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Department of Bioorganic Chemistry is one of 14 departments of Faculty of Chemistry, Wrocław University of Science and Technology. It is headed by Łukasz Berlicki and formed by 5 research groups of: prof. Paweł Kafarski, prof. Artur Mucha, prof. Łukasz Berlicki, Dr. Rafał Kowalczyk and Dr. Rafał Latajka. The main research areas are on a border of chemistry and biology.





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Opublikowany przez Berlicki Lab Poniedziałek, 27 lipca 2020

Recent papers

Phosphonopeptides containing free phosphonic groups: recent advances
Kafarski, P.
RCS Adv. 2020, 10, 25898
DOI: 10.1039/d0ra04655h

Phosphonopeptides are mimetics of peptides in which phosphonic acid or related (phosphinic, phosphonous etc.) group replaces either carboxylic acid group present at C-terminus, is located in the peptidyl side chain, or phosphonamidate or phosphinic acid mimics peptide bond. Acting as inhibitors of key enzymes related to variable pathological states they display interesting and useful physiologic activities with potential applications in medicine and agriculture. Since the synthesis and biological properties of peptides containing C-terminal diaryl phosphonates and those with phosphonic fragment replacing peptide bond were comprehensively reviewed, this review concentrate on peptides holding free, unsubstituted phosphonic acid moiety. There are two groups of such mimetics: (i) peptides in which aminophosphonic acid is located at C-terminus of the peptide chain with most of them (including antibiotics isolated from bacteria and fungi) exhibiting antimicrobial activity; (ii) non-hydrolysable analogues of phosphonoamino acids, which are useful tools to study physiologic effects of phosphorylations.

Recent papers

Nuclear immunophilin FKBP39 from Drosophila melanogaster drives spontaneous liquid-liquid phase separation.
Tarczewska, A.; Wycisk, K.; Orłowski, M.;Waligórska, A.; Dobrucki, J.; Drewniak-Świtalska, M.; Berlicki, Ł.; Ożyhar, A.
Int. J. Biol. Macromol. 2020, 163, 108
DOI: 10.1016/j.ijbiomac.2020.06.255
The FKBP39 from Drosophila melanogaster is a multifunctional regulatory immunophilin. It contains two globular domains linked by a highly charged disordered region. The N-terminal domain shows homology to the nucleoplasmin core domain, and the C-terminal domain is characteristic for the family of the FKBP immunophilin ligand binding domain. The specific partially disordered structure of the protein inspired us to investigate whether FKBP39 can drive spontaneous liquid-liquid phase separation (LLPS). Preliminary analyses using CatGranule and Pi-Pi contact predictors suggested a propensity for LLPS. Microscopy observations revealed that FKBP39 can self-concentrate to form liquid condensates. We also found that FKBP39 can lead to LLPS in the presence of RNA and peptides containing Arg-rich linear motifs derived from selected nuclear and nucleolar proteins. These heterotypic interactions have a stronger propensity for driving LLPS when compared to the interactions mediated by self-associating FKBP39 molecules. To investigate whether FKBP39 can drive LLPS in the cellular environment, we analysed it in fusion with YFP in COS-7 cells. The specific distribution and diffusion kinetics of FKBP39 examined by FRAP experiments provided evidence that immunophilin is an important driver of phase separation. The ability of FKBP39 to go into heterotypic interaction may be fundamental for ribosome subunits assembly.

Recent papers

A novel approach for obtaining alpha,beta-diaminophosphonates bearing structurally diverseside chains and their interactions with transition metal ions studied by ITC
Lenartowicz, P.; Witkowska, D.; Żyszka-Haberecht, B.; Dziuk, B.; Ejsmont, K.; Świątek-Kozłowska, J.; Kafarski, P.
RSC Adv. 2020, 10, 24045
DOI: 10.1039/d0ra03764h

Aminophosphonates are an important group of building blocks in medicinal and pharmaceutical chemistry.Novel representatives of this class of compounds containing nontypical side chains are still needed. The aza-Michael-type addition of amines to phosphonodehydroalanine derivatives provides a simple andeffective approach for synthesizingN0-substituteda,b-diaminoethylphosphonates and thus affordsgeneral access to aminophosphonates bearing structurally diverse side chains. Thermodynamic analysisof the chosen aminophosphonates at physiological pH proves that they serve as potent chelators forcopper(II) ions and moderate chelators for nickel(II) ions.

Recent papers

P1′ Residue-Oriented Virtual Screening for Potent and Selective Phosphinic (Dehydro) Dipeptide Inhibitors of Metallo-Aminopeptidases
Talma, M.; Mucha, A.
Biomolecules 2020, 10, 659
Designing side chain substituents complementary to enzyme binding pockets is of great importance in the construction of potent and selective phosphinic dipeptide inhibitors of metallo-aminopeptidases. Proper structure selection makes inhibitor construction more economic, as the development process typically consists of multiple iterative preparation/bioassay steps. On the basis of these principles, using noncomplex computation and modeling methodologies, we comprehensively screened 900 commercial precursors of the P1′ residues of phosphinic dipeptide and dehydrodipeptide analogs to identify the most promising ligands of 52 metallo-dependent aminopeptidases with known crystal structures. The results revealed several nonproteinogenic

residues with an improved energy of binding compared with the best known inhibitors. The data are discussed taking into account the selectivity and stereochemical implications of the enzymes. Using this approach, we were able to identify nontrivial structural elements substituting the recognized

phosphinic peptidomimetic scaffold of metallo-aminopeptidase inhibitors.

