Peteris Trapencieris

Latvian Institute of Organic Synthesis | Latvian IOS · Department of Organic Chemistry

Resistance to β-lactam antibacterials, importantly via production of β-lactamases, threatens their widespread use. Bicyclic boronates show promise as clinically useful, dual-action inhibitors of both serine- (SBL) and metallo- (MBL) β-lactamases. In combination with cefepime, the bicyclic boronate taniborbactam is in phase 3 clinical trials for tre...

β-Lactamases comprise the most important known mode of resistance to β-lactam antibiotics. Boronic acids/boronate esters show promise as a new class of β-lactamase inhibitors with the potential to inhibit both the metallo- and serine-β-lactamases. We report studies employing representative β-lactamases concerning a bicyclic boronate ester with a th...

Rational design of pharmaceutically active small molecules is usually based on a paradigm where one small molecule targets a single protein molecule and this way exhibits its medically relevant effect. This paradigm has recently changed toward the idea that design to affect several targets instead of one can provide superior therapeutic effect. Her...

Novel pyrazole-based EZH2 inhibitors have been prepared through a molecular pruning approach from known inhibitors bearing a bicyclic moiety as a central scaffold. The hit compound 1o (N-((4,6-dimethyl-2-oxo-1,2-dihy-dropyridin-3-yl)methyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide) showed low micromolar EZH2/PRC2 inhibition and high selectivity...

The histone methyltransferase EZH2 plays a role in maintenance of the stem component of cancer, and its overexpression and/or mutation typically drives tumor aggressiveness, drug resistance and patients’ poor prognosis. In this study, we use mouse and human medulloblastoma stem-like cells belonging to the Sonic Hedgehog subgroup (SHH MB-SLCs) and d...

Carbonic anhydrase IX (CAIX) is a pH-regulating enzyme that plays a key role in maintaining an alkaline intracellular pH under hypoxic conditions. It is overexpressed in a variety of solid cancers, including breast cancer (BC), and has been implicated in the migration, invasion and stemness of breast cancer cells. Therefore, CAIX recently emerged a...

Abstract. Background: Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin’s lymphoma characterized by hyperactive neoplastic B-cells and extended tumor cell survival. Bruton’s tyrosine kinase (BTK), a crucial kinase in the B-cell antigen receptor signaling pathway, has emerged as a novel target of MCL therapy. A novel BTK-targeting inhibitor Ju...

Plasmepsin II (PMII) is one of the ten plasmepsins (PMs) identified in the genome of Plasmodium falciparum , the causative agent of the most severe and deadliest form of malaria. Owing to the emergence of P. falciparum strains that are resistant to current antimalarial agents such as chloroquine and sulfadoxine/pyrimethamine, there is a constant pr...

The study represents a comprehensive retrospective morphological and immunohistochemical profiling of pancreatic neuroendocrine neoplasms (PNENs) in order to reveal the associations between morphological and molecular parameters. The local tumour spread (T), presence of metastases in regional lymph nodes (N) and distant organs (M), tumour grade (G)...

Colorectal cancer is among the most frequent malignant tumours. Liver metastases develop in 70-75% of patients affected by colorectal carcinoma. Nowadays, surgical treatment can significantly improve the 5-year survival ranging 40-58% of the patients undergoing liver surgery. The operation extent ranges from nonanatomic minor resection to major hep...

Carbonic anhydrase IX (CAIX) is a hypoxia-inducible enzyme with extracellular catalytic domain that is overexpressed in a variety of cancers including breast cancer and plays a crucial role in maintaining favourable intracellular pH and reducing extracellular pH. The purpose of the current study was to elucidate the prognostic significance of CAIX...

A series of modified saccharin sulfonamides have been designed as carbonic anhydrase (CA) inhibitors and synthesized. Their binding to CA isoforms I, II, VII, XII, and XIII was measured by the fluorescent thermal shift assay (FTSA) and isothermal titration calorimetry (ITC). Saccharin bound the CAs weakly, exhibiting the affinities of 1-10 mM for f...

A new series of compounds containing a sulfamide moiety as zinc-binding group (ZBG) has been synthesized and tested for determining inhibitory properties against four human carbonic anhydrase (hCA) isoforms, namely, CAs I, II, IX, and XII. The X-ray structure of the cytosolic dominant isoform hCA II in complex with the best inhibitor of the series...

Acyl group migration from N to C in aziridine-2-carboxylates takes place in deprotonation reactions and, as a result, aziridine-2,2-dicarboxylates are formed. Mechanistic studies proved that the observed migration is an intramolecular reaction.

Abstract The new histone deacylases inhibitors (HDACi) were synthesized in the class of 5-membered cyclic hydroxamic acids (5-CHA), showing medium size CHA as a new Zn-binding group. New reaction sequence was proposed for the synthesis of 5-membered alkylidene-cyclic-hydroxamic acids starting from butyrolactone. Compound 10c showed low µM activity...

