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Information storage at the molecular level commonly entails encoding in the form of ordered sequences of different monomers and subsequent fragmentation and tandem mass spectrometry analysis to read this information. Recent approaches also include the use of mixtures of distinct molecules noncovalently bonded to one another. Here, we present an alternate isotope ratio encoding approach utilizing deuterium-labeled monomers to produce hundreds of oligomers endowed with unique isotope distribution patterns. Mass spectrometric recognition of these patterns then allowed us to directly readout encoded information with high fidelity. Specifically, we show that all 256 tetramers composed of four different monomers of identical constitution can be distinguished by their mass fingerprint using mono-, di-, tri-, and tetradeuterated building blocks. The method is robust to experimental errors and does not require the most sophisticated mass spectrometry instrumentation. Such isotope ratio-encoded oligomers may serve as tags that carry information, but the method mainly opens up the capability to write information, for example, about molecular identity, directly into a pure compound via its isotopologue distribution obviating the need for additional tagging and avoiding the use of mixtures of different molecules.

The dual‐specificity tyrosine‐regulated kinases DYRK1A and DYRK1B play a key role in controlling the quiescence‐proliferation switch in cancer cells. Serum reduction of U87MG 2D cultures or multi‐cellular tumour spheroids induced a quiescent like state characterized by increased DYRK1B and p27, and decreased pRb and cyclin D1. VER‐239353 is a potent, selective inhibitor of the DYRK1A and DYRK1B kinases identified through fragment and structure‐guided drug discovery. Inhibition of DYRK1A/B by VER‐239353 in quiescent U87MG cells increased pRb, DYRK1B and cyclin D1 but also increased the cell cycle inhibitors p21 and p27. This resulted in exit from G0 but subsequent arrest in G1. DYRK1A/B inhibition reduced the proliferation of U87MG cells in 2D and 3D culture with greater effects observed under reduced serum conditions. Paradoxically, the induced re‐expression of cell cycle proteins by DYRK1A/B inhibition further inhibited cell proliferation. Cell growth arrest induced in quiescent cells by DYRK1A/B inhibition was reversible through the addition of growth‐promoting factors. DYRK inhibition‐induced DNA damage and synergized with a CHK1 inhibitor in the U87MG spheroids. In vivo, DYRK1A/B inhibition‐induced tumour stasis in a U87MG tumour xenograft model. These results suggest that further evaluation of VER‐239353 as a treatment for glioblastoma is therefore warranted.

Összefoglaló. A betegségek mögött meghúzódó biokémiai, sejtbiológiai változások molekuláris szintű megértése a korszerű gyógyszerkutatás alapját képezi. A kiválasztott biológiai célpont, leggyakrabban egy fehérje, működésének gátlásától vagy fokozásától azt reméljük, hogy elősegíti a gyógyulást. A hagyományos gyógyszerkutatási megközelítések molekuláris alapját a kiválasztott fehérjével való közvetlen kölcsönhatás jelentette. Ugyanakkor a sejten belüli molekuláris biológiai folyamatok részletesebb megértése több új megközelítést nyitott a gyógyszerkutatás számára. A közlemény ezeket a gyógyszerkutatási irányzatokat mutatja be, külön kitérve biztonságosságukra. Summary. Human diseases originate from and are accompanied by changes in the biochemistry of cells. The molecular level understanding of these deviations from normal functioning is key to the curing of the diseases, therefore a principal objective of drug discovery. The key-lock principle postulated by Emil Fischer serves well the understanding of most enzymatic processes and has been helping researchers both in academia and industry to discover new drugs. The binding of a small molecule to the target protein and inhibiting or activating its function is the basis for the efficient functioning of a long list of current drugs. Sometimes the desired biological effect comes from the selective action on a single protein, in other instances it is the combined effect on the working of several proteins. The appropriate selectivity profile is key to the safety and efficiency of the drug in both cases. The completion of the Human Genome Project, in parallel with a significant improvement in the performance of the analytical instrumentation, increased our molecular and systemic level understanding of diseases immensely. Analysis of the differences between healthy and diseased cells and tissues led to the identification of new targets, a lot of which are not classical enzymes but proteins exerting their effect through molecular interactions with other proteins or nucleic acids. Although these proteins were considered undruggable some decades ago, their disease modifying potential led to the discovery of new approaches and modalities to target them. The inhibition of protein-protein interactions, for example, requires the selective targeting of hydrophobic surfaces, sometimes with very high affinity. Drug candidates acting through this molecular mechanism are typically beyond the size of classical drugs that might complicate their development. Besides interacting directly with the protein of interest we might also impact its working through manipulating its quantity within the cell. Interference with the proteasomal degradation of cellular proteins, blocking its working, or hijacking it to selectively increase the degradation of our protein of choice are promising new modalities that are transitioning from research into clinical practice. Alternatively, one might also interfere with the transcriptional machinery. Selective blocking of the messenger RNA responsible for carrying the sequence information of the targeted protein by using so called antisense oligonucleotides, small interfering RNAs, or micro RNAs can result in a decreased synthesis of the protein. Appropriately designed oligonucleotides can also enhance protein synthesis or lead to an alteration of the sequence to synthesize for a given protein. Finally, we might also target the epigenetic regulatory machinery, which is in charge of unpacking the DNA double helix from its storage form and making it available for transcription. This interference typically leads to a more complex change, the parallel modulation of the level of several proteins at the same time.

