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Diversity-oriented synthesis (DOS) is a rich source for novel lead structures in Medicinal Chemistry. In this study, we present a DOS-compatible method for synthesis of compounds bearing a free thiol moiety. The procedure relies on Rh(II)-catalyzed coupling of dithiols to diazo building blocks. The synthetized library was probed against metallo-β-lactamases (MBLs) NDM-1 and VIM-1. Biochemical and biological evaluation led to identification of novel potent MBL inhibitors with antibiotic adjuvant activity.

Examples of the use of α-diazocarbonyl compounds in the N–H insertion reactions with the formation of the products of selective N-alkylation of various five-membered nitrogen heterocycles and their derivatives are considered. The literature data is systematized according to the number of N atoms in the heterocycle. The review contains information published in the period from 2003 to 2020.

N-Alkyl a-diazo-g-butyrolactams previously found to be unstable and undergo unproductive dimerization to bis-hydrazones, were successfully converted immediately to various X-H insertion products with alcohols, aromatic amines and thiols via an in situ RhII-catalyzed reaction. With aliphatic amines or unreactive, sterically hindered anilines, the reaction tends to yield enamine adducts.

The only cyclic α-diazocarbonyl compound employed in the Büchner–Curtius–Schlotterbeck ring expansion of cyclic ketones to date was α-diazo-γ-butyrolactone. Encouraged by the recent success using α-diazo acetamides in related Tiffeneau–Demjanov type ring expansions, we extended this approach to various α-diazo-γ-butyrolactams, which produced, under BF3·OEt2-promoted conditions, spirocyclic seven-membered ketones. These findings substantially enhance the possibilities offered by cyclic α-diazocarbonyl compounds in constructing privileged spirocyclic scaffolds for drug design.

To expand the chemical toolkit for targeted protein degradation, we report the generation of a new series of non-thalidomide Cereblon (CRBN) ligands. Readily available 2-methylidene glutarimide was converted to a series of 2-((hetero)aryl(methyl))thio glutarimides via the thio-Michael addition reaction. The compounds thus synthesized were evaluated for their affinity to the thalidomide-binding domain of human CRBN and their binding modes studied via X-ray crystallography. This helped identify several promising glutarimide derivatives which bind stronger to CRBN compared to thalidomide and contain a functional group which permits further chemical conjugation. Oxidation of the sulfur atom in a select group of 2-((hetero)aryl(methyl))thio glutarimides produced the respective sulfones which were found to possess a markedly stronger antiproliferative profile against multiple myeloma cell lines and a sophisticated structural binding mode with additional hydrogen bonding interactions. The newly identified Cereblon ligands form the basis for the synthesis of novel PROTAC protein degraders.

The cycloaddition reactions of α-diazo-β-ketosulfones and α-diazo-β-ketophosphonates with various dipolarophiles are considered.

Three novel template bis-bidentate ligands based on {3,6-di(thien-2-yl)pyridazine} skeleton and four binuclear Pt(II) complexes containing these metalating templates were synthesized and characterized including photophysical study of two emissive compounds. These complexes display phosphorescence from triplet excited state localized primarily at the thienyl-pyridazine aromatic system, the emission bands being unusually strong shifted (ca. 100 nm/4380 cm−1) to the NIR region compared to analogous phenyl-pyridazine complexes. The absorption and emission characteristics of the complexes were analyzed by using DFT and TD DFT calculations. The results of calculations confirm that emission originates from a mixture of 3LC, 3MLCT, 3LLCT with major contribution of the former excited state and show reasonable agreement with the experimental data.

Diversity-oriented synthesis (DOS) is a rich source for novel lead structures in Medicinal Chemistry. In this study, we present a DOS-compatible method for synthesis of compounds bearing a free thiol moiety. The procedure relies on Rh(II)-catalyzed coupling of dithiols to diazo building blocks. The synthetized library was probed against metallo-β-lactamases (MBLs) NDM-1 and VIM-1. Biochemical and biological evaluation led to identification of novel potent MBL inhibitors with antibiotic adjuvant activity.

