ADC - Špaková Raschmanová, J.; Martinková, M.*; Gonda, J.; Bago Pilátová, M.; Kuchár, J.; Jáger, D. „Synthesis and in vitro biological evaluation of 3-amino-3-deoxydihydrosphingosines and their related analogues“ Tetrahedron 2020, 76, article number 130803, 1‒17. IF (2019) = 2.235, Q2, quoted: 1

ADC - Fábian, M.; Gonda, J.; Jacková, D.; Martinková, M.*; Bago Pilátová, M.; Jáger, D. „Synthesis and in vitro cytotoxic evaluation of spiro-β-lactone-γ-lactam scaffolds” Tetrahedron 2020, 76, article number 131144, 1‒11.IF (2019) = 2.235, Q2, quoted: 3

ADC - Špaková Raschmanová, J.; Martinková, M.*; Gonda, J.; Bago Pilátová, M.; Kupka, D.; Jáger, D. „Synthesis of cytotoxic phytosphingosines and their isomeric analogues“ Carbohydr. Res. 2018, 468, 1‒12. IF(2017) = 2.074, Q2, quoted: 2

ADC - Gonda, J.*; Fazekašová, S.; Martinková, M.; Mitríková, T.; Roman, D.; Bago Pilátová, M. „Synthesis and biological activity of sphingosines with integrated azobenzene switches“ Org. Biomol. Chem. 2019, 17, 3361‒3373. IF( 2018): 3.490, Q1, quoted: 5

ADC - Jacková, D.; Martinková, M.*; Gonda, J.; Vilková, M.; Bago Pilátová, M.; Takáč, P. “Stereoselective synthesis and anticancer activity of broussonetine analogues” Tetrahedron: Asymmetry 2017, 28, 1175–1182. IF (2016) = 2.126, Q2, quoted: 4

VEGA 1/0047/18: Stereoconvergent synthesis of the isomeric sphingoid bases and related long-chain amino alcohols as the promising anticancer agents. 2018-2020, project leader

Stereoconvergent synthesis of the enantiomerically pure isomeric sphingoid bases and related long-chain amino alcohols will start from the homochiral dimethyl l-tartrate (the chiron approach) and will utilize the [3,3]-heterosigmatropic rearrangements and the well-established olefin cross metathesis reaction (OCM) as the key transformations. With the aim to rationalize the observed stereoselectivities, high-level density functional theory (DFT) calculations will be also carried out. The obtained results from the realized studies of the rearrangement reactions will provide further insight into the scope and limitations of the aza-Claisen rearrangements of chiral allylic thiocyanates and trichloroacetimidates. It should be noted that the discovery of new anticancer agents still remains a key factor to progress in cancer treatment. In an effort to find new candidates with the interesting biological profile based on the modulation of sphingolipid metabolism, the target molecules will be evaluated for in vitro antiproliferative/cytotoxic activities on selected human cancer cell lines. 

VEGA 1/0168/15: The stereoconvergent total synthesis of broussonetines broussonetinovusing heterosigmatropic rearrangemets as the key reaction. 2015-2017, project leader

Total synthesis of enantiomerically pure forms of some representatives of the group of lipophilic pyrrolidine alkaloids, referred to as broussonethins, based on simple sugar templates (chiral pool approach) and using [3,3]-heterosigmatropic rearrangements as key reactions for the incorporation of the new stereogenic center bearing nitrogen functionality. These mentioned experiments afford the novel data about the diastereoselectivity course of studied reactions and can generate further insight into the scope and limitations of the [3,3]-sigmatropic rearrangements of allylic thiocyanates and trichloroimidates. Resulting target molecules will be subjected to biological testing, which will focus primarily on antitumor activity, as these have not yet been studied for these substances.

VEGA 1/0375/19: Stereoselective synthesis of photoactiove molecules with pyrrolidine phrmacophores based on broussonetines, oxazolomycines, and lactacystin. 2019-2021, project leader: prof. RNDr. Jozef Gonda, DrSc., after his death in June 2019, the formal leader was doc. RNDr. Mária Vilková, PhD., the fulfillment of the project objectives was under the full responsibility of Assoc. prof. RNDr. Miroslava Martinkova, PhD., project representative.

The project deals with the stereoselective construction of photoactive molecules with embedded pyrrolidine pharmacophores based on boussonetines, oxazolomycins and lactacystin. Incorporated azobenzene switches and photosensitive protecting groups will allow the possibility of a targeted change in their biological activity.

APVV-14-0883: Stereoselective synthesis and in vitro structural modulation of the biological activity of functionalized sphingosines, 2015-2018, project representative.

The project deals with the stereoselective and asymmetric synthesis of functionalized sphingosines and the study of the modulation of their biological activity in vitro. A total synthesis of enantiomerically pure forms of lipophilic pyrrolidine alkaloids - broussonetines, will be performed, starting from sugar templates and using [3,3]-sigmatropic rearrangements as key transformations. The resulting target molecules with photosensitive protecting groups and azobenzene switches will be subjected to biological testing for antitumor activity.

Prepared sphingosines may be promising lead compounds in the development of new drugs for diabetes, viral infections and oncological diseases.

„Open scientific community for modern interdisciplinary research in medicine (OPENMED)“, ITMS2014+: 313011V455 supported by the Operational Programme Integrated Infrastructure, funded by the ERDF. 09/2020 – 06/2023, project leader of 313V45500003 - H3 activity. "Development of intelligent photosensitive drugs and nanoporous drug delivery systems"

The main goal of this activity is the development of a new generation of photosensitive biologically active sphingosines for personalized medicine. The activity deals with the synthesis of functionalized sphingosines and the study of the modulation of their biological activity in vitro. Total synthesis of enantiomerically pure forms of lipophilic sphingolipids will be performed, starting from saccharide chirons and using heterosigmatropic rearrangements and metathesis as key reactions. The resulting target molecules will be provided with photosensitive groups and subjected to biological testing for antitumor activity under dynamic conditions.

VEGA 1/0278/23: Synthesis and in vitro biological profile of novel stereoisomeric diaminoanalogues of natural D-ribo-phytosphingosine. 2023-2025, project leader. 

The stereoselective synthesis of enantiomerically pure 3,4-diamino-3,4-dideoxyphytosphingosines (eight stereoisomers with different character of a carbon side chain) as novel analogues of natural D-ribo-phytosphingosine utilises four commercially available synthons: dimethyl L- and D-tartrate, D-isoascorbic acid, and L-arabinose (the Chiron approach). The proposed strategy relies on two types of aza-Claisen rearrangements (sequential and simple) and a late stage olefin cross metathesis reaction as the key reaction steps. The corresponding [3,3]-sigmatropic rearrangements will be investigated under conditions of a simple asymmetric induction and 1,3-chirality transfer. The obtained results will provide further insight into the scope and limitations of the aforementioned transformations of allylic trichloroacetimidates and thiocyanates derived from the chiral templates. Modulation of sphingolipid metabolism is a promising strategy for cancer therapy that has already opened innovative approaches for the development of novel chemical entities with potential therapeutic use. The simple sphingolipid natural products very often serve as lead compounds for the design of new modulators of sphingolipid metabolism. Therefore, the ability of our target sphingoid bases to inhibit the proliferation of cancer cells in vitro will be evaluated on a panel of several human malignant cell lines. The observed results from viability experiments could generate novel insight into the structure-activity relationships of this family of synthesised phytosphingosine analogues. Until now, such types of compounds have not been prepared.