Following the identification of thieno[2,3-d]pyrimidine-based selective and potent inhibitors of MCL-1, we explored the effect of core swapping at different levels of advancement. During hit-to-lead optimization, X-ray-guided S-N replacement in the core provided a new vector, whose exploration led to the opening of the so-called deep-S2 pocket of MCL-1. Unfortunately, the occupation of this region led to a plateau in affinity and had to be abandoned. As the project approached selection of a clinical candidate, a series of core swap analogues were also prepared. The affinity and cellular activity of these compounds showed a significant dependence on the core structure. In certain cases, we also observed an increased and accelerated epimerization of the atropoisomers. The most potent core replacement analogues showed considerable in vivo PD response. One compound was progressed into efficacy studies and inhibited tumor growth.

Hydrofluoroolefin (HFO) gases are state-of-the-art cooling agents with widespread household and industrial applications. Considering their structural benefits these fluorous feedstocks have gained the attention of organic chemists in the last couple of years. In this short review we summarized the existing synthetic transformations of these gaseous starting material and present their applicability in the synthesis of fluorine-containing organic molecules, which have potential importance as building blocks and reagents for diverse syntheses.1 Introduction2 Addition Reactions3 Substitutions4 Organometallic Chemistry4.1 Organolithium Compounds4.2 Organometallic Complexes4.3 Silicon Organic Chemistry4.4 Boron Organic Chemistry4.5 Palladium-Catalyzed Transformations4.6 Metathesis4.7 Hydroesterification, Hydroformylation5 Conclusions

The serine/threonine kinase DYRK1A has been implicated in regulation of a variety of cellular processes associated with cancer progression, including cell cycle control, DNA damage repair, protection from apoptosis, cell differentiation, and metastasis. In addition, elevated-level DYRK1A activity has been associated with increased severity of symptoms in Down's syndrome. A selective inhibitor of DYRK1A could therefore be of therapeutic benefit. We have used fragment and structure-based discovery methods to identify a highly selective, well-tolerated, brain-penetrant DYRK1A inhibitor which showed in vivo activity in a tumor model. The inhibitor provides a useful tool compound for further exploration of the effect of DYRK1A inhibition in models of disease.

A novel fluoroalkyl iodide was synthesized on multigram scale from refrigerant gas HFO-1234yf as cheap industrial starting material in a simple, solvent-free, and easily scalable process. We demonstrated its applicability in a metal-free photocatalytic ATRA reaction to synthesize valuable fluoroalkylated vinyl iodides and proved the straightforward transformability of the products in cross-coupling chemistry to obtain conjugated systems.

