Structure of putative tumor suppressor ALDH1L1

Putative tumor suppressor ALDH1L1, the product of natural fusion of three unrelated genes, regulates folate metabolism by catalyzing NADP+-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO2. Cryo-EM structures of tetrameric rat ALDH1L1 revealed the architecture and functional domain interactions of this complex enzyme. Highly mobile N-terminal domains, which remove formyl from 10-formyltetrahydrofolate, undergo multiple transient inter-domain interactions. The C-terminal aldehyde dehydrogenase domains, which convert formyl to CO2, form unusually large interfaces with the intermediate domains, homologs of acyl/peptidyl carrier proteins (A/PCPs), which transfer the formyl group between the catalytic domains. The 4′-phosphopantetheine arm of the intermediate domain is fully extended and reaches deep into the catalytic pocket of the C-terminal domain. Remarkably, the tetrameric state of ALDH1L1 is indispensable for catalysis because the intermediate domain transfers formyl between the catalytic domains of different protomers. These findings emphasize the versatility of A/PCPs in complex, highly dynamic enzymatic systems.

Synthesis of [1,4]Oxathiepino[5,6-b]quinolines via Base-Mediated Intramolecular Hydroalkoxylation

A base-mediated intramolecular hydroalkoxylation that was used to prepare a series of seven-membered S,O-heterocycles is described. 2-Thiopropargyl-3-hydroxymethyl quinolines were prepared starting from 2-mercaptoquinoline-3-carbaldehydes, via S-propargylation and reduction of a formyl group. Interestingly, 2-mercaptopropargyl-3-hydroxymethyl quinolines were converted into the corresponding oxathiepinoquinolines in the presence of t-BuOK. It is proposed that the S-propargyl moiety, in the presence of base, is converted into its allenyl isomer; subsequent addition of a hydroxyl group to the terminal double bond yields the 3-methyl-5H-[1,4]oxathiepino[5,6-b]quinoline in good to high yield. Notably, the procedure is adaptable to the conversion of N-propargyl indole-2-methanol into the corresponding intramolecular hydroalkoxylation product.

Kinetic control of nascent protein biogenesis by peptide deformylase

Synthesis of bacterial proteins on the ribosome starts with a formylated methionine. Removal of the N-terminal formyl group is essential and is carried out by peptide deformylase (PDF). Deformylation occurs co-translationally, shortly after the nascent-chain emerges from the ribosomal exit tunnel, and is necessary to allow for further N-terminal processing. Here we describe the kinetic mechanism of deformylation by PDF of ribosome-bound nascent-chains and show that PDF binding to and dissociation from ribosomes is rapid, allowing for efficient scanning of formylated substrates in the cell. The rate-limiting step in the PDF mechanism is a conformational rearrangement of the nascent-chain that takes place after cleavage of the formyl group. Under conditions of ongoing translation, the nascent-chain is deformylated rapidly as soon as it becomes accessible to PDF. Following deformylation, the enzyme is slow in releasing the deformylated nascent-chain, thereby delaying further processing and potentially acting as an early chaperone that protects short nascent chains before they reach a length sufficient to recruit other protein biogenesis factors.

3-(3-Hydroxypropyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxaldehyde Methyl Hemiacetal

The synthesis of 3-(3-hydroxypropyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxaldehyde as a stable methyl hemiacetal through a convenient 3-step procedure is reported. The molecule is multifunctional as it contains a formyl group, a hydroxyl group and the imide moiety. Each of these groups can play a role in specific transformations or uses.

Stereochemical Effect of the Small Ring Unit in 7-R-3,4-Cyclopropano- and 7-R-3,4-Epoxy-bicyclo[4.2.0]octan-1,5-Dienes on Conrotatory Ring Opening Torquoselectivity

Application of the differential activation energy approach suggests that the strong inward opening tendency of the formyl group in 3,4-cyclopropano-7-formyl-bicyclo[4.2.0]octan-1,5-diene and also 3,4-epoxy-7-formyl-bicyclo[4.2.0]octan-1,5-diene is either counter balanced to a level that the reaction turns torquo-neutral or it rotates outward, depending upon the stereo-relationship of the small ring unit with the formyl substituent. The NBO interaction approach, however, predicts inward selectivity throughout. These molecules, therefore, can be used as excellent test examples to judge the validity of one approach over the other.

