense technology, and the synthesis of constrained sphingolipids involved in the metabolism of cancer cells leading to their starvation and death.

Hanessian Group Philosophy

As a group, we are exhilarated by the process of discovery and combining innovation with practicality. In addition to a variety of academic projects dealing with the above mentioned areas of research, we have had the privilege of having multiple academic collaborations with a wide selection of pharmaceutical, biotech, and agrochemical companies worldwide resulting in over 120 research publications and many patents. Among the hundreds of alumni of our group are those who have been responsible for the development of several marketed drugs. Others have excelled as academics. A testimony of their continued good relations with the group is their initiative to establish the Hanessian Group Alumni Student Scholarship at the University of Montreal. Nurturing independent thinking and developing interpersonal skills to function in a large group of young students and postdocs from across the globe has been very rewarding, including the adaptive challenge in finding harmony among diverse cultures. Serious and rigorous research work requires discipline, time management, resilience, and the resolve to persevere even in the face of impasses.  Finding the right formula to balance these tasks while living healthy lives may be the path to a successful and fulfilling life. The Greek historian Thucydides is known to have said: “How are we to divine the unseen future that lies hidden in the present“.  In other words, do your best while you can.
Research areas of past and current interest are summarized below according to general themes with representative Figures and relevant publications.

Financial Support

Medicinal Chemistry and Drug Prototypes

A number of past and current research programs deal with the validation of hypotheses relating to the mode of action of biologically active compounds through rational design of drug molecule prototypes. This also provides proof of concept for proposed interactions with enzymes and receptors. When available, X-ray co-crystal structures of synthetic molecules with medicinally relevant proteins offer powerful insights into the binding poses of small molecules. Depending on the nature of the interactions, the principles of constraint can be exploited to create peptidomimetics as enzyme inhibitors, or receptor agonists or antagonists.  In many cases, we have been inspired by the structures of bioactive natural products which can be chemically modified to improve activity and to probe new pharmacophoric sites. Collaborative projects with pharma and biotech companies address challenging syntheses of molecules as academic projects that cannot be done internally within the companies. This allows the group to engage in dialogue with industrial scientists and a better appreciation of drug development toward unmet medical needs. 

Total synthesis of bioactive natural products
We have had a long-standing interest in the design and synthesis of natural products that have potent activities in a number of medicinally validated tests. Our strategies are based on the recognition of symmetry elements and functional group overlaps within the target and appropriate precursors. This is the basis of the Chiron Approach which has been very successful because it combines the aesthetic value of stereochemical decoding with the intellectual stimulation of asymmetric synthesis. Our current efforts are focused on developing strategies that combine the merits of generality, practicality and overall appeal. The Why, What , and How of natural product synthesis can be appreciated in the 2013 book entitled “Design and Strategy in Organic Synthesis: from the Chiron approach to catalysis” , Wiley/VCH.

Nucleic Acids for Antisense Technology

Antisense technology, in its basic form, involves binding of a short oligonucleotide sequence to a complementary messenger ribonucleic acid (mRNA), which can ultimately result in disease prevention by stopping the production of pathogenic proteins. The underlying principle of this mechanism is that mRNA must remain as a single stranded entity in order to undergo translation (protein synthesis). Oligonucleotides composed of natural nucleic acids are capable of high-affinity binding recognition to complementary RNA and DNA sequences; however, they rapidly undergo intracellular digestion through the action of nucleases and are thus unsuitable for antisense-based therapeutics. Currently, there is considerable interest in the design and synthesis of nucleic acid modifications that maintain Watson-Crick base pairing properties, but demonstrate substantial increases in nuclease resistance and target (RNA/DNA) binding affinity. Our objectives are to develop new nucleic acid analogues that can be incorporated into sequences of oligonucleotides to confer higher stability in duplex formation with complimentary RNA and DNA. In collaboration with scientists at Ionis Pharmaceuticals, we have designed and synthesized novel bicyclic and tricyclic nucleosides and studied their biophysical properties as antisense constructs.