The kinase DYRK1A is an attractive target for drug discovery programs due to its implication in multiple diseases. Through a fragment screen, we identified a simple biaryl compound that is bound to the DYRK1A ATP site with very high efficiency, although with limited selectivity. Structure-guided optimization cycles enabled us to convert this fragment hit into potent and selective DYRK1A inhibitors. Exploiting the structural differences in DYRK1A and its close homologue DYRK2, we were able to fine-tune the selectivity of our inhibitors. Our best compounds potently inhibited DYRK1A in the cell culture and in vivo and demonstrated drug-like properties. The inhibition of DYRK1A in vivo translated into dose-dependent tumor growth inhibition in a model of ovarian carcinoma.

Combining the selective targeting of tumor cells through antigen-directed recognition and potent cell-killing by cytotoxic payloads, antibody-drug conjugates (ADCs) have emerged in recent years as an efficient therapeutic approach for the treatment of various cancers. Besides a number of approved drugs already on the market, there is a formidable follow-up of ADC candidates in clinical development. While selection of the appropriate antibody (A) and drug payload (D) is dictated by the pharmacology of the targeted disease, one has a broader choice of the conjugating linker (C). In the present paper, we review the chemistry of ADCs with a particular emphasis on the medicinal chemistry perspective, focusing on the chemical methods that enable the efficient assembly of the ADC from its three components and the controlled release of the drug payload.

Myeloid cell leukemia 1 (Mcl-1) has emerged as an attractive target for cancer therapy. It is an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we report the discovery of our clinical candidate S64315, a selective small molecule inhibitor of Mcl-1. Starting from a fragment derived lead compound, we have conducted structure guided optimization that has led to a significant (3 log) improvement of target affinity as well as cellular potency. The presence of hindered rotation along a biaryl axis has conferred high selectivity to the compounds against other members of the Bcl-2 family. During optimization, we have also established predictive PD markers of Mcl-1 inhibition and achieved both efficient in vitro cell killing and tumor regression in Mcl-1 dependent cancer models. The preclinical candidate has drug-like properties that have enabled its development and entry into clinical trials.

The trifluoromethylation of aromatic and heteroaromatic cores has attracted considerable interest in recent years due to its pharmacological relevance. We studied the extension of a simple copper-catalyzed trifluoromethylation protocol to alkoxy-substituted iodopyridines and their benzologs. The trifluoromethylation proceeded smoothly in all cases, and the desired compounds were isolated and characterized. In the trifluoromethylation of 3-iodo-4-methoxyquinoline, we observed a concomitant O-N methyl migration, resulting in the trifluoromethylated quinolone as a product. Overall, the described procedure should facilitate the broader use of copper-catalyzed trifluoromethylation in medicinal chemistry.

Chemistry - a European journal 26(72), 17366 - 17370 (2020). doi:10.1002/chem.202004064, Helically folded aromatic oligoamide foldamers have a size and geometrical parameters very distinct from those of α‐helices and are not obvious candidates for α‐helix mimicry. Nevertheless, they offer multiple sites for attaching side chains. It was found that some arrays of side chains at the surface of an aromatic helix make it possible to mimic extended α‐helical surfaces. Synthetic methods were developed to produce quinoline monomers suitably functionalized for solid phase synthesis. A dodecamer was prepared. Its crystal structure validated the initial design and showed helix bundling involving the α‐helix‐like interface. These results open up new uses of aromatic helices to recognize protein surfaces and to program helix bundling in water., Published by Wiley-VCH, Weinheim

Metadynamics simulations were used to describe the conformational energy landscapes of several helically folded aromatic quinoline carboxamide oligomers bearing a single chiral group at either the C or N terminus. The calculations allowed the prediction of whether a helix handedness bias occurs under the influence of the chiral group and gave insight into the interactions (sterics, electrostatics, hydrogen bonds) responsible for a particular helix sense preference. In the case of camphanyl-based and morpholine-based chiral groups, experimental data confirming the validity of the calculations were already available. New chiral groups with a proline residue were also investigated and were predicted to induce handedness. This prediction was verified experimentally through the synthesis of proline-containing monomers, their incorporation into an oligoamide sequence by solid phase synthesis and the investigation of handedness induction by NMR spectroscopy and circular dichroism.

Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation when observed in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy, has emerged as an attractive target for cancer therapy. Here, we report the discovery of selective small molecule inhibitors of Mcl-1 that inhibit cellular activity. Fragment screening identified thienopyrimidine amino acids as promising but nonselective hits that were optimized using nuclear magnetic resonance and X-ray-derived structural information. The introduction of hindered rotation along a biaryl axis has conferred high selectivity to the compounds, and cellular activity was brought on scale by offsetting the negative charge of the anchoring carboxylate group. The obtained compounds described here exhibit nanomolar binding affinity and mechanism-based cellular efficacy, caspase induction, and growth inhibition. These early research efforts illustrate drug discovery optimization from thienopyrimidine hits to a lead compound, the chemical series leading to the identification of our more advanced compounds S63845 and S64315.

We describe our work to establish structure- and fragment-based drug discovery to identify small molecules that inhibit the anti-apoptotic activity of the proteins Mcl-1 and Bcl-2. This identified hit series of compounds, some of which were subsequently optimized to clinical candidates in trials for treating various cancers. Many protein constructs were designed to identify protein with suitable properties for different biophysical assays and structural methods. Fragment screening using ligand-observed NMR experiments identified several series of compounds for each protein. The series were assessed for their potential for subsequent optimization using 1H and 15N heteronuclear single-quantum correlation NMR, surface plasmon resonance, and isothermal titration calorimetry measurements to characterize and validate binding. Crystal structures could not be determined for the early hits, so NMR methods were developed to provide models of compound binding to guide compound optimization. For Mcl-1, a benzodioxane/benzoxazine series was optimized to a Kd of 40 μM before a thienopyrimidine hit series was identified which subsequently led to the lead series from which the clinical candidate S 64315 (MIK 665) was identified. For Bcl-2, the fragment-derived series were difficult to progress, and a compound derived from a published tetrahydroquinone compound was taken forward as the hit from which the clinical candidate (S 55746) was obtained. For both the proteins, the work to establish a portfolio of assays gave confidence for identification of compounds suitable for optimization.

Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.

7-Azaindole has been identified as a novel bidentate anchor point for allosteric glucokinase activators. A systematic investigation around three principal parts of the new small molecule glucokinase activators led to a robust SAR in agreement with structural data that also helped to assess the conformational flexibility of the allosteric activation site. The increase in glucose uptake resulting from glucokinase activation in hepatocytes in vitro translated into the efficient lowering of glucose levels in vivo with the best compounds.

A series of new derivatives of the natural β-carboline alkaloid harmine, introducing hydrophobic substituents into positions 7 and 9 were synthesized as potential anticancer agents. Their binding affinities for human serum albumin (HSA) and α1-acid glycoprotein (AAG) were investigated by affinity chromatography combined with fluorescence, circular dichroism (CD) and UV absorption spectroscopy. The weak binding of harmine to both proteins (Ka ∼ 3 × 104 M−1) was highly increased by aromatic substitutions (Ka ∼ 105–106 M−1). Derivatives having a substituted benzyl group in the N9-position of the β-carboline nucleus showed about tenfold and hundredfold affinity enhancement for HSA and AAG, respectively. Such a strong plasma protein interaction would be of pharmacokinetic relevance for these potential drug candidates. Induced CD spectra indicated the variant selective, dimeric binding of the 7-pyridylethoxy derivative to AAG. Absorbance and fluorescence spectra refer to the binding preference of the neutral form of the studied β-carbolines for both proteins.

Efficient copper-catalyzed trifluoromethylation of aromatic iodides was achieved with TMSCF3 in the presence of trimethylborate. The Lewis acid was used to anchor the in situ generated trifluoromethyl anion and suppress its rapid decomposition. Broad applicability of the new trifluoromethylating reaction was demonstrated in the functionalization of different aromatic and heteroaromatic iodides.

For biological applications, the control of the helix handedness of water-soluble quinoline-based oligoamide foldamers has been investigated by the installation of chiral end groups at either the C or N terminus. This has resulted in the development of monomer units capable of unequivocally inducing helical sense without impacting the aqueous solubility. Furthermore, we showed that very slow helix handedness inversion in water can be exploited. The incorporation of a chiral moiety with no handedness-induction properties allows the chromatographic separation of P and M helices as diastereoisomers with kinetically locked handedness.