Antimalarial hit 1 SR (TCMDC-134674) identified in a GlaxoSmithKline cell based screening campaign was evaluated for inhibitory activity against the digestive vacuole plasmepsins (Plm I, II, and IV). It was found to be a potent Plm IV inhibitor with no selectivity over Cathepsin D. A cocrystal structure of 1 SR bound to Plm II was solved, providing...

Literature methods for the synthesis of macromonocyclic hydroxamic acids are reviewed, covering the period of the last 45 years.

O-Carbamates derived from 2-hydroxy- and 3-hydroxy-thiophenes generated o-directed carbanions, which were transformed to the corresponding methyl sulfides and methyl and trimethylsilyl substituted thiophenes. Dedicated to Professor Viktoras Snieckus, an eminent organic chemist and initiator of Balticum Organicum Syntheticum (BOS), in occasion of hi...

Abstract A novel matrix metalloproteinase-2 (MMP-2) inhibitor JaZ-30, which belongs to the class of C(2)-monosubstituted aziridine - aryl-1,2,3-triazole conjugates, was developed. MTT and crystal violet assays were used to determine cytotoxicity- IC(50) values of compound JaZ-30 on melanoma cell line B16 4A5. Our study proves the anti-cancer proper...

A series of (aryltriazolyl)methylaziridines was synthesized and evaluated as selective inhibitors of matrix metalloproteinase-2. They constitute a novel class of hydroxamic acid-free matrix metalloproteinase inhibitors. The triazole fragment serves as a linker between the hydrophilic aziridine and the lipophilic part of the molecule. The best inhib...

A general and reproducible protocol for preparation of the title compounds is developed with a view to studies on novel carbonic anhydrase inhibitors.

An improved method for the preparation of 6-sulfamoylsaccharin (3-oxo-2,3-dihydro-1,2-benzo-thiazole-6-sulfonamide 1,1-dioxide) has been developed and studies of its possible direct alkylation have been carried out. It was shown that alkylation occurs regioselectively at the isothiazoline ring nitrogen atom.

Literature methods for synthesis of small and medium size monocyclic hydroxamic acids are reviewed, covering the last 30 years.

A simple and reproducible procedure for the synthesis of bioisosteres of coumarin—1,2-benzoxathiine 2,2-dioxide is presented. The developed method is based on the intramolecular aldol cyclization of derivatives of mesylsalicyl aldehydes in the presence of strong organic bases, where best results were obtained with 1,8-diazabicyclo[5.4.0]undec-7-ene...

2-Substituted 3-chlorobenzaldehydes were prepared from the corresponding 2-(3-chlorophenyl)-1,3-dioxolanes using an ortho-lithiation strategy. The 6-chloro-2-formylbenzamide exists only in a ring form, but 6-chloro-2-formylbenzoic acid esters were isolated in both forms as open chain and cyclic tautomers. 7-Chloro-3-hydroxy-3H-isobenzofuran-1-one r...

Using the reaction of diaziridine-3,3-dicarboxylic acid dihydrazide with acetone, new bicyclic diaziridines 7a,b have been obtained instead of expected tricyclic heterocycle 8.

Rat Serum Carboxylesterase Partly Hydrolyses Gamma-Butyrobetaine Esters Although described some time ago, gamma-butyrobetaine esters and related compounds have not gained much attention from researchers, and their physiological function remains obscure. Formerly we detected GBB-esterase enzymatic activity in rat blood serum using phenylated gamma-b...

[872-50-4] C5H9NO (MW 99.15) InChI = 1S/C5H9NO/c1-6-4-2-3-5(6)7/h2-4H2,1H3InChIKey = SECXISVLQFMRJM-UHFFFAOYSA-N(special solvent;1 source of enolates2)Alternate Names: NMP; N-methylpyrrolidone.Physical Data: mp −24.4 °C; bp 202 °C; d 1.030 g cm−3.Solubility: completely misc H2O and virtually all organic solvents.Form Supplied in: colorless liquid.D...

Although described some time ago, gamma-butyrobetaine esters and related compounds have not gained much attention from researchers, and their physiological function remains obscure. Formerly we detected GBB-esterase enzymatic activity in rat blood serum using phenylated gamma-butyrobetaine as an artificial substrate of the enzyme and HPLC. The aim...

A series of N-substituted amides and esters of aziridine-2-carboxylic acids have been prepared and have been subjected to deprotonation with lithium diisopropylamide. The intermediate carbanions reacted more readily with the carbonyl groups of the substrates than with methyl iodide. So, in place of the expected amides or esters of methylaziridine-2...

