Mojmír Suchý

A Remarkably Simple Protocol for the N-Formylation of Amino Acid Esters and Primary Amines

A simple, convenient, and wide scope protocol for the N-formylation of amino acid esters and primary amines has been developed utilizing only imidazole in warm DMF.

Simultaneous in vivo pH and temperature mapping using a PARACEST‐MRI contrast agent

Altered tissue temperature and/or pH is a common feature in pathological conditions, where metabolic demand exceeds oxygen supply such as in tumors and following stroke. Therefore, in vivo tissue temperature and pH may become valuable biomarkers for disease detection and the monitoring of disease progression or treatment response in conditions with altered metabolic demand. In this study, pH is measured using the amide protons of a thulium (Tm3+) complex with a DOTAM‐Glycine‐Lysine (ligand: Tm3+‐DOTAM‐Gly‐Lys). The pH was uniquely determined from the linewidth of the asymmetry curve of the chemical exchange saturation transfer spectrum, independent of contrast agent concentration, or temperature for a given saturation pulse. pH maps with an inter‐pixel standard deviation of less than 0.1 pH units were obtained in 10 mM Tm3+‐DOTAM‐Gly‐Lys solutions with pH ranging from 6.0 to 8.0 pH units at 37°C. Temperature maps were simultaneously obtained using the chemical shift of the chemical exchange saturation transfer peak. Temperature and pH maps are demonstrated in the mouse leg (N = 3), where the mean and standard deviation for pH was 7.2 ± 0.2 pH unit and temperature was 37.4 ± 0.5°C. Magn Reson Med, 70:1016–1025, 2013.

Spirocyclization strategy toward indole phytoalexins. The first synthesis of (′)-1-methoxyspirobrassinin, (′)-1-methoxyspirobrassinol, and (′)-1-methoxyspirobrassinol methyl ether

Abstract The first syntheses of cruciferous indole phytoalexins (±)-1-methoxyspirobrassinin, (±)-1-methoxyspirobrassinol, (±)-1-methoxyspirobrassinol methyl ether as well as a new syntheses of phytoalexins (±)-spirobrassinin and cyclobrassinin were achieved by dioxane dibromide (DDB)-mediated spirocyclization of brassinin and its 1-substituted derivatives.

A paramagnetic chemical exchange-based MRI probe metabolized by cathepsin D: design, synthesis and cellular uptake studies.

Overexpression of the aspartyl protease cathepsin D is associated with certain cancers and Alzheimers disease; thus, it is a potentially useful imaging biomarker for disease. A dual fluorescence/MRI probe for the potential detection of localized cathepsin D activity has been synthesized. The probe design includes both MRI and optical reporter groups connected to a cell penetrating peptide by a cathepsin D cleavable sequence. This design results in the selective intracellular deposition (determined fluorimetrically) of the MRI and optical reporter groups in the presence of overexpressed cathepsin D. The probe also provided clearly detectable in vitro MRI contrast by the mechanism of paramagnetic chemical exchange effects (OPARACHEE).

Analogs of Eu3+ DOTAM-Gly-Phe-OH and Tm3+ DOTAM-Gly-Lys-OH: Synthesis and magnetic properties of potential PARACEST MRI contrast agents

Chelated lanthanide ions, especially gadolinium, have found wide use as contrast agents in magnetic resonance imaging. A new paradigm for generating contrast, termed PARACEST, was recently described that requires the slow exchange of water or other exchangeable protons present in the ligand framework. In previous work, we have described a synthetic method for the preparation of dipeptide conjugates of DOTAM for use as PARACEST agents. Two compounds possessed interesting magnetic properties: the Eu(3+) complex of DOTAM-Gly-Phe-OH and the Tm(3+) complex of DOTAM-Gly-Lys-OH. To understand the relationship between the structure of these complexes and their magnetic properties, we have expanded our synthetic methodology and prepared several new complexes. Ligands have been prepared in which the terminal phenylalanine moieties have been replaced with tryptophan or tyrosine, the distance to the amino acid residue possessing an alpha-substituent has been changed, or phenylalanine and lysine have been combined in the peptide sequence. The preparation of lanthanide(III) complexes of these ligands has been achieved and their PARACEST properties have been determined.

