Vasiliy A. Bakulev

The CK1 Family: Contribution to Cellular Stress Response and Its Role in Carcinogenesis.

Members of the highly conserved and ubiquitously expressed pleiotropic CK1 family play major regulatory roles in many cellular processes including DNA-processing and repair, proliferation, cytoskeleton dynamics, vesicular trafficking, apoptosis, and cell differentiation. As a consequence of cellular stress conditions, interaction of CK1 with the mitotic spindle is manifold increased pointing to regulatory functions at the mitotic checkpoint. Furthermore, CK1 is able to alter the activity of key proteins in signal transduction and signal integration molecules. In line with this notion, CK1 is tightly connected to the regulation and degradation of β-catenin, p53, and MDM2. Considering the importance of CK1 for accurate cell division and regulation of tumor suppressor functions, it is not surprising that mutations and alterations in the expression and/or activity of CK1 isoforms are often detected in various tumor entities including cancer of the kidney, choriocarcinomas, breast carcinomas, oral cancer, adenocarcinomas of the pancreas, and ovarian cancer. Therefore, scientific effort has enormously increased (i) to understand the regulation of CK1 and its involvement in tumorigenesis- and tumor progression-related signal transduction pathways and (ii) to develop CK1-specific inhibitors for the use in personalized therapy concepts. In this review, we summarize the current knowledge regarding CK1 regulation, function, and interaction with cellular proteins playing central roles in cellular stress-responses and carcinogenesis.

Palladium‐Catalyzed Chain‐Growth Polycondensation of AB‐type Monomers: High Catalyst Turnover and Polymerization Rates

Chain-growth catalyst-transfer polycondensations of AB-type monomers is a new and rapidly developing tool for the preparation of well-defined π-conjugated (semiconducting) polymers for various optoelectronic applications. Herein, we report the Pd/PtBu3-catalyzed Negishi chain-growth polycondensation of AB-type monomers, which proceeds with unprecedented TONs of above 100,000 and TOFs of up to 280 s(-1). In contrast, related AA/BB-type step-growth polycondensation proceeds with two orders of magnitude lower TONs and TOFs. A similar trend was observed in Suzuki-type polycondensation. The key impact of the intramolecular (vs. intermolecular) catalyst-transfer process on both polymerization kinetics and catalyst lifetime has been revealed.

Reaction of heterocyclic thioamides with dimethyl acetylenedicarboxylate. Synthesis of novel 2-azolyl-5-methoxycarbonylmethylene thiazolin-4-ones

Abstract A systematic study of the reactions of dimethyl acetylenedicarboxylate (DMAD) with heterocyclic thioamides has been carried out and a number of new 2-isoxazolyl-( 8 ), imidazolyl-( 13a , b and 17a ), 1,2,3-triazolyl-( 13d , e ) and 1,2,3-thiadiazolyl ( 17b ) thiazolines have been prepared. The higher reactivity of the thioamide group in comparison with the amino group in these reactions has been established.

Inhibition of HIV-1 replication by a bis-thiadiazolbenzene-1,2-diamine that chelates zinc ions from retroviral nucleocapsid zinc fingers.

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) nucleocapsid p7 (NCp7) protein holds two highly conserved “CCHC” zinc finger domains that are required for several phases of viral replication. Basic residues flank the zinc fingers, and both determinants are required for high-affinity binding to RNA. Several compounds were previously found to target NCp7 by reacting with the sulfhydryl group of cysteine residues from the zinc fingers. Here, we have identified an N,N′-bis(1,2,3-thiadiazol-5-yl)benzene-1,2-diamine (NV038) that efficiently blocks the replication of a wide spectrum of HIV-1, HIV-2, and simian immunodeficiency virus (SIV) strains. Time-of-addition experiments indicate that NV038 interferes with a step of the viral replication cycle following the viral entry but preceding or coinciding with the early reverse transcription reaction, pointing toward an interaction with the nucleocapsid protein p7. In fact, in vitro, NV038 efficiently depletes zinc from NCp7, which is paralleled by the inhibition of the NCp7-induced destabilization of cTAR (complementary DNA sequence of TAR). A chemical model suggests that the two carbonyl oxygens of the esters in this compound are involved in the chelation of the Zn2+ ion. This compound thus acts via a different mechanism than the previously reported zinc ejectors, as its structural features do not allow an acyl transfer to Cys or a thiol-disulfide interchange. This new lead and the mechanistic study presented provide insight into the design of a future generation of anti-NCp7 compounds.

Two directions of cyclization of α-diazo-β-dithioamides. New rearrangements of 12,3,-triazole-4-carbothiamides.

The cyclization processes of 2-diazomalondithioamides, generated by five different methods, have been studied. The ambient character of the derivatives of 2-diazomalondithioamide is the cause of previously unknown rearrangements of 5-mereapto-1,2,3-triazole- and 5-amino-1,2,3-thiadiazole-4-N-R-carbothioamides to 5-N-R-amino-1,2,3-thiadiazole-4-carbothioamides. NMR 1H and 13C spectra and mass-spectra are presented for the series of 5-amino-1,2,3-thiadiazole derivatives.

High Conductivity in Molecularly p‐Doped Diketopyrrolopyrrole‐Based Polymer: The Impact of a High Dopant Strength and Good Structural Order

[3]-Radialene-based dopant CN6-CP studied herein, with its reduction potential of +0.8 versus Fc/Fc+ and the lowest unoccupied molecular orbital level of -5.87 eV, is the strongest molecular p-dopant reported in the open literature, so far. The efficient p-doping of the donor-acceptor dithienyl-diketopyrrolopyrrole-based copolymer having the highest unoccupied molecular orbital level of -5.49 eV is achieved. The doped films exhibit electrical conductivities up to 70 S cm(-1) .