Currently, available glioblastoma (GBM) treatment remains ineffective, with relapse after initial response and low survival rate of GBM patients. The reasons behind limited capacities for GBM treatment are high tumor heterogeneity, invasiveness, and occurrence of drug resistance. Therefore, developing novel therapeutic strategies is of utmost importance. Thioredoxin reductase (TrxR) is a novel, promising target due to its overexpression in many cancer types and important role in cancer progression. Previous research on Ugi-type Michael acceptors-inhibitors of TrxR showed desirable anticancer properties, with significant selectivity toward cancer cells. Herein, two TrxR inhibitors, 5 and 6, underwent in-depth study on multidrug-resistant (MDR) glioma cell lines. Besides the antioxidative effects, 5 and 6 induced cell death, decreased cell proliferation, and suppressed invasion and migration of glioma cells. Both compounds showed a synergistic effect in combination with temozolomide (TMZ), a first-line chemotherapeutic for GBM treatment. Moreover, 5 and 6 affected activity of P-glycoprotein extrusion pump that could be found in cancer cells and in the blood-brain barrier (BBB), thus showing potential for suppressing MDR phenotype in cancer cells and evading BBB. In conclusion, investigated TrxR inhibitors are effective anticancer compounds, acting through inhibition of the thioredoxin system and perturbation of antioxidative defense systems of glioma cells. They are suitable for combining with other chemotherapeutics, able to surpass the BBB and overcome MDR. Thus, our findings suggest further exploration of Ugi-type Michael acceptors-TrxR inhibitors' potential as an adjuvant therapy for GBM treatment.

Two NIR emitting platinum [Pt(N^N^C)(phosphine)] and iridium [Ir(N^C)2(N^N)]+, complexes containing reactive succinimide groups were synthesized and characterized with spectroscopic methods (N^N^C ...

A hypothesis that simultaneous targeting cancer-related carbonic anhydrase hCA IX and hCA XII isoforms (whose overexpression is a cancer cell’s defence mechanism against hypoxia) along with thioredoxin reductase (overexpressed in cancers as a defence against oxidative stress) may lead to synergistic antiproliferative effects was confirmed by testing combinations of the two inhibitor classes against pancreatic cancer cells (PANC-1). Combining both pharmacophoric motifs within one molecule led to a sharp increase of cytotoxicity. This preliminary observation sets the ground for a fundamentally new approach to anticancer agent design., Graphical Abstract

Albumins are very promising carrier family for various types of small functional molecules, including (pro)drugs, sensors, and imaging agents. In this study, we demonstrate that one of the most crucial features of albumin—its ability to internalize into cancer cells—is strongly affected by its aggregation state. We used 14 different luminescent complexes (polynuclear heterometallic Ag(I)-Au(I) and Cu(I)-Au(I) clusters and a series of mononuclear water-soluble and hydrophobic Pt(II) complexes) able to form either covalent conjugates or non-covalent adducts with human serum albumin (HSA) to investigate the impact of preparation conditions on aggregation behavior of HSA. We demonstrated that preparation of non-aggregated HSA-based conjugates/adducts requires compliance with rather strict reaction conditions (aqueous solution with as low as possible organic co-solvent content and complex/HSA molar ratio not exceeding some critical value) while bypassing these rules (e.g., using the reaction mixtures enriched by organic solvent, high complex/HSA molar ratio or bulky hydrophobic molecules) may lead to HSA aggregation or even instability of the conjugates in solution. Further, we showed that non-aggregated HSA conjugates with water-soluble Pt complex easily internalize into cancer HeLa cells, while fully aggregated non-covalent HSA adducts with heterometallic Cu-Au clusters do not. Ultimately, in this study, we put forward two major points. First, we formulate general rules providing simple preparation route for non-aggregated cell-penetrable HSA-based conjugates, particularly, phosphorescent probes. Second, we demonstrate that the aggregation state of albumin is a very important parameter, which should be controlled while preparing its conjugates.

Seven novel binuclear Pt(II) metalated complexes based on substituted 3,6-diphenylpyridazines have been synthesized and structurally characterized using XRD crystallography, NMR spectroscopy and HR ESI mass-spectrometry. Three of these complexes contain two {Pt(CˆN)} metalated fragments located at diphenylpyridazine, the square-planar environment at platinum centres are completed with two terminal and one bridging chloride ligands. Substitution of terminal chlorides for various phosphines gave another group of complexes, which keep intact the metalated moieties and bridging chloride to form essentially similar structural motif. The compounds obtained display relatively weak green-orange phosphorescence in organic solvents with the quantum yield ranging from 1.0 to 3.4% in degassed solution. The experimental photophysical data and results of TDDFT calculations indicate that the observed emission occurs from the excited states of the mixed IL/MLCT nature, the contribution of the former dominates in chloride complexes, whereas in the phosphine derivatives the MLCT component of the emissive state shows considerable growth without visible variations in emission energy.

