Milos Budesinsky - Academia.edu (original) (raw)

Papers by Milos Budesinsky

ChemInform Abstract: Reactions of PO(NCS)3 with 4-Hydroxy-1,3-dioxanes. Crystal Structure of rel-(2S,4R,5S,6S)-2,6-Diethyl-5-methyl-4-(N′-benzylthioureido)-1,3- dioxane

ChemInform, Aug 21, 2010

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Journal of Materials Chemistry C

Self-assembly of two complementary single-stranded DNA chains via hybridization increases (approx... more Self-assembly of two complementary single-stranded DNA chains via hybridization increases (approximately doubles) the single molecule DNA conductance leading to additive transport in double-stranded DNA molecular circuits.

Journal of Medicinal Chemistry, 2019

Cyclic dinucleotides are second messengers in the cGAS-STING pathway which plays an important rol... more Cyclic dinucleotides are second messengers in the cGAS-STING pathway which plays an important role in recognizing tumor cells and viral or bacterial infections. They bind to the STING adaptor protein and trigger expression of cytokines via TBK1/IRF3 and IKK/NFκB signaling cascades. In this report we describe an enzymatic preparation of 2'-5', 3'-5' cyclic dinucleotides (2'3'CDNs) with use of cyclic GMP-AMP synthases (cGAS) from human, mouse and chicken. We profile substrate specificity of these enzymes by employing a small library of NTP analogues and use them to prepare thirty-three 2'3'CDNs. We also determine affinity of these CDNs to five different STING haplotypes in cell-based and biochemical assays, and describe properties needed for their optimal activity toward all STING haplotypes. Next, we study their effect on cytokines and chemokines induction by human peripheral blood mononuclear cells (PBMC) and evaluate their cytotoxic effect on monocytes. Additionally, we report X-ray crystal structures of two new CDNs bound to STING protein and discuss structure activity relationship by using quantum and molecular mechanical (QM/MM) computational modeling.

Organic Letters, 2018

A unique asymmetric total synthesis of the unnatural enantiomer of pregnanolone, as well as a stu... more A unique asymmetric total synthesis of the unnatural enantiomer of pregnanolone, as well as a study of its biological activity at the NMDA receptor, is reported. The asymmetry is introduced by a highly atom-economic organocatalytic Robinson annulation. A new method for the construction of the cyclopentane D-ring consisting of Cu Icatalyzed conjugate addition and oxygenation followed by thermal cyclization employing the persistent radical effect was developed. ent-Pregnanolone sulfate is surprisingly only 2.6-fold less active than the natural neurosteroid.

$Research paper thumbnail of {"__content__"=>"The benchmark of P NMR parameters in phosphate: a case study on structurally constrained and flexible phosphate.", "sup"=>{"__content__"=>"31"}}$

Physical chemistry chemical physics : PCCP, Jan 6, 2017

A benchmark for structural interpretation of the P NMR shift and the J NMR spin-spin coupling in ... more A benchmark for structural interpretation of the P NMR shift and the J NMR spin-spin coupling in the phosphate group was obtained by means of theoretical calculations and NMR measurements in diethylphosphate (DEP) and 5,5-dimethyl-2-hydroxy-1,3,2-dioxaphosphinane 2-oxide (cDEP). The NMR parameters were calculated employing the B3LYP, BP86, BPW91, M06-2X, PBE0, KT2, KT3, MP2, and HF methods, and the 6-31+G(d), Iglo-n (n = II, III), cc-pVnZ (n = D, T, Q, 5), aug-cc-pVnZ (n = D, T and Q), and pcS-n and pcJ-n (n = 1, 2, 3, 4) bases, including the solvent effects described with explicit water molecules and/or the implicit Polarizable Continuum Model (PCM). The effect of molecular dynamics (MD) on NMR parameters was MD-calculated using the GAFF force field inclusive of explicit hydration with TIP3P water molecules. Both the optimal geometries and the dynamic behaviors of the DEP and cDEP phosphates differed notably, which allowed a reliable theoretical benchmark of the P NMR parameters fo...

