Laboratory of Chemical Pharmacology

Head: Mikhail Y. Krasavin

 

1. Design of new heterocyclic compounds with biological activity

 

The main interest of our group is in creating, using the so-called small molecules, new chemical tools for interrogation and functional regulation of either specific components of a living cell or a cell as a whole. Our research is, therefore, interdisciplinary and we aim to maintain strong focus on practical outcomes, be it a novel, biologically characterized set of compound or, ideally, a prospective drug candidate. The biologically active compounds that we create, primarily on the basis of heterocyclic scaffold, can be of significant use as:

  • Novel tool compounds for studying the fundamental biological mechanisms
  • Drug leads

We have a significant experience working in and liaising with the pharmaceutical industry sector and we use this asset to direct our efforts toward the patentable chemical series that carry a sufficient level of pharmacological characterization to enable further preclinical development.

 

Recent publications in this area:

  1. Krasavin, M.; Sosnov, A. V.; Karapetian, R.; Konstantinov, I.; Soldatkina, O.; Godovykh, E.; Zubkov, F.; Bai, R.; Hamel, E.; Gakh, A. Antiproliferative 4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamides, a new tubulin inhibitor chemotype. Bioorg. Med. Chem. Lett.2014, 24, 4477-4481.
  2. Sarnpitak, P.; Mujumdar, P.; Morisseau, C.; Hwang, S. H.; Hammock, B.; Iurchenko, V.; Zozulya, S.; Gavalas, A.; Geronikaki, A.; Ivanenkov, Y.; Krasavin, M.* Potent, orally available, selective COX-2 inhibitors based on 2-imidazoline core. Eur. J. Med. Chem. 2014, 84, 160-172.
  3. Gakh, A. A.; Sosnov, A. V.; Krasavin, M.; Nguyen, T. L.; Hamel, E. Identification of Diaryl 5-Amino-1,2,4-oxadiazoles as Tubulin Inhibitors: the Special Case of 3-(2-Fluorophenyl)-5-(4-methoxyphenyl)amino-1,2,4-oxadiazole. Bioorg. Med. Chem. Lett.2013, 23, 1262-1268.
  4. Kulebyakin, K.; Karpova, L.; Lakontseva, E.; Krasavin, M.; Boldyrev, A. Carnosine protects neurons against oxidative stress and modulates the time profile of MAPK cascade signaling. Amino Acids2012, 43, 91-96.

2. Development of innovative synthetic methodology toward novel scaffolds belonging to poorly populated areas of the chemical space (scaffold-oriented synthesis)

The significant experience of success and failure in small molecule drug development amassed by the pharmaceutical industry to-date, leads one to conclude that the high failure rates afflicting the new drug development process may be related to the poor quality of the early drug discovery starting points.

In 2012, the Nadin group at Astra Zeneca published a seminal report of their thorough analysis of the synthetic organic chemistry literature from the standpoint of synthesis of compound that might or will find utility in drug discovery process. They concluded that ‘…relying on precedented synthetic methodology has an unintentional bias towards the synthesis of less drug-like products leading to a preponderance of these molecules…’ To emphasize the seriousness of this bias and the significant void in the chemistry space denoted as ‘lead-like’, they ‘…describe for the first time the concept of lead-oriented synthesis and the opportunity for its adoption to increase the range and quality of molecules used to develop new medicines…’

(Nadin, A. et al. Lead-Oriented Synthesis: A New Opportunity for Synthetic Chemistry. Angew. Chem. Int. Ed. 2012, 51, 1114-1122).

We, as a group, have joined the scientific community aiming to tackle this challenge and have been diligently contributing new scaffolds and methodologies in the lead-like area.

 

Recent publications in this area:

  1. Krasavin, M.; Sapegin, A.; Dorogov, M. Convenient preparation of diversely substituted fused 2-amino- and 2-mercaptonicotinonitriles under microwave irradiation. Tetrahedron Lett. 2015, 56, 56-50.
  2. Taheri, A.; Quinn, R. J.; Krasavin, M.* Naturally occurring scaffolds for compound library design: convenient access to bis-aryl 1-azaadamantanes carrying a vicinal amino alcohol motif. Tetrahedron Lett. 2014, 55, 5390-5393.
  3. Mujumdar, P.; Sapegin, A.; Dorogov, M.; Krasavin, M.* An expeditious and atom-economic synthesis of lead-like, medicinally important 4,5-dihydropyrazolo[1,5-a]pyrazin-6-ones. Tetrahedron Lett. 2014, 55, 5732-5735.

 

3. Developing synthetic methodology based on multicomponent reactions

Our group has been quite active researching in the area of multicomponent reactions (MCR). The isocyanide-based MCRs (IMCRs), such as the Ugi and the Groebke-Blackburn-Byename reactions, have been a focal point of our research efforts for year. Recently, we have also turned our attention to another powerful MCR that also involves the imine component – the Castagnoli-Cushman reaction.