Detailed structural and computational investigations have been carried out to elucidate the unprecedented structural properties of NHC-derived tetrazinones. The provocative structural contradictions featured by this class of molecules as emerged from single crystal X-ray diffraction studies include the non-coplanar core ring system with an inter-ring C–C single bond indicating aromaticity but a pattern of bond alteration consistent with an overall quinoidal structure. Combination of periodic and gas-phase calculations identified two key factors affecting the overall structure. The first is a strong tendency to avoid cross-conjugation resulting in a coupled aromatic–quinoidal system whereas the second is the steric demand of the substituents determining the conformational behaviour of the rings. The peculiar electron distribution yields remarkably large polarizations and dipole moments for these molecules which can be key in their potential applications.

Mcl-1 is highly expressed in a variety of human cancers (including those of hematopoietic and lymphoid origin) and is exploited by cancer cells to evade cell death and to develop resistance to diverse chemotherapeutic agents. We disclose, for the first time, the structure of S64315 (also named MIK665) a highly potent and selective inhibitor of Mcl-1 with improved potency over its predecessor S63845 (Kotschy et al, Nature, 2016). S64315/MIK665 is currently in phase 1 in AML (Acute Myeloid Leukemia) and MDS (Myelodysplastic Syndrome) (EudraCT 2016-003768-38, NCT 02979366) and in MM (Multiple Myeloma) and lymphoma (NCT02992483). A fragment-based, structure-guided drug discovery effort led to the identification of S64315/MIK665 that binds to human Mcl-1 with a sub-nanomolar affinity (Ki 0.048 nM) and selectively over other anti-apoptotic Bcl-2 family members. It has similar affinity for human, rat, dog and monkey Mcl-1 but about a ten-fold lower affinity for mouse Mcl-1. S64315/MIK665 causes dose-dependent activation of the intrinsic apoptosis pathway in a Bax/Bak-dependent manner, as measured by increased caspase activity and cleaved PARP. S64315/MIK665 shows strong cell killing activity in a diverse panel of human hematological tumor cell lines, including AML, lymphoma and MM. The activity profile of S64315/MIK665 is distinct from that of venetoclax, a selective Bcl2 inhibitor. In vivo, S64315 as single agent demonstrated potent and dose-dependent apoptotic and antitumor response after intravenous administration in several human hematological tumor models grafted in immuno-compromised mice and rats. Complete regression of established tumors, at well tolerated doses, was achieved using different intravenous dosing regimens in rats as well as in mice. Finally, dual BH3-mimetic targeting approach combining S64315/MIK665 with BCL2 inhibitors showed strong and durable antitumor responses in several hematological tumor models both in vitro and in vivo. Citation Format: Ana Leticia Maragno, Prakash Mistry, András Kotschy, Zoltán Szlavik, James Murray, James Davidson, Gaëtane Le Toumelin-Braizat, Maïa Chanrion, Alain Bruno, Audrey Claperon, Heiko Maacke, Erick Morris, Youzhen Wang, Alix Derreal, Márton Csekei, Attila Paczal, Zoltán Szabo, Szabolcs Sipos, Agnes Proszenyak, Balázs Balint, Allan Surgenor, Pawel Dokurno, Natalia Matassova, Ijen Chen, Gaëlle Lysiak-Auvity, Anne-Marie Girard, Fabienne Grave, Frédéric Colland, Ensar Halilovic, Olivier Geneste. S64315 (MIK665) is a potent and selective Mcl1 inhibitor with strong antitumor activity across a diverse range of hematologic tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4482.