Stereochemical Effect of the Small Ring Unit in 7-R-3,4-Cyclopropano- and 7-R-3,4-Epoxy-bicyclo[4.2.0]octan-1,5-Dienes on Conrotatory Ring Opening Torquoselectivity

Application of the differential activation energy approach suggests that the strong inward opening tendency of the formyl group in 3,4-cyclopropano-7-formyl-bicyclo[4.2.0]octan-1,5-diene and also 3,4-epoxy-7-formyl-bicyclo[4.2.0]octan-1,5-diene is either counter balanced to a level that the reaction turns torquo-neutral or it rotates outward, depending upon the stereo-relationship of the small ring unit with the formyl substituent. The NBO interaction approach, however, predicts inward selectivity throughout. These molecules, therefore, can be used as excellent test examples to judge the validity of one approach over the other.

Ratiometric Near-Infrared Fluorescent Probes Based on Hemicyanine Dyes Bearing Dithioacetal and Formal Residues for pH Detection in Mitochondria

Ratiometric near-infrared fluorescent probes (AH+ and BH+) have been prepared for pH determination in mitochondria by attaching dithioacetal and formal residues onto a hemicyanine dye. The reactive formyl group on probe BH+ allows for retention inside mitochondria as it can react with a protein primary amine residue to form an imine under slightly basic pH 8.0. Probes AH+ and BH+ display ratiometric fluorescent responses to pH changes through the protonation and deprotonaton of a hydroxy group in hemicyanine dyes with experimentally determined pKa values of 6.85 and 6.49, respectively. Calculated pKa values from a variety of theoretical methods indicated that the SMDBONDI method of accounting for solvent and van der Waals radii plus including a water molecule located near the site of protonation produced the closest overall agreement with the experimental values at 7.33 and 6.14 for AH+ and BH+ respectively.

Synthesis, molecular and crystalline structure of 8-formylharmine

For the first time, synthesis of 8-formylharmine by the Vilsmeier reaction was carried out. 8-Formylharmine was obtained by treating alkaloid harmine with dichloromethoxymethane in the presence of SnCl4.The yield of the target product was 64 %. The structure of the obtained compound was established on the basis of 1H and 13C NMR spectroscopy as well as mass-spectrometry data. The crystalline structure of 8-formylharmine was determined by X-ray diffraction. It has been shown that the replacement of the hydrogen atom in the harmine molecule with a formyl group occurs at the C8 atom. It was revealed that the methoxy group at the C7 atom changes its orientation to the opposite one as compared to the orientation in the harmine molecule and its salts due to the mutual Van der Waals repulsion of the methoxy and formyl groups. A weak intramolecular hydrogen bond was found in the crystal between the O2 atom of the formyl group and the hydrogen atom of the secondary amino group. It was shown that molecules in the crystal form an intermolecular hydrogen bond between the same atoms (О2 and НN9A), as a result of which dimers are formed.

Synthesis and Influence of 3-Amino Benzoxaboroles Structure on Their Activity against Candida albicans

Benzoxaboroles emerged recently as molecules of high medicinal potential with Kerydin® (Tavaborole) and Eucrisa® (Crisaborole) currently in clinical practice as antifungal and anti-inflammatory drugs, respectively. Over a dozen of 3-amino benzoxaboroles, including Tavaborole’s derivatives, have been synthetized and characterized in terms of their activity against Candida albicans as a model pathogenic fungus. The studied compounds broaden considerably the structural diversity of reported benzoxaboroles, enabling determination of the influence of the introduction of a heterocyclic amine, a fluorine substituent as well as the formyl group on antifungal activity of those compounds. The determined zones of the growth inhibition of examined microorganism indicate high diffusion of majority of the studied compounds within the applied media as well as their reasonable activity. The Minimum Inhibitory Concentration (MIC) values show that the introduction of an amine substituent in position “3” of the benzoxaborole heterocyclic ring results in a considerable drop in activity in comparison with Tavaborole (AN2690) as well as unsubstituted benzoxaborole (AN2679). In all studied cases the presence of a fluorine substituent at position para to the boron atom results in lower MIC values (higher activity). Interestingly, introduction of a fluorine substituent in the more distant piperazine phenyl ring does not influence MIC values. As determined by X-ray studies, introduction of a formyl group in proximity of the boron atom results in a considerable change of the boronic group geometry. The presence of a formyl group next to the benzoxaborole unit is also detrimental for activity against Candida albicans.