Recent papers

New crystal structures of fluorinated α-aminophosphonic acid analogues of phenylglycine
Wanat, W.; Dziuk, B.; Kafarski, P.
Struct. Chem. 2020, 31, 1197
DOI: 10.1007/s11224-020-01508-w
The four novel phosphonic acid analogues of phenylglycine with various substituents in phenyl ring (mostly fluorine atoms) have been synthesized by using procedure of amidoalkylation of phosphorus trichloride with aromatic aldehydes and acetamide. The NMR, ESI-MS spectroscopy, and single-crystal X-Ray diffraction methods were used to characterize unusual structures: the amino-(4-trifluoromethylbenzyl)-(1), amino-(3,4-difluorobenzyl)-(2), amino-(2,4,6-trifluorobenzyl)-(3), and amino-(2-fluoro-4-hydroxybenzyl)-(4) phosphonic acids. Since the α-aminophosphonates have a potential for biological activity and could be used as building blocks in medicinal chemistry, it is important to know their detail crystal structures and properties which, in turn, may extend the knowledge on their interaction with physiologic receptors.

Recent papers

Phosphonic Acid Analogs of Fluorophenylalanines as Inhibitors of Human and Porcine Aminopeptidases N: Validation of the Importance of the Substitution of the Aromatic Ring
Wanat, W.; Talma, M.; Dziuk, B.; Pirat, J.-L.; Kafarski, P.
Biomolecules 2020, 10, 1
DOI: 10.3390/biom10040579

A library of phosphonic acid analogs of phenylalanine substituted with fluorine, chlorine and trifluoromethyl moieties on the aromatic ring was synthesized and evaluated for inhibitory activity against human (hAPN) and porcine (pAPN) aminopeptidases. Fluorogenic screening indicated that these analogs are micromolar or submicromolar inhibitors, both enzymes being more active against hAPN. In order to better understand the mode of the action of the most active compounds, molecular modeling was used. It confirmed that aminophosphonic portion of the enzyme is bound nearly identically in the case of all the studied compounds, whereas the difference in activity results from the placement of aromatic side chain of an inhibitor. Interestingly, both enantiomers of the individual compounds are usually bound quite similarly.

Recent papers

Three-Component Reaction od Diamines with Triethyl Orthoformate and Diethyl Phosphite and Anti-Proliferative and Antiosteoporotic Activities of the Products
Petruczynik, P.; Kafarski, P.; Psurski, M.; Wietrzyk, J.; Kiełbowicz, Z.; Kuryszko, J.; Chmielewska, E.
Molecules 2020, 25, 1
DOI: 10.3390/molecules25061424

A three-component reaction between diamines (diaminobenzenes, diaminocyclohexanes, and piperazines), triethyl orthoformate, and diethyl phosphite was studied in some detail. In the case of 1,3- and 1,4-diamines and piperazines, products of the substitution of two amino moieties—the corresponding tetraphosphonic acids—were obtained. In the cases of 1,2-diaminobenzene, 1,2-diaminocyclohexanes and 1,2-diaminocyclohexenes, only one amino group reacted. This is most likely the result of the formation of hydrogen bonding between the phosphonate oxygen and a hydrogen of the adjacent amino group, which caused a decrease in the reactivity of the amino group. Most of the obtained compounds inhibited the proliferation of RAW 264.7 macrophages, PC-3 human prostate cancer cells, and MCF-7 human breast cancer cells, with 1, trans-7, and 16 showing broad nonspecific activity, which makes these compounds especially interesting in the context of anti-osteolytic treatment and the blocking of interactions and mutual activation of osteoclasts and tumor metastatic cells. These compounds exhibit similar activity to zoledronic acid and higher activity than incadronic acid, which were used as controls. However, studies of sheep with induced osteoporosis carried out with compound trans-7 did not support this assumption.

Recent papers

Peptide and Pseudopeptide Bond Synthesis in Phosphorus Dipeptide Analogs.
Mucha, A.; Kafarski, P.
Methods Mol. Biol. 2020, 2103, 287
DOI: 10.1007/978-1-0716-0227-0_20
Peptide analogs modified with a phosphorus-based moiety (phosphonate, phosphonamidate, or phosphinate)have emerged as invaluable tools in fundamental and medicinal, mechanistic, and inhibitory studies of proteolytic enzymes and other catalytic proteins that process the amino acids and peptides. The first stages of the chemical synthesis of these compounds frequently involve formation of peptide or pseudopeptide bond between a suitably protected α-amino acid and an α-aminoalkyl phosphorus derivative. These preparative protocols are distinct from conventional solution and solid-phase peptide syntheses that have become routine and automatized. In the following chapter, we describe in details the methods and techniques utilized to perform this nonstandard coupling and to obtain P-terminal dipeptidyl phosphonates and pseudodipeptides containing the internal phosphonamidate or phosphinate linkages. Methods of products’ purification, the deprotection conditions, and stability issues are also presented and discussed.

Recent papers

Halogenated aromatic thiosemicarbazones as potent inhibitors of tyrosinase and melanogenesis
Hałdys K., Goldeman W., Jewgiński M., Wolińska E., Anger-Góra N., Rossowska J., Latajka R.
Bioorganic Chemistry 2020, 94, 103419
DOI: 10.1016/j.bioorg.2019.103419

Recent papers

Applications of Thermal Activation, Ball-milling and Aqueous Medium in Stereoselective Michael Addition of Nitromethane to Enynones Catalyzed by Chiral Squaramides
Ignatiuk, Z. A.; Janicki, M. J.; Gora, R. W.; Konieczny, K.; Kowalczyk, R.
Advanced Synthesis & Catalysis 2019, 361, 1108
DOI: 10.1002/adsc.201801498