Background and Purpose Small-molecule glucokinase activators (GKAs) are currently being investigated as therapeutic options for the treatment of type 2 diabetes (T2D). Because liver overexpression of glucokinase is thought to be associated with altered lipid profiles, this study aimed at assessing the potential lipogenic risks linked to oral GKA administration. Experimental Approach Nine GKA candidates were qualified for their ability to activate recombinant glucokinase and to stimulate glycogen synthesis in rat hepatocytes and insulin secretion in rat INS-1E cells. In vivo activity was monitored by plasma glucose and HbA1c measurements after oral administration in rodents. Risk-associated effects were assessed by measuring hepatic and plasma triglycerides and free fatty acids, as well as plasma aminotransferases, and alkaline phosphatase. Key Results GKAs, while efficiently decreasing glycaemia in acute conditions and HbA1c levels after chronic administration in hyperglycemic db/db mice, were potent inducers of hepatic steatosis. This adverse outcome appeared as soon as 4 days after daily oral administration at pharmacological doses and was not transient. GKA treatment similarly increased hepatic triglycerides in diabetic and normoglycaemic rats, together with a pattern of metabolic phenotypes including different combinations of increased plasma triglycerides, free fatty acids, alanine and aspartyl aminotransferases, and alkaline phosphatase. GKAs belonging to three distinct structural families induced hepatic steatosis in db/db mice, arguing in favour of a target-mediated, rather than a chemical class-mediated, effect. Conclusion and Implications Given the risks associated with fatty liver disease in the general population and furthermore in patients with T2D, these findings represent a serious warning for the use of GKAs in humans. Linked Article This article is commented on by Rees and Gloyn, pp. 335–338 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.02201.x

Dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is an emerging biological target with implications in diverse therapeutic areas such as neurological disorders (Down syndrome, in particular), metabolism, and oncology. Harmine, a natural product that selectively inhibits DYRK1A amongst kinases, could serve as a tool compound to better understand the biological processes that arise from DYRK1A inhibition. On the other hand, harmine is also a potent inhibitor of monoamine oxidase A (MAO-A). Using structure-based design, we synthesized a collection of harmine analogues with tunable selectivity toward these two enzymes. Modifications at the 7-position typically decreased affinity for DYRK1A, whereas substitution at the 9-position had a similar effect on MAO-A inhibition but DYRK1A inhibition was maintained. The resulting collection of compounds can help to understand the biological role of DYRK1A and also to assess the interference in the biological effect originating in MAO-A inhibition.

The palladium-catalyzed ring closure of aryl O-bromo-benzylketones, easily accessible from aromatic aldehydes and 2-bromobenzylbromide, provides a straightforward route to 2-arylbenzofurans.A study of the ring closure revealed that a heterocyclic carbenebased catalyst provides the best results.

An efficient one-pot protocol was developed for the construction of the benzofuran system from aryl halides and protected iodophenols using carbinol-based acetylene sources. The sequence includes alternating palladium-catalyzed Sonogashira couplings and deprotection steps concluded by a ring closure. The developed one-pot procedure was compared with the stepwise approach and its efficiency was also demonstrated by the total synthesis of vignafuran, a benzofuran natural product.

The Sonogashira coupling of aryl halides in the presence of 1-ethynyl-cyclohexanol as an acetylene source provides an efficient method for the synthesis of diarylacetylenes without the isolation of the appropriate arylacetylenes.

In the last decades catalytic enantioselective transformations have became one of the most studied fields in synthesis chemistry. With the advancement of biphasic catalysis several of these reactions have been adapted to be run in ionic liquids. The variability of ionic liquids provides the means to fine tune catalytic processes, and even more importantly, the ionic liquids might be used to immobilize the catalyst and allow its easy recycling. The present review aims to provide an overview of the state of the art of enantioselective homogeneous catalytic transformations in ionic liquids.

α,α-Diphenylbenzo[b]thien-2-ylmethanol was treated with a series of aryl bromides in the presence of palladium(II) acetate and tricyclohexylphosphane to give the appropriate 2-aryl-benzo[b]thiophenes in good to excellent yield with concomitant formation of benzophenone. The reaction wassuccessfully extended to α,α-diphenylbenzo[b]thien-3-ylmethanol, although in certain cases the transformation was biased by concurrent ortho arylation. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Selected pyridazino[4,5-d]pyridazine derivatives were reacted with polar organometallic reagents to result in the addition of the organic moiety onto the 5-position of the ring system with high selectivity.