RNA binding antibiotics and antiprotozoal
Aminocyclitol antibiotics exert their bactericidal activity by binding to subunits of the bacterial ribosome where proteins are synthesized. Among the earliest antibiotics to combat G.positive and G. negative infections are the aminocyclitols exemplified by marketed drugs such as gentamicin and neomycin. In addition to some toxicity upon prolonged clinical use, they are also susceptible to inactivating enzymes produced by resistant bacteria which curtails their utilization without taking precautions. We have used structure-based design relying on X-ray co-crystallographic data to chemically modify aminoglycosides and render them less susceptible to the above mentioned factors. Pactamycin is a highly complex aminocyclopentitol with antiprotozoal and antimalarial activity. Our total synthesis of pactamycin has made it possible to study the structure activity relationships and find new binding modes within the ribosome.

Principles of constraint, and mimetics of small molecule ligands

The interaction of small molecules with biological targets such as proteins involves many factors that rely on physical, structural, and stereochemical properties. Acyclic molecules such as peptides will bind in their energetically most favorable conformations which, in the best scenario may also be the bioactive conformation. Introducing an element of constraint as in a ring, or a macrocycle of appropriate size in such acyclic peptides may confer stability and better binding by restricting the degrees of freedom of rotatable bonds hence a favorable entropic effect.We have applied these design principles to introduce constraint in peptidic motifs, and generated peptidomimetics with interesting  topologies and three dimensional shapes. The same principles have been applied to create glycomimetics  (glycomers) and morphinomimetics. 

Bioorganic chemistry, chemical biology and exploring the third dimension
Proteins exist in a number of fascinating three dimensional secondary and tertiary structures that can be simulated with shorter sequences to study their biophysical and structural properties. Among these are beta-sheets and helical motifs whose structures can be studied in solution and the crystalline state. At times, the results can  unexpected and reveal fascinating inter- and intramolecular interactions resulting in 3-dimensional arrays. These in turn could be studied as nucleating motifs for initiating helical structures. In the absence of definitive structural information by spectroscopy, X-Ray crystallography can be of primordial importance in securing such structures in the solid state. Molecules can also self assemble in fascinating and often unpredictable ways as in the observation that amines and alcohols can associate in supramolecular chiral helices (Supraminols).

Reagent methodology, asymmetric processes and catalysis

Organic synthesis  is primarily achieved by bond-forming reactions in a multitude of ways. Chemoselectivity and stereoselectivity are prerquisites when target molecules are endowed with stereogenic centers harboring  carbon, nitrogen, halogen, and other substituents. Asymmetric processes relying on stoichiometric or catalytic reactions are sought after objectives. Added features such as the creation of quaternary centers present challenges that bring out creative solutions. The compatibility of protective groups in multistep reactions sequences requires careful consideration of orthogonal protective groups in order to avoid their destruction or unnecessary over utilization. Over the years we have  contributed to various aspects of reagent design, protective group strategies, asymmetric bond formation, catalysis in aldol and Michael type reactions, design and reactivity of nucleofugal ​and the consideration of environmentally benign conditions. We have also devised methods of glycoside synthesis in solution and in solid phase with minimal use of protecting groups.

Aspects of drug delivery
The manner in which drug substances are administered and reach  the intended target organs to be effective is a continuing challenge in the treatment of disease. The pharmaceutical industry has pioneered the delivery of small molecule drugs depending on the type of treatment regimen.  The advent of gene therapy, antibody conjugated drugs has caused a paradigm shift in the treatment of certain cancers and other unmet medical needs. We have devised “out-of-the-box” ideas of drug delivery in model systems as a proof of principle. For example, attachment of the antitumor agent camphtothecin to an polyvinylamine- polyvinylalcohol polymer containing superparamagnetic iron oxide nanoparticles was able to penetrate melanoma cancer cells under the influence of magnetic steering. The affinity of sialic acid residues for receptors on liver hepatocytes provides the opportunity to deliver antitumor drugs to the liver. Many years ago, we used the ability of beta-lactamases to release cis-platinum drugs.