Angewandte Chemie (International ed. in English), Jan 15, 2017

A series of oxahelicenes composed of ortho/meta-annulated benzene/pyridine and 2H-pyran rings wer... more A series of oxahelicenes composed of ortho/meta-annulated benzene/pyridine and 2H-pyran rings were synthesized on the basis of the cobalt(I)-mediated (or rhodium(I)- or nickel(0)-mediated) double, triple, or quadruple [2+2+2] cycloisomerization of branched aromatic hexa-, nona-, or dodecaynes, thus allowing the construction of 6, 9, or 12 rings in a single operation. The use of a flow reactor was found to be beneficial for the multicyclization reactions. The stereogenic centers present in some of the oligoynes steered the helical folding in such a way that the final oxa[9]-, [13]-, [17]- and [19]helicenes were obtained in both enantiomerically and diastereomerically pure form. Specifically, the oxa[19]helicenes beat the current record in the length of a helicene backbone. Single-molecule conductivity was studied by the mechanically controllable break-junction method with a pyridooxa[9]helicene.

Journal of Peptide Science, 2017

The rise of CuI‐catalyzed click chemistry has initiated an increased demand for azido and alkyne ... more The rise of CuI‐catalyzed click chemistry has initiated an increased demand for azido and alkyne derivatives of amino acid as precursors for the synthesis of clicked peptides. However, the use of azido and alkyne amino acids in peptide chemistry is complicated by their high cost. For this reason, we investigated the possibility of the in‐house preparation of a set of five Fmoc azido amino acids: β‐azido l‐alanine and d‐alanine, γ‐azido l‐homoalanine, δ‐azido l‐ornithine and ω‐azido l‐lysine. We investigated several reaction pathways described in the literature, suggested several improvements and proposed several alternative routes for the synthesis of these compounds in high purity. Here, we demonstrate that multigram quantities of these Fmoc azido amino acids can be prepared within a week or two and at user‐friendly costs. We also incorporated these azido amino acids into several model tripeptides, and we observed the formation of a new elimination product of the azido moiety upon ...

Journal of Medicinal Chemistry, 2017

Human insulin-like growth factor 1 (IGF-1) is a 70 amino acid protein hormone, with key impact on... more Human insulin-like growth factor 1 (IGF-1) is a 70 amino acid protein hormone, with key impact on growth, development, and lifespan. The physiological and clinical importance of IGF-1 prompted challenging chemical and biological trials toward the development of its analogs as molecular tools for the IGF-1 receptor (IGF1-R) studies and as new therapeutics. Here, we report a new method for the total chemical synthesis of IGF-1 analogs, which entails the solid-phase synthesis of two IGF-1 precursor chains that is followed by the Cu I-catalyzed azide−alkyne cycloaddition ligation and by biomimetic formation of a native pattern of disulfides. The connection of the two IGF-1 precursor chains by the triazole-containing moieties, and variation of its neighboring sequences (Arg36 and Arg37), was tolerated in IGF-1R binding and its activation. These new synthetic IGF-1 analogs are unique examples of disulfide bonds' rich proteins with intra main-chain triazole links. The methodology reported here also presents a convenient synthetic platform for the design and production of new analogs of this important human hormone with non-standard protein modifications.

ChemInform Abstract: Simple Preparation of Epimeric 2,6-Dimethyl-4-(N′-substituted thioureido)-1,3-dioxanes and Crystal Structure of rel-2S,4S,6S-2,6- Dimethyl-4-(N′-benzylthioureido)-1,3-dioxane

ChemInform, Aug 22, 2010

Collection of Czechoslovak Chemical Communications, 2001

A complete series of 2,3-dideoxy-2,3-epimino- and 3,4-dideoxy-3,4-epimino-1,6-anhydro-β-D-hexopyr... more A complete series of 2,3-dideoxy-2,3-epimino- and 3,4-dideoxy-3,4-epimino-1,6-anhydro-β-D-hexopyranoses were prepared by lithium aluminum hydride reduction of the corresponding trans-azido tosylates or trans-azido epoxides of 1,6-anhydro-β-D-hexopyranoses. The structure of the epimino derivatives was confirmed by 1H and 13C NMR spectra.

Acta Crystallographica Section B Structural Science, Crystal Engineering and Materials, 2017

Ten new crystal structures of cis and trans bicyclic diketopiperazines (DKPs) of thia-pipecolic a... more Ten new crystal structures of cis and trans bicyclic diketopiperazines (DKPs) of thia-pipecolic acid (with sulfur in the β, γ or δ position) or thia-proline (with sulfur in the β or γ position) and N-methyl phenylalanine [(NMe)Phe]: cyclo[(β-S)Pip-(NMe)Phe], cyclo[(γ-S)Pip-(NMe)Phe], cyclo[(δ-S)Pip-(NMe)Phe], cyclo[(β-S)Pro-(NMe)Phe] and cyclo[(γ-S)Pro-(NMe)Phe] were determined with X-ray crystallography. Density functional theory calculations of these molecules in the gas phase succeed in reproducing the observed molecular conformations in the crystal remarkably well. This illustrates the weak to moderate impact of intermolecular packing forces in the absence of classical N—H...O hydrogen bonds. The effect of sulfur on the geometry of the DKP ring and details of amide bond non-planarity are discussed. Molecular flexibility of the DKP ring, as estimated from the calculated deformation energies of its endocyclic ring torsion angles, is not in general the decisive factor for the occur...