The recent combinatorial approach in synthetic organic chemistry started a new age in drug discovery. The generation of compound libraries in combination with high-throughput screening has become the method of choice for the production of new pharmacological leads for chemical optimization. Characterization and separation of such pool of compounds have been lagging behind the synthetic and screening methodologies. Overpressured layer chromatography (OPLC) is an instrumentalized planar liquid chromatographic technique associated with the use of optimized layers prepared from particles of narrow particle size distribution and small diameter. On one hand, uni-directional OPLC allows the simultaneous separation of large number of samples in minutes. On the other hand, two-dimensional OPLC offers multidimensional separation on a single layer. This paper shows the complete multidimensional separation of a tetrazine library prepared by parallel combinatorial synthesis. In general, this approach may become the method of choice for the characterization of compound libraries.

The novel method for the copper-catalyzed trifluoromethylation of aromatic and heteroaromatic iodides uses silane (II) in the presence of trimethyl borate.

1-Amino-2-methyl-1,3-pentadienes were treated with dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate to give diazatricyclo[2.2.2.0]octenes and dimethyl 4-methylpyridazine-3,6-dicarboxylate, the product distribution being largely dependent on the nature of the amino substituent. Under similar conditions the analogous 1-morpholino-1,3-butadiene afforded dimethyl pyridazine-3,6-dicarboxylate as the major product. The tricyclic products underwent selective thermal decomposition to give dimethyl 4-methylpyridazine-3,6-dicarboxylate in excellent yield. The proposed mechanism of the formation as well as of the decomposition was supported by quantum chemical calculations and experimental evidence. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Dihydroisoquinoline derivatives and their analogues, prepared by the Bischler-Napieralsky reaction, were converted to their indole-fused derivatives. Scope and limitations of the palladium-catalyzed reaction, proceeding through the tautomeric enamine forms of these compounds, were studied and the process was extended to the preparation of racemic mangochinine.

Ferrocenecarboxaldehyde hydrazones were converted into palladium complexes on treatment with sodium tetrachloropalladate. The substitution pattern of the ferrocenylhydrazones was found to have a marked influence on the mode the palladium was attached to the organic moiety. The catalytic activity of the new palladium complexes in cross-coupling reactions was examined in detail, and it was compared with conventional catalyst systems.

The m- and p-phenylene-bridged bis-azolopyridinium salts have been synthesized and converted into the corresponding bis-dienamines by reaction with pyrrolidine. These dienamines react readily with dimethyl 1,2,4,5-tetrazine-dicarboxylate to yield the bis-azolylvinyl-pyridazines.

Chemical reaction rate constants of the nucleophilic ortho-positronium (o-Ps) atom with a series of tetrazine derivatives were determined in dimethylformamide (DMF) solutions by positron annihilation lifetime spectroscopy. The observed rate constants are in the range that corresponds to that of the diffusion-controlled reactions. It was shown that this pronounced reactivity of tetrazines toward o-Ps stems from the electron-deficient tetrazine core. The introduction of electron-donating substituents onto the tetrazine ring, as expected, decreases the reactivity of the molecule toward o-Ps. The measured reaction rate constants of o-Ps resulted in a good linear correlation with the calculated LUMO energies of the tetrazines. The reactivity of tetrazines toward o-Ps correlated well also with their reactivity toward classical nucleophiles.

A series of tetrazines were reacted with organometallic reagents. Depending on the nature of the metal azaphilic addition, reduction of the tetrazine or simple complex formation was the predominant transformation and usually high selectivity was observed.

A simple one-pot procedure was elaborated for the preparation of hydroxylated benzofurans from halogenated phenols and was successfully applied to the first total synthesis of Cicerfuran, a natural defence agent of wild chickpea.

Cyclization of condensed [1,2,4]triazolo[4,3-b]pyridazine-3(2H)-6(5H)-ones with α,ω-dibromoalkanes afforded a series of novel ring systems including zwitterions and isomeric tetracyclic lactams. The product distribution is controlled by the chain-length of the reagent, the polarity of the solvent and the structure of ring A in the substrate. The observed substrate selectivity was interpreted on the basis of amide-I IR frequencies and by the results of ab initio B3LYP DFT calculations carried out at 6-31G and 6-31G(d) basis sets using IPCM solvation model. The cycloalkylation with 1,4-dibromobutane gave also macrocyles as detectable by-products which underwent ring contraction yielding lactams on attempted chromatographic separation.