THE IDEA ABOUT EXISTENCE OF an electron transfer system outside the nervous system arises from simple consideration that if the signal transfer from nerve fibres to organs is of electric nature, a recurrent flow of electrons from effector cells to nervous system should exist in order to form a closed electric circuit. Several lines of scientific co...

A series of N-unsubstituted esters of aziridine-2-carboxylic acid has been obtained by transesterification in basic medium using primary, secondary, and tertiary alcohols. Methods of transesterification using various bases (K2CO3, ROLi, t-BuOK) have been compared. Transesterification with lithium alcoholates also affords the possibility of obtainin...

This paper describes the synthesis of the biologically important indole scaffold by using the Nenitzescu reaction. The scope and limitation of the reaction is investigated by multivariate methods where concentration, ratio of substrate and reactant, solvent, temperature and time are varied in a systematic way. The present investigation is the first...

[151-56-4] C2H5N (MW 43.08) InChI = 1S/C2H5N/c1-2-3-1/h3H,1-2H2InChIKey = NOWKCMXCCJGMRR-UHFFFAOYSA-N(aminoalkylating agent1)Alternate Name: aziridinePhysical Data: mp −74 °C; bp 56.7 °C; d 0.829 g cm−3.Solubility: miscible with H2O and virtually all organic solvents.Form Supplied in: colorless liquid.Handling, Storage, and Precautions: highly toxi...

[54080-06-7] C3H5NO2 (MW 87.08) InChI = 1S/C3H5NO2/c5-3(6)2-1-4-2/h2,4H,1H2,(H,5,6)InChIKey = WBGBOXYJYPVLQJ-UHFFFAOYSA-N(building block for chiral amino acids;2 can be used for synthesis of heterocycles3)Physical Data: Li salt: mp 260–268 °C; methyl ester: bp 68 °C/11 mmHg; n20D 1.440; nitrile: bp 38 °C/0.1 mmHg; n20D 1.475; amide: mp 132–133 °C.S...

A new method for the preparation of 5beta-cholestan-26-oic acids 7 and their analogs is described. The key steps in the synthesis are: iodination of bis- and tris-formyloxy-5beta-cholan-24-ols 3; nucleophilic substitution of iodides 4 with diethyl sodiomalonate; complete alkaline hydrolysis of esters 5; and subsequent decarboxylation of geminal dia...

1-Aniline-substituted 3,4-dihydroisoquinolines were obtained in various ways using the Bischler-Napieralski reaction. The effect of the protecting group at the aniline nitrogen atom on the course of the reaction has been studied and it was found that the N-phthalyl group was stable under the cyclization conditions. The dihydroisoquinolines were red...

A new method for the preparation of 5β-cholestan-26-oic acids 7 and their analogs is described. The key steps in the synthesis are: iodination of bis- and tris-formyloxy-5β-cholan-24-ols 3; nucleophilic substitution of iodides 4 with diethyl sodiomalonate; complete alkaline hydrolysis of esters 5; and subsequent decarboxylation of geminal diacids 6...

Bicycle (±)-1 crystallises as a conglomerate (space group P21) and undergoes spontaneous resolution on crystallisation from chloroform or acetone (16–44% ee). The absolute configuration (S)-(–)-1 was determined by synthesis from (S)-Ser-OMe; mutarotation due to the partial conversion of 1 into the corresponding isopropylidene 4 was observed in MeOH...

Transfer hydrogenation using the Noyori catalyst 5-Ts is effective for the enantioselective hydrogenation of imines containing fully substituted nitrogen groups (12 or 13). Analogues such as 11c could not be reduced in practical yield, apparently due to product inhibition of the catalyst. Asymmetric transfer hydrogenation of the aniline imine 8a wa...

The methodology of aziridine-2-carboxylic acid methyl ester (4) synthesis by aziridine ring formation from methyl 3-(2,2,2-trimethylhydrazinio)propionate bromide (1a) has been developed by N−N bond cleavage. The process gives the title compound in 75% theoretical yield (>99% purity). We found important factors for a successful key reaction, includi...

The methodology of aziridine-2-carboxylic acid methyl ester (4) synthesis by aziridine ring formation from methyl 3-(2,2,2-trimethylhydrazinio)propionate bromide (1a) has been developed by N-N bond cleavage. The process gives the title compound in 75% theoretical yield (>99% purity). We found important factors for a successful key reaction, includi...

Betaines derived from α-, β- and γ-amino acids (obtained by alkylation of the corresponding amino acids with O-methyl-N.N'- diisopropylisourea) as well as β-hydrazino acids (prepared by de- hydrohalogenative hydrolysis of methyl 3-(2-a1ky1-2,2-dimethy1hydrazinium) propionate halides catalyse typical phase transfer reactions (dichlorocyclopropanatio...