Journal of natural products, Jan 21, 2016

Venoms of hymenopteran insects have attracted considerable interest as a source of cationic antim... more Venoms of hymenopteran insects have attracted considerable interest as a source of cationic antimicrobial peptides (AMPs). In the venom of the solitary bee Hylaeus signatus (Hymenoptera: Colletidae), we identified a new hexadecapeptide of sequence Gly-Ile-Met-Ser-Ser-Leu-Met-Lys-Lys-Leu-Ala-Ala-His-Ile-Ala-Lys-NH2. Named HYL, it belongs to the category of α-helical amphipathic AMPs. HYL exhibited weak antimicrobial activity against several strains of pathogenic bacteria and moderate activity against Candida albicans, but its hemolytic activity against human red blood cells was low. We prepared a set of HYL analogues to evaluate the effects of structural modifications on its biological activity and to increase its potency against pathogenic bacteria. This produced several analogues exhibiting significantly greater activity compared to HYL against strains of both Staphylococcus aureus and Pseudomonas aeruginosa even as their hemolytic activity remained low. Studying synergism of HYL p...

Molecules (Basel, Switzerland), Jan 30, 2015

Scorzonera species are used in different folk medicines to combat many diseases, including the il... more Scorzonera species are used in different folk medicines to combat many diseases, including the illnesses connected with inflammation. Previous experiments showed anti-inflammatory activity of Scorzonera extracts in vivo. S. latifolia, S. cana var. jacquiniana, S. tomentosa, S. mollis ssp. szowitsii, S. eriophora, S. incisa, S. cinerea, and S. parviflora extracts were, therefore, evaluated for their inhibitory activities of TNF-α and IL-1β production, and NF-κB nuclear translocation in THP-1 macrophages. The HPLC analysis was carried out to elucidate and to compare the composition of these extracts. Major compounds of the tested extracts have been isolated using different chromatographic techniques and further tested for their inhibitory activities on TNF-α and IL-1β production. Several extracts showed promising anti-inflammatory activity in these in vitro tests. Results of HPLC analysis revealed chlorogenic acid as a compound present in all tested extracts. Hyperoside, quercetin-3-O...

Scientific reports, Jan 21, 2016

Insulin is a key hormone of human metabolism with major therapeutic importance for both types of ... more Insulin is a key hormone of human metabolism with major therapeutic importance for both types of diabetes. New insulin analogues with more physiological profiles and better glycemic control are needed, especially analogues that preferentially bind to the metabolic B-isoform of insulin receptor (IR-B). Here, we aimed to stabilize and modulate the receptor-compatible conformation of insulin by covalent intra-chain crosslinking within its B22-B30 segment, using the Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction of azides and alkynes. This approach resulted in 14 new, systematically crosslinked insulin analogues whose structures and functions were extensively characterized and correlated. One of the analogues, containing a B26-B29 triazole bridge, was highly active in binding to both IR isoforms, with a significant preference for IR-B. Our results demonstrate the potential of chemistry-driven modulation of insulin function, also shedding new light on the functional importanc...

Nucleic acids symposium series (2004), 2008

We have synthesized two different groups of oligonucleotides containing chiral isopolar nonisoste... more We have synthesized two different groups of oligonucleotides containing chiral isopolar nonisosteric phosphonate internucleotide linkages, and studied their properties in combination with natural phosphodiester ones. The improved synthetic procedures for the monomers preparation are also reported.

