Nickel-Catalyzed N-Arylation of NH-Sulfoximines with Aryl Halides via Paired Electrolysis.

A novel strategy for the N-arylation of NH-sulfoximines has been developed by merging nickel catalysis and electrochemistry (in an undivided cell), thereby providing a practical method for the construction of sulfoximine derivatives. Paired electrolysis is employed in this protocol, so a sacrificial anode is not required. Owing to the mild reaction conditions, excellent functional group tolerance and yield are achieved. A preliminary mechanistic study indicates that the anodic oxidation of a NiII species is crucial to promote the reductive elimination of a C-N bond from the resulting NiIII species at room temperature.

Synthetic approaches towards alkaloids bearing α-tertiary amines.

Alkaloids account for some of the most beautiful and biologically active natural products. Although they are usually classified along biosynthetic criteria, they can also be categorized according to certain structural motifs. Amongst these, the α-tertiary amine (ATA), i.e. a tetrasubstituted carbon atom surrounded by three carbons and one nitrogen, is particularly interesting. A limited number of methods have been described to access this functional group and fewer still are commonly used in synthesis. Herein, we review some approaches to asymmetrically access ATAs and provide an overview of alkaloid total syntheses where those have been employed.

Carbolithiation of N-alkenyl ureas and N-alkenyl carbamates.

N-Alkenyl ureas and N-alkenyl carbamates, like other N-acyl enamines, are typically nucleophilic at their ß-carbon. However, by incorporating an α-aryl substituent, we show that they will also undergo attack at the ß-carbon by organolithium nucleophiles, leading to the products of carbolithiation. The carbolithiation of E and Z N-alkenyl ureas is diastereospecific, and N-tert-butoxycarbonyl N-alkenyl carbamates give carbolithiation products that may be deprotected in situ to provide a new connective route to hindered amines.

Back in Person: Frontiers in Medicinal Chemistry 2023.

The Frontiers in Medicinal Chemistry (FiMC) is the largest international Medicinal Chemistry conference in the German speaking area and took place from April 3rd to 5th 2023 in Vienna (Austria). Fortunately, after being cancelled in 2020 and two years (2021-2022) of entirely virtual meetings, due to the COVID-19 pandemic, the FiMC could be held in a face-to-face format again. Organized by the Division of Medicinal Chemistry of the German Chemical Society (GDCh), the Division of Pharmaceutical and Medicinal Chemistry of the German Pharmaceutical Society (DPhG), together with the Division of Medicinal Chemistry of the Austrian Chemical Society (GÖCH), the Austrian Pharmaceutical Society (ÖPhG), and a local organization committee from the University of Vienna headed by Thierry Langer, the meeting brought together 260 participants from 21 countries. The program included 38 lectures by leading scientists from industry and academia as well as early career investigators. Moreover, 102 posters were presented in two highly interactive poster sessions.

Targeting the aryl hydrocarbon receptor (AhR) with BAY 2416964: a selective small molecule inhibitor for cancer immunotherapy.