In vivo detection of PARACEST agents with relaxation correction

Several pulse sequences have been used to detect paramagnetic chemical exchange saturation transfer (PARACEST) contrast agents in animals to quantify the uptake over time following a bolus injection. The observed signal change is a combination of relaxation effects and PARACEST contrast. The purpose of the current study was to isolate the PARACEST effect from the changes in bulk water relaxation induced by the PARACEST agent in vivo for the fast low‐angle shot pulse sequence. A fast low‐angle shot–based pulse sequence was used to acquire continuous images on a 9.4‐T MRI of phantoms and the kidneys of mice following PARACEST agent (Tm3+‐DOTAM‐Gly‐Lys) injection. A WALTZ‐16 pulse was applied before every second image to generate on‐resonance paramagnetic chemical exchange effects. Signal intensity changes of up to 50% were observed in the mouse kidney in the control images (without a WALTZ‐16 preparation pulse) due to altered bulk water relaxation induced by the PARACEST agent. Despite these changes, a clear on‐resonance paramagnetic chemical exchange effect of 4‐7% was also observed. A four‐pool exchange model was used to describe image signal intensity. This study demonstrates that in vivo on‐resonance paramagnetic chemical exchange effect contrast can be isolated from tissue relaxation time constant changes induced by a PARACEST agent that dominate the signal change. Magn Reson Med 63:1184–1192, 2010.

Pyrimidine-fused heterocyclic frameworks based on an N4-arylcytosine scaffold: synthesis, characterization, and PNA oligomerization of the fluorescent cytosine analogue 5,6-benzopC.

A synthesis of an intrinsically fluorescent cytosine analogue 5,6-benzopC has been developed utilizing the reductive Ni-mediated cyclization of an N4-aryl,N4-(Boc)cytosine intermediate as a key step. 5,6-BenzopC was found to possess interesting fluorescence properties (Φ = 0.79, EtOH; Stokes shift 113 nm). Peptide nucleic acid (PNA) oligomerization of the 5,6-benzopC monomer was carried out, followed by hybridization studies with complementary deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) which showed the modification to be well tolerated in the sequence contexts examined. Initial attempts to synthesize the heterocyclic skeleton present in 5,6-benzopC resulted in the discovery of routes to the pyrimido[1,6-a]benzimidazole, pyrimido[1,6-a]quinazoline, and pyrimido[1,6-a]benzo[b]6-bora-1,3-diazine heterocyclic frameworks.

A new approach to the synthesis of rare thiazino[6,5-b]indol-4-one derivatives. First total synthesis of the indole phytoalexin cyclobrassinon

Abstract The first synthesis of the indole phytoalexin cyclobrassinon and some of its analogues, possessing a thiazino[6,5- b ]indol-4-one tricyclic ring system was performed starting from 1-substitued 2-chloroindole-3-carboxaldehydes. The route employed the intramolecular Et 3 N-mediated or photochemical nucleophilic substitution of a chlorine atom in the 2-position of the indole ring with a sulfur atom as a key step. Examination of biological activity against the selected tumor cell lines, bacteria and fungi revealed no expressive activity of synthesized compounds.

“Click” chemistry toward bis(DOTA-derived) heterometallic complexes: potential bimodal MRI/PET(SPECT) molecular imaging probes

A general synthetic methodology has been developed for the preparation of DOTA-derived heterometallic omplexes as potential bimodal MRI/PET(SPECT) molecular probes. Both alkyne- and azide substituted DOTA-derived chelators have been synthesized and metallated with Gd3+ (MRI reporter) or “cold” isotopes of Cu2+, Ga3+ and In3+ (potential PET or SPECT reporters). The Cu+-catalyzed Huisgen [3 + 2] cycloaddition has been utilized as a key step in the synthesis of potential bimodal MRI/PET(SPECT) molecular probes. A preliminary optimization of the reaction conditions has been carried out to make the reaction conditions compatible with the radioactive isotopes of Cu2+, Ga3+ and In3+ possessing short life times. The MRI sensitivity of the potential bimodal MRI/PET(SPECT) molecular probes has been determined and compared to that associated with a clinically used MRI contrast agent.

A DOTAM-based paraCEST agent favoring TSAP geometry for enhanced amide proton chemical shift dispersion and temperature sensitivity.

The Tm(3+) chelate of DOTAM [1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane] possessing sterically demanding t-butyl amide substitution favors TSAP geometry. This chelate displayed a paraCEST signal associated with the highly shifted amide proton signal at approximately -100 ppm that was beyond the frequency of macromolecule magnetization transfer. This signal also displayed high temperature dependence (0.57 ppm °C(-1)) in the range of 35-42 °C and at neutral pH.