The Journal of Physical Chemistry B, 2009

The Journal of Physical Chemistry B, 2008

The L-alanyl-L-alanine (AA) molecule behaves differently in acidic, neutral, and basic environmen... more The L-alanyl-L-alanine (AA) molecule behaves differently in acidic, neutral, and basic environments. Because of its molecular flexibility and strong interaction with the aqueous environment, its behavior has to be deduced from the NMR spectra indirectly, using statistical methods and comparison with ab initio predictions of geometric and spectral parameters. In this study, chemical shifts and indirect spin-spin coupling constants of the AA cation, anion, and zwitterion were measured and compared to values obtained by density functional computations for various conformers of the dipeptide. The accuracy and sensitivity of the quantum methods to the molecular charge was also tested on the (mono)-alanine molecule. Probable AA conformers could be identified at two-dimensional potential energy surfaces and verified by the comparison of the computed parameters with measured NMR data. The results indicate that, whereas the main-chain peptide conformations of the cationic (AA +) and zwitterionic (AA ZW) forms are similar, the anion (AA-) adopts also another, approximately equally populated conformer in the aqueous solution. Additionally, the NH 2 group can rotate in the two main chain conformations of the anionic form AA-. According to a vibrational quantum analysis of the two-dimensional energy surfaces, higher-energy conformers might exist for all three charged AA forms but cannot be detected directly by NMR spectroscopy because of their small populations and short lifetimes. In accord with previous studies, the NMR parameters, particularly the indirect nuclear spin-spin coupling constants, often provided an excellent probe of a local conformation. Generalization to peptides and proteins, however, has to take into account the environment, molecular charge, and flexibility of the peptide chain.

The Journal of Physical Chemistry A, 2002

Nuclear magnetic resonance (NMR) and Raman optical activity (ROA) spectra of the cyclic dipeptide... more Nuclear magnetic resonance (NMR) and Raman optical activity (ROA) spectra of the cyclic dipeptide were measured and analyzed with respect to their ability to sense molecular structure and conformation. Data obtained by both techniques were simulated using ab initio quantum mechanical computations. Calculated chemical shifts, hydrogen-hydrogen spin-spin coupling constants and ROA intensities agreed well with the experimental values. The spin-spin NMR coupling constants were found to be most suitable for estimating of the conformational ratio. The ROA intensities provided additional information about the absolute configuration. The relation of the NMR chemical shifts to molecular structure was obscured by the solvent effect. The experimental results and calculated relative conformer energies suggest that equilibrium of three conformations takes place in the solution at the room temperature with a prevalence (∼80%) of the conformation present in the crystalline state.

Physical Chemistry Chemical Physics, 2013

The nuclear magnetic resonance (NMR) spectroscopy combined with theoretical calculations is an im... more The nuclear magnetic resonance (NMR) spectroscopy combined with theoretical calculations is an important tool for fullerene identification. However, the accuracy of available theoretical methods is often not adequate. Therefore, in this work, different computational aspects needed to simulate realistically chemical shifts in the C 70 molecule are investigated by density functional theory (DFT) calculations. The importance of the functional choice, basis set, solvent, and molecular motions was assessed. The solvent was simulated using the implicit conductor-like polarized continuum model. The molecular motions were included via anharmonic corrections and averaging of snapshots obtained from classical and first-principles molecular dynamics (MD) simulations. Comparison to experiment revealed that density functional calculations typically overestimate the 13 C NMR chemical shifts. Hybrid functionals, such as BHandH and BHandHLYP, and long-range corrected functionals, such as wB97xd and CAM-B3LYP, give the best results. While the solvent has a minor effect (chemical shift changes by B1 ppm), the vibrational and dynamical effects are surprisingly large, causing changes up to 9 ppm. Consideration of the latter was also necessary to explain the observed temperature dependence. While the dynamical corrections for MD performed in vacuum were overestimated, inclusion of the solvent in simulations provided more realistic results. The study thus points out the importance of an appropriate solvent model and a complex approach to the modelling, balancing the static, dynamic and environmental factors.

Journal of the American Chemical Society, 2005

With the aid of labeling with stable isotopes (15 N and 13 C) a complete set of chemical shifts a... more With the aid of labeling with stable isotopes (15 N and 13 C) a complete set of chemical shifts and indirect spin-spin coupling constants was obtained for the zwitterionic form of L-alanyl-L-alanine in aqueous solution. Different sensitivities of the NMR parameters to the molecular geometry were discussed on the basis of comparison with ab initio (DFT) calculated values. An adiabatic two-dimensional vibrational wave function was constructed and used for determination of the main chain torsion angle dispersions and conformational averaging of the NMR shifts and coupling constants. The quantum description of the conformational dynamics based on the density functional theory and a polarizable continuum solvent model agrees reasonably with classical molecular dynamics simulations using explicit solvent. The results consistently evidence the presence of a single form in the aqueous solution with equilibrium main chain torsion angle values (ψ) 147°,)-153°), close to that one found previously in an X-ray study. Under normal temperature the torsion angles can vary by about 10°around their equilibrium values, which leads, however, to minor corrections of the NMR parameters only. The main chain heavy atom chemical shifts and spin-spin coupling constants involving the R-carbon and hydrogen atoms appear to be most useful for the peptide structural predictions.