BACKGROUND: The metabolism of tryptophan to kynurenines (KYN) by indoleamine-2,3-dioxygenase or tryptophan-2,3-dioxygenase is a key pathway of constitutive and adaptive tumor immune resistance. The immunosuppressive effects of KYN in the tumor microenvironment are predominantly mediated by the aryl hydrocarbon receptor (AhR), a cytosolic transcription factor that broadly suppresses immune cell function. Inhibition of AhR thus offers an antitumor therapy opportunity via restoration of immune system functions. METHODS: The expression of AhR was evaluated in tissue microarrays of head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). A structure class of inhibitors that block AhR activation by exogenous and endogenous ligands was identified, and further optimized, using a cellular screening cascade. The antagonistic properties of the selected AhR inhibitor candidate BAY 2416964 were determined using transactivation assays. Nuclear translocation, target engagement and the effect of BAY 2416964 on agonist-induced AhR activation were assessed in human and mouse cancer cells. The immunostimulatory properties on gene and cytokine expression were examined in human immune cell subsets. The in vivo efficacy of BAY 2416964 was tested in the syngeneic ovalbumin-expressing B16F10 melanoma model in mice. Coculture of human H1299 NSCLC cells, primary peripheral blood mononuclear cells and fibroblasts mimicking the human stromal-tumor microenvironment was used to assess the effects of AhR inhibition on human immune cells. Furthermore, tumor spheroids cocultured with tumor antigen-specific MART-1 T cells were used to study the antigen-specific cytotoxic T cell responses. The data were analyzed statistically using linear models. RESULTS: AhR expression was observed in tumor cells and tumor-infiltrating immune cells in HNSCC, NSCLC and CRC. BAY 2416964 potently and selectively inhibited AhR activation induced by either exogenous or endogenous AhR ligands. In vitro, BAY 2416964 restored immune cell function in human and mouse cells, and furthermore enhanced antigen-specific cytotoxic T cell responses and killing of tumor spheroids. In vivo, oral application with BAY 2416964 was well tolerated, induced a proinflammatory tumor microenvironment, and demonstrated antitumor efficacy in a syngeneic cancer model in mice. CONCLUSIONS: These findings identify AhR inhibition as a novel therapeutic approach to overcome immune resistance in various types of cancers.

Intramolecular vinylation of secondary and tertiary organolithiums.

Deprotonation of benzylic ureas, carbamates, and thiocarbamates bearing N'-alkenyl substituents generates carbanions which undergo intramolecular migration of the alkenyl group to the carbanionic center. Solvolysis of the urea products generates α-alkenylated amines. With an enantiomerically pure starting urea, migration proceeds stereospecifically, generating in enantiomerically enriched form products containing allylic quaternary stereogenic centers bearing N. Computational and in situ IR studies suggest that the reaction, formally a nucleophilic substitution at an sp(2) carbon atom, proceeds by a concerted addition-elimination pathway.

Frontiers in Medicinal Chemistry 2022 Goes Virtual.

The Frontiers in Medicinal Chemistry (FiMC) meeting, which represents the largest international medicinal chemistry conference in Germany, took place from March 14th to 16th 2022 in a fully virtual format. Organized by the Division of Medicinal Chemistry of the German Chemical Society (GDCh) together with the Division of Pharmaceutical & Medicinal Chemistry of the German Pharmaceutical Society (DPhG) and a "local" organization committee from the University of Freiburg headed by Manfred Jung, the meeting brought together 271 participants from around 20 countries. The program included 33 lectures by leading scientists from industry and academia as well as early career investigators. 67 posters were presented in two poster sessions and with over 20.000 poster abstract downloads. The general organization and the time-shift function were very much appreciated as demonstrated by almost 600 on-demand contents retrieved. The online format fitted perfectly to bring together medicinal chemists from academia and industry across the globe.

The potent AMPK inhibitor BAY-3827 shows strong efficacy in androgen-dependent prostate cancer models.

PURPOSE: 5' adenosine monophosphate-activated kinase (AMPK) is an essential regulator of cellular energy homeostasis and has been associated with different pathologies, including cancer. Precisely defining the biological role of AMPK necessitates the availability of a potent and selective inhibitor. METHODS: High-throughput screening and chemical optimization were performed to identify a novel AMPK inhibitor. Cell proliferation and mechanistic assays, as well as gene expression analysis and chromatin immunoprecipitation were used to investigate the cellular impact as well as the crosstalk between lipid metabolism and androgen signaling in prostate cancer models. Also, fatty acid turnover was determined by examining lipid droplet formation. RESULTS: We identified BAY-3827 as a novel and potent AMPK inhibitor with additional activity against ribosomal 6 kinase (RSK) family members. It displays strong anti-proliferative effects in androgen-dependent prostate cancer cell lines. Analysis of genes involved in AMPK signaling revealed that the expression of those encoding 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), fatty acid synthase (FASN) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2), all of which are involved in lipid metabolism, was strongly upregulated by androgen in responsive models. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) analysis identified several androgen receptor (AR) binding peaks in the HMGCR and PFKFB2 genes. BAY-3827 strongly down-regulated the expression of lipase E (LIPE), cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B) and serine-threonine kinase AKT3 in responsive prostate cancer cell lines. Also, the expression of members of the carnitine palmitoyl-transferase 1 (CPT1) family was inhibited by BAY-3827, and this was paralleled by impaired lipid flux. CONCLUSIONS: The availability of the potent inhibitor BAY-3827 will contribute to a better understanding of the role of AMPK signaling in cancer, especially in prostate cancer.