Of particular interest to us are such synthetic ideas that, if realized, would give rise to unusual, rare, or hitherto undescribed heterocyclic systems.

 

The judicial, creative and sometimes serendipitous use of the MCR chemistry arsenal can afford, in a minimum number of synthetic operations/steps, complex molecular scaffold with a full control over the periphery substituents.

     

Recent publications in this area:

  1. Sarnpitak, P.; Krasavin, M. Convenient access to novel functionalized pyrazino[1,​2-​b]​isoquinolin-​6-​one and diazepino[1,​2-​b]​isoquinolin-​7-​one scaffolds via the Cushman multicomponent reaction followed by post-​condensation. TetrahedronLett.2014, 55, 2299-2303.
  2. Sarnpitak, P.; Krasavin, M. Synthesis of 1,2,4-triazoles employing isocyanides. Tetrahedron 2013, 69, 2289-2295.
  3. Krasavin, M.; Nikulnikov, M. M. Increased dipeptoid diversity resulting from post-condensational manipulation of the Ugi reaction products. Mendeleev Commun.2012, 21, 41-42.
  4. Sarnpitak, P.; Tsirulnikov, S.; Krasavin, M.* Synthesis of N1,N3-disubstituted formamidrazones via the TMSCl-promoted reaction of isocyanides with thiosemicarbazones. Tetrahedron Lett. 2012, 53, 6540-6543. 
  5. Tsaloev, A.; Ilyin, A.; Tkachenko, S.; Ivachtchenko, A.; Kravchenko, D.; Krasavin, M. Cyclic Products of the Ugi Reaction of Aldehydo and Keto Carboxylic Acids: Chemoselective Modification. Tetrahedron Lett.2011, 52, 1800-1803.
  6. Ivachtchenko, A. V.; Ivanenkov Ya. A.; Kysil, V. M.; Krasavin, M.; Ilyin A. P. Multicomponent Reactions of Isocyanides in the Synthesis of Heterocycles. Russ. Chem. Rev.2010, 79, 787-817.

4. Chemistry of 2-imidazolines

2-Imidazolines belong to so-called privileged scaffolds, i. e. the heterocyclic cores that give rise to compounds endowed with an ability to modulate diverse biological targets and, therefore, exhibit many different kinds of biological activities.

Recently, we developed a reliable method for Pd-catalyzed arylation to 2-imidazolines and applied this new reaction in the design and synthesis of a wide range of biologically active compounds (anti-inflammatory, antitubercular compounds, inhibitors of important human protein kinases).

On a serendipity side, we discovered several cases of imidazoline instability and put these findings to work in creating access to unusual, therapeutically sound organic compounds.

Recent publications in this area:

  1. Krasavin, M. Biologically active compounds based on the privileged 2-imidazoline scaffold: the world beyond adrenergic/imidazoline receptor modulators (Invited Review for Special Issue on Bioactive Heterocycles). Eur. J. Med. Chem. 2015, in press. (doi:10.1016/j.ejmech.2014.11.028)
  2. Mujumdar, P.; Sarnpitak, P.; Shetnev, A.; Dorogov, M. Pd-catalyzed amination of imidazolin-1-yl azines: toward a new kinase-inhibitory chemotype. Tetrahedron Lett., Submitted.
  3. Mujumdar, P.; Korsakov, M.; Dorogov, M.; Krasavin, M. Atom-economical construction of a rare 6,7-dihydropyrido[3',2':4,5]imidazo[1,2-d][1,4]benzodiazepine scaffold. SYNLETT2014, 25, 2323-2326.
  4. Krasavin, M. Pd-Catalyzed N-arylation of 2-imidazolines provides convenient access to selective cyclooxygenase-2 inhibitors. Lett. Org. Chem. 2013, 10, 235-239.
  5. Krasavin, M. Novel diversely substituted 1-heteroaryl-2-imidazolines for fragment-based drug discovery. Tetrahedron Lett. 2012, 53, 2876-2880.

 

5. Exploiting intuitive approaches in synthetic and medicinal chemistry                                      

Our research program is based on creating new and using the existing synthetic methods and our interests are in using the resultant organic compounds (small molecules) to modulate the living system functions in general. We are, to a large extent, motivated by the ample room for serendipitous discovery that our interdisciplinary are of research is particularly prominent for! In our view, unexpected discoveries are an excellent doorway toward new research projects and. Moreover, paying attention to serendipitous outcomes of research (and taking them seriously!) is also a proven way to find yourself contributing valuable results in the areas where one wouldn’t plan to end up in.