Influence of Semiconductor Thickness and Molecular Weight on the Charge Transport of a Naphthalenediimide-Based Copolymer in Thin-Film Transistors

The N-type semiconducting polymer, P(NDI2OD-T2), with different molecular weights (MW=23, 72, and 250 kg/mol) was used for the fabrication of field-effect transistors (FETs) with different semiconductor layer thicknesses. FETs with semiconductor layer thicknesses from ∼15 to 50 nm exhibit similar electron mobilities (μs) of 0.2-0.45 cm2 V(-1) s(-1). Reduction of the active film thickness led to decreased μ values; however, FETs with ∼2 and ∼5 nm thick P(NDI2OD-T2) films still exhibit substantial μs of 0.01-0.02 and ∼10(-4) cm2 V(-1) s(-1), respectively. Interestingly, the lowest molecular weight sample (P-23, MW≈23 kg/mol, polydispersity index (PDI)=1.9) exhibited higher μ than the highest molecular weight sample (P-250, MW≈250 kg/mol, PDI=2.3) measured for thicker devices (15-50 nm). This is rather unusual behavior because typically charge carrier mobility increases with MW where improved grain-to-grain connectivity usually enhances transport events. We attribute this result to the high crystallinity of the lowest MW sample, as confirmed by differential scanning calorimetry and X-ray diffraction studies, which may (over)compensate for other effects.

The regioselectivity of the formation of 2-pyrazolylthiazoles and their precursors from the reaction of 2-hydrazinothiazoles with 4,4,4-trifluoro-1-hetaryl-1,3-butanediones

Abstract Reaction of 2-hydrazinothiazoles 1 with 1-thienyl- and 1-furyl-1,3-butanediones 2a,b in methanol in the presence of hydrochloric acid mainly leads to a mixture of pyrazoles 3 and pyrazolines 4 or pyrazoles 3 and 5 in strong acidic conditions. Isomeric hydrazones 6 and pyrazolines 4 were formed and isolated in these reactions in the absence of hydrochloric acid. It has been shown that the regioselectivity in the reaction of diketones 2 with hydrazine 1 is governed by both the concentration of acid and the nature of substituents in the 1,3-diketones 2. Cyclization of hydrazones 6 is shown to occur under milder conditions than dehydration for pyrazolines 4. The new heterocyclic compounds were prepared and fully characterized by NMR spectra and by X-ray analysis for 3c.

The effect of modafinil on the rat dopamine transporter and dopamine receptors D1–D3 paralleling cognitive enhancement in the radial arm maze

A series of drugs have been reported to increase memory performance modulating the dopaminergic system and herein modafinil was tested for its working memory (WM) enhancing properties. Reuptake inhibition of dopamine, serotonin (SERT) and norepinephrine (NET) by modafinil was tested. Sixty male Sprague–Dawley rats were divided into six groups (modafinil-treated 1–5–10 mg/kg body weight, trained and untrained and vehicle treated trained and untrained rats; daily injected intraperitoneally for a period of 10 days) and tested in a radial arm maze (RAM), a paradigm for testing spatial WM. Hippocampi were taken 6 h following the last day of training and complexes containing the unphosphorylated or phosphorylated dopamine transporter (DAT-CC and pDAT-CC) and complexes containing the D1–3 dopamine receptor subunits (D1–D3-CC) were determined. Modafinil was binding to the DAT but insignificantly to SERT or NET and dopamine reuptake was blocked specifically (IC50 = 11.11 μM; SERT 1547 μM; NET 182 μM). From day 8 (day 9 for 1 mg/kg body weight) modafinil was decreasing WM errors (WMEs) in the RAM significantly and remarkably at all doses tested as compared to the vehicle controls. WMEs were linked to the D2R-CC and the pDAT-CC. pDAT and D1–D3-CC levels were modulated significantly and modafinil was shown to enhance spatial WM in the rat in a well-documented paradigm at all the three doses and dopamine reuptake inhibition with subsequent modulation of D1–3-CC is proposed as a possible mechanism of action.

Novel method for the synthesis of 4-(azol-5-yl)isoxazoles

In contrast to monocyclic and condensed isoxazoles, which are widely represented in the scientific and patent literature, bicyclic assemblies of isoxazoles with other azoles are poorly studied [1, 2]. In particular, isoxazoles linked to 1,2,3-thiadiazole and isothiazole rings have not been reported in the literature. Current methods for the preparation of 4-(azol-5-yl)isoxazoles are not numerous and include the construction of either an azole or an isoxazole ring. The formation of an isoxazole ring through reactions of various derivatives of 1,3-dicarbonyl compounds, -ketoesters, -ketonitriles, and malononitrile derivatives with hydroxylamine has been used for the preparation of 4-(azol-5-yl)isoxazoles [1]. The cycloaddition reaction of azolylacetylenes to nitrile oxides [1, 3] represents an alternative way of preparing this type of compound. Despite the good yields, for the majority of reactions these methods are limited by the poor availability of the starting compounds. The Suzuki cross-coupling reaction is complex in experimental settings and hence has a limited use for the synthesis of 4-(azol-5-yl)isoxazoles [4].