Laboratory of Carbofunctional Compounds

I.Kalvins
Dr. habil. chem. Ivars Kalviņš
Head of Laboratory
e-mail: 
Phone: (+371) 67014800

With the aim of finding new active drug substances, the studies of the synthetic methods of new low molecular weight compounds are being performed in the laboratory. The main directions of research are the development of anti-cancer preparations as well as synthesis and studies of the regulators of metabolism to control the cardiovascular diseases related to metabolic syndrome. The search for the regulators of energy metabolism upon hypoxia conditions and agonists of hydroxycarboxylic acid receptors HCA1, HCA2, HCA3 is ongoing.

To control malignant neoplasms, the possible drug substances that act on various enzymatic systems, critical for cancer growth and development, are being searched. In this field, the laboratory research activities are related mainly to activity modulators of the Krebs cycle enzymes, arginase and NO-synthase, and inhibitors of histone deacetylase and nicotinamide nicotinamide phosphoribosyltransferase. Most of them are carried out in collaboration with partners in the EU countries.

Consequently, the laboratory research work covers the following projects:

  1. The synthesis and research of p-FOX (partial fatty acid oxidation) inhibitors. These studies are connected with the mechanism of action of the original anti-ischemic cytoprotector meldonium (Mildronate), discovered by prof. Kalviņš and the search for the new generation meldonium analogues. A series of novel pharmaceuticals has been developed and protected by patents as a result of the studies. The clinical usage of meldonium has also been significantly expanded.
  2. The preparation and anti-cancer activity testing of the regulators of NO-synthase and arginase activity. So far, a new class of compounds with high anti-cancer activity using human pancreas xenograft model and cell cultures has been developed and protected by patents. The prospective direction of this study is to search for the new derivatives of the anti-cancer immunomodulator leokadin, developed by prof. Kalviņš. Therefore, the lead structure is being further optimized to find novel candidates for clinical trials.
  3. The search for new histone deacetylase (HDAC) inhibitors with the aim of developing more active inhibitors which could be also selective towards HDAC sub-types. A series of structurally different compounds with HDCA inhibitory properties has been synthesized and investigated. In collaboration with the company TopoTarget (UK/Denmark) an anti-cancer medication Belinostat has been developed. The FDA has approved the medication for the treatment of the peripheral T-cell lymphoma but its possible usage for the treatment of other cancer forms with different localization is still being investigated (phase II and phase III clinical trials). Some of the compounds synthesised in the laboratory have turned out to be promising tools for the treatment of malaria, Hantington disease, psoriase, and African tripanosomniasis.
  4. The development of methods for the synthesis of new nicotinamide phosphoribosyltransferase The cancer cell development is characterized by accelerated metabolic processes. To ensure these processes the compounds involved in providing energy to cells are synthesised in cancer cells faster than in normal ones. One of such compounds is nicotinamide adenine dinucleotide (NAD+) which synthesis from nicotinamide in vivo is catalyzed by nicotinamide phosphoribosyltransferase (NAMPT). Taking into account the fact that the NAMPT level in many cancer-cell lines is higher than in normal cells, NAMPT activity regulation could be a promising target for the novel anti-cancer compound development.
  5. The investigation of the possibility to correct Krebs cycle chemical anomalies in cancer cells by regulation of isocitrate dehydrogenase, fumarate dehydratase and succinate dehydrogenase activity.
  6. The development of novel antimetastatic preparations on the small molecule (NO, CO and other endothelial functions regulating molecules) concentration regulatory basis.

The design and synthesis of the potential ligands of hydroxycarboxylic acid receptors HCA1, HCA2 and HCA3. Some potential agonists of hydroxycarbolic acid receptors HCA1, HCA2, HCA3 have been discovered. They could be further used as lead compounds for the investigation of their structure-activity relationship with the aim of creating new preparations for dyslipidemia control.

 

Recent publications:

  1. Liepinhs E.; Makrecka M.; Kuka J.; Vilskersts R.; Makarova E.; Cirule H.; Loza E.; Loļa D.; Grinberga S.; Pugovics O.; Kalvinsh I.; Dambrova M. Inhibition of L-carnitine biosynthesis and transport by methyl-γ-butyrobetaine decreases fatty acid oxidation and protects against myocardial infarction. J. Pharmacol. 2015, vol.172(5), 1319-1332.
  2. Kuka J.; Liepinsh E.; Makrecka M.; Liepins J.; Cirule H.; Gustina D.; Loža E.; Zharkova-Malkova O. ; Grinberga S.; Pugovics O.; Dambrova M. Suppression of intestinal microbiota-dependent production of pro-atherogenic trimethylamine N-oxide by shifting L-carnitine microbial degradation. Life Sciences. 2014, 117, 84-92.
  3. Liepinhs E.; Makrecka M.; Kūka J.; Vilskersts R.; Makarova E.; Cirule H.; Loza E.; Lola D.; Grinberga S.; Pugovics O.; Kalvinsh I.; Dambrova M. Therapeutic targeting of the γ-butyrobetaine dioxygenase and OCTN2 by methyl-γ-butyrobetaine decreases long chain fatty acid oxidation and protects against acute myocardial infarction. J. Pharmacol. 2014, “online” (Manuscript ID 2014-BJP-0453-RP.). DOI: 10.1111/bph.13004 PMID: 25363063
  4. Bobileva O.; Bokaldere R.; Gailite V.; Kaula I.; Ikaunieks M.; Duburs G.; Petrovska R; Mandrika I.; Klovins J.; Loza E. Synthesis and evaluation of (E)-2-(acrylamido)-cyclohex-1-enecarboxylic acid derivatives as HCA1, HCA2, and HCA3 receptor agonists. Med. Chem. 2014, 22, 3654-3669.
  5. Liepinsh E.; Makrecka M.; Kuka J.; Cirule H.; Makarova E.; Sevostjanovs E.; Grinberga S.; Vilskersts R.; Lola D.; Loza E.; Stonans I.; Pugovics O.; Dambrova M. Selective inhibition of OCTN2 is more effective than inhibition of gamma-butyrobetaine dioxygenase to decrease the availability of L-carnitine and to reduce myocardial infarct size. Pharmacol. Res. 2014, 85, 33-38.

Recent patents:

  1. Kalvins I.; Ponomarjovs J.; Varačeva L.; Cernobrovijs A.; Lebedevs A. A method for the preparation of lenalidomide. WO 2015/057043 A1 (23.4. 2015).
  2. Dambrova M.; Cirule H.; Kalvins I.; Liepins E.; Makarova E.; Stonans I.; Misane I. Use of 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium or a pharmaceutically acceptable salt thereof in the prevention and treatment of diabetes. WO 2015/044828 A1 (2.4.2015).
  3. Kalvins I.; Ponomarjovs J.; Cernobrovijs A.; Lebedevs A. A method for preparation of erlotinib. WO 2015/023170 (A1) (19.2.2015).
  4. Venskus Dite; Kalvins I.; Pjanova Dace; Auziņš Jurģis; Petrovska R. Genetically stable oncolytic RNA virus, method of manufacturing and use thereof. WO 2015/007788 A1 (22.1.2015).
  5. Kalvins I.; Vilskersts R.; Pugovics O.; Dambrova M.; Stonans I.; Kuka J.; Liepins E.; Loza E.; Andrianovs V.; Grīnberga S.; Gustina D.; Lola D.; Makrecka M. Use of 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium or a pharmaceutically acceptable salts thereof in the treatment of atherosclerosis . WO2014/096133 A1 (26.6.2014).