 

sRecent publications in this area:

  1. Mujumdar, P.; Sarnpitak, P.; Shetnev, A.; Dorogov, M. Pd-catalyzed amination of imidazolin-1-yl azines: toward a new kinase-inhibitory chemotype. SYNLETT, Submitted.
  2. Sapegin, A.V.; Kalinin, S. A.; Smirnov, A. V.; Dorogov, M. V.; Krasavin, M.* Efficient Use of 1,2-Dihaloazine Synthons in Transition Metal-Free Preparation of Diverse Heterocycle-Fused 1,4-Oxazepines. Eur. J. Org. Chem. 2015, accepted 17.11.2014 (DOI:10.1002/ejoc.201403397).
  3. Krasavin, M.; Sapegin, A.; Dorogov, M. Convenient preparation of diversely substituted fused 2-amino- and 2-mercaptonicotinonitriles under microwave irradiation. Tetrahedron Lett. 2015, 56, 56-50.
  4. Mujumdar, P.; Grkovic, T.; Krasavin, M. A simple two-step access to diversely substituted imidazo[4,5-b]pyridines and benzimidazoles from readily available 2-imidazolines. Tetrahedron Lett. 2013, 54, 3336-3340.
  5. Golubev, V.; Zubkov, F.; Krasavin, M. A simple, three-component synthesis of 2-aminothiazoles using trimethylsilyl isothiocyanate. Tetrahedron Lett. 2013, 54, 4844-4847.
  6. Konstantinov, I.; Bukhryakov, K.; Gezentsvey, Y.; Krasavin, M. Practical Method for Parallel Synthesis of Diversely Substituted 1-Phenylpiperazines. Lett. Org. Chem. 2011, 8, 628-630.
  7. Parchinsky, V.; Shumsky, A.; Krasavin, M. Microwave-assisted aza-Prins reaction. Part 2: straightforward access to 2,6-disubstituted 1-azaadamantanes. Tetrahedron Lett. 2011, 52, 7161-7163.

 

 

SCIENTIFIC COLLABORATION

Due to the interdisciplinary character of our research that includes constant search for the new directions for using our small molecules as tool compounds or drug leads, we maintain and grow a diversified network of collaborations. Shown below is the list of scientific groups with whom we collaborate (early-2015).

 

Prof Mikhail Dorogov

 

Yaroslavl State Pedagogical University

Scaffold-oriented synthesis

A/Prof Fedor Zubkov

 

People’s Friendship University of Russia

Natural-like scaffolds

A/Prof Lukin

 

Moscow Institute for Fine Chemical Technology

Multiple directions

Dr Yan Ivanenkov

 

Moscow Institute of Physics and Technology

In-silico modeling, chemoinformatics

Prof Tatiana Vinogradova

 

Phthisiopulmonology Research Institute (St Petersburg)

Antitubercular drug discovery

Dr Sergey Zozulya

 

Bienta, Ltd.

Biological screening, ADMET/PK, animal experiements

Dr Maxim Platonov

 

Enamine, Ltd.

In-silico modeling, chemoinformatics

Dr Ivan Kondratov

 

Enamine, Ltd.

Medicinal chemistry

Dr Ruben Karapetian

 

Chemical Diveristy Research Institute

Biological screening, ADMET/PK, animal experiements

Dr. Andrea Chicca

 

University of Bern

 

Chemical modulation of endocannabinoid system

Prof Athina Geronikaki

 

University of Thessaloniki

Animal models for drug efficacy estimation

Prof Claudiu Supuran

 

University of Florence

Carbonic anhydrase inhibitors

Prof Bruce Hammock

 

University of California, Davis

Cyclooxygenase & soluble epoxide hydrolase inhibitors

Prof Rostislav Trifonov

 

St Petersburg State University

Laboratory member in Translational Biomedicine Research Institute

Prof Aleksandr Vasilyev

 

St Petersburg State University

Scaffold-oriented synthesis

A/Prof Dmitry Daryin

 

St Petersburg State University

Multicomponent reacitons

 

 

FINANCIAL SUPPORT

 

List of financial sources for independent academic research and research infrastructure

 

1) The Russian Scientific Fund grant ‘Translational biomedicine at SPbSU’ (750 mln. Roubles, 2014-2018 гг., principal investigator)

2) Australian Research Council grant - Quinn RJ, Krasavin M, Wood S. “Natural Product Scaffolds: an Approach to Privileged Structures”. ARC Discovery Project DP130102400 (2013-2016) AU$390,000

3) Therapeutic Innovations Australia (Federal Agency) grant - Quinn RJ, Krasavin M, Parisot J, Arndt G. “Translating Health Discoveries Super Science project 2012-2013: Drug Screening”. AU$2,500,000

4) Krasavin M. “Broad druglike, natural-like scaffold diversity accessed via isocyanide multicomponent chemistry”. Griffith University New Researcher Grant (2012). AU$10,000

5) Krasavin M. “Broad druglike, natural-like scaffold diversity accessed via isocyanide multicomponent chemistry” Griffith University Encouragement Award (2012). AU15,000

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