A series of peptidomimetic compounds incorporating an electrophilic moiety was synthesized using the Ugi reaction. These compounds (termed the Ugi Michael acceptors or UMAs) were designed to target the selenocysteine catalytic residue of thioredoxin reductase 1 (TrxR1), a promising cancer target. The compounds were assessed for their potential to inhibit TrxR1 using human neuroblastoma (SH-SY5Y) cell lysate. Based on this initial screening, six compounds were selected for testing against recombinant rat TrxR1 and in the insulin assay to reveal low-micromolar to submicromolar potency of these inhibitors. The same frontrunner compounds were evaluated for their ability to exert antiproliferative activity and induce cell death and this activity was compared to the UMA effects on the levels of reactive oxygen and nitrogen species (RONS). Collectively, the UMA compounds class presented itself as a rich source of leads for TrxR1 inhibitor discovery for anticancer application. Compound 7 (DVD-445) was nominated a lead for further optimization. © 2019 Elsevier Masson SAS

Spirocycles represent an emerging class of privileged motifs for drug discovery. The versatility of diazo compounds in constructing cyclic frameworks in general makes cyclic diazo compounds a potentially highly prolific source of spirocyclic scaffolds. While the first examples of obtaining a spirocycle from a cyclic diazo compound are dated as far back as 42 years ago, there appears to be a resurgence of novel methodologies based on this premise. The present Digest Article aims to cover the literature on the subject to-date.

In the present work we obtained a series of NIR luminescent platinum(II) complexes with a pincer N^N^C ligand based on the conjugated {benzoimidazo[1,2-a]pyrazine} system with the [Pt(N^N^C)L]n+ structural motif (L = phosphine, alkynyl or pyridine-type ligands). We have also synthesized two complexes with bidentate phosphines that demonstrate different types of coordination: 1) as chelating ligand (in case of 1,2-bis(diphenylphosphino)benzene), that led to de-coordination of pyridine ring of N^N^C ligand and formation of a [Pt(N^C)dppb]+ complex; 2) as a bridging ligand (in case of bis(diphenylphosphino)methane) between two {Pt(N^N^C)} fragments in a dimeric complex of type [{Pt(N^N^C)}2dppm]2+. The complexes obtained were fully characterized using spectroscopic methods, and their ground-state structures and photophysical properties were studied by DFT and TD DFT methods. According to the data obtained the aromatic {benzoimidazo[1,2-a]pyrazine} fragment plays a key role in the photophysics of this type of complexes and the triplet 3LC state located at the N^N^C ligand proved to be the only emissive state in all the complexes prepared. Unexpectedly variations in the nature of the ligands occupying the fourth coordination position in the square-planar structural motif, changes in the mode of the N^N^C ligand coordination and even the Pt-Pt bond formation did not result in significant variations of the emission profile. The photophysical behavior of these complexes has been analyzed using DFT calculations, which are in complete agreement with the experimental data and confirmed that the lowest relaxed triplet configuration responsible for the phosphorescence in the complexes studied is located at the N^N^C ligand.

A series of analogs of the earlier reported lead compound DVD-445 (thioredoxin reductase inhibitor with anticancer activity) has been synthesized via a modified Ugi reaction and investigated. Seven most potent compounds (with IC50 below 5.00 μM against recombinant rTrxR1 enzyme) were examined for their effect on cell growth and viability, oxidative stress induction and P-glycoprotein (P-gp) inhibition in human glioblastoma cells cell line U87 and its corresponding multidrug resistant (MDR) cell line U87-TxR. Several of these frontrunner compounds were shown to be superior over DVD-445. Besides providing promising candidates for anticancer therapy, our study further validates the small electrophilic Ugi Michael acceptor (UMA) chemotype as efficacious inhibitor of thioredoxin reductase.

The growing attention to the luminescent nanocarriers is strongly stimulated by their potential application as drug delivery systems and by the necessity to monitor their distribution in cells and tissues. In this communication we report on the synthesis of amphiphilic polypeptides bearing C-terminal phosphorescent label together with preparation of nanoparticles using the polypeptides obtained. The approach suggested is based on a unique and highly technological process where the new phosphorescent Pt-cysteine complex serves as initiator of the ring-opening polymerization of α-amino acid N-carboxyanhydrides to obtain the polypeptides bearing intact the platinum chromophore covalently bound to the polymer chain. It was established that the luminescent label retains unchanged its emission characteristics not only in the polypeptides but also in more complicated nanoaggregates such as the polymer derived amphiphilic block-copolymers and self-assembled nanoparticles. The phosphorescent nanoparticles display no cytotoxicity and hemolytic activity in the tested range of concentrations and easily internalize into living cells that makes possible in vivo cell visualization, including prospective application in time resolved imaging and drug delivery monitoring.