Tandem beta-alkylation-alpha-arylation of amines by carbolithiation and rearrangement of N-carbamoyl enamines (vinyl ureas).

Organolithiums add in an umpolung fashion to the beta-carbon of N-carbamoyl enamines (N-vinyl ureas). The reaction proceeds with syn diastereospecificity and provides urea-stabilized, configurationally defined organolithiums. Facilitated by coordinating solvents (THF or DMPU), these undergo intramolecular attack on an N'-aryl group, resulting in retentive arylation of the organolithium and hence overall addition of an alkyl or aryl group to both carbon atoms of the urea-substituted alkene. Facile deprotection in hot butanol permits the rapid, multicomponent construction of heavily substituted amines.

Damage Incorporated: Discovery of the Potent, Highly Selective, Orally Available ATR Inhibitor BAY 1895344 with Favorable Pharmacokinetic Properties and Promising Efficacy in Monotherapy and in Combination Treatments in Preclinical Tumor Models.

The ATR kinase plays a key role in the DNA damage response by activating essential signaling pathways of DNA damage repair, especially in response to replication stress. Because DNA damage and replication stress are major sources of genomic instability, selective ATR inhibition has been recognized as a promising new approach in cancer therapy. We now report the identification and preclinical evaluation of the novel, clinical ATR inhibitor BAY 1895344. Starting from quinoline 2 with weak ATR inhibitory activity, lead optimization efforts focusing on potency, selectivity, and oral bioavailability led to the discovery of the potent, highly selective, orally available ATR inhibitor BAY 1895344, which exhibited strong monotherapy efficacy in cancer xenograft models that carry certain DNA damage repair deficiencies. Moreover, combination treatment of BAY 1895344 with certain DNA damage inducing chemotherapy resulted in synergistic antitumor activity. BAY 1895344 is currently under clinical investigation in patients with advanced solid tumors and lymphomas (NCT03188965).

The Novel ATR Inhibitor BAY 1895344 Is Efficacious as Monotherapy and Combined with DNA Damage-Inducing or Repair-Compromising Therapies in Preclinical Cancer Models.

The DNA damage response (DDR) secures the integrity of the genome of eukaryotic cells. DDR deficiencies can promote tumorigenesis but concurrently may increase dependence on alternative repair pathways. The ataxia telangiectasia and Rad3-related (ATR) kinase plays a central role in the DDR by activating essential signaling pathways of DNA damage repair. Here, we studied the effect of the novel selective ATR kinase inhibitor BAY 1895344 on tumor cell growth and viability. Potent antiproliferative activity was demonstrated in a broad spectrum of human tumor cell lines. BAY 1895344 exhibited strong monotherapy efficacy in cancer xenograft models that carry DNA damage repair deficiencies. The combination of BAY 1895344 with DNA damage-inducing chemotherapy or external beam radiotherapy (EBRT) showed synergistic antitumor activity. Combination treatment with BAY 1895344 and DDR inhibitors achieved strong synergistic antiproliferative activity in vitro, and combined inhibition of ATR and PARP signaling using olaparib demonstrated synergistic antitumor activity in vivo Furthermore, the combination of BAY 1895344 with the novel, nonsteroidal androgen receptor antagonist darolutamide resulted in significantly improved antitumor efficacy compared with respective single-agent treatments in hormone-dependent prostate cancer, and addition of EBRT resulted in even further enhanced antitumor efficacy. Thus, the ATR inhibitor BAY 1895344 may provide new therapeutic options for the treatment of cancers with certain DDR deficiencies in monotherapy and in combination with DNA damage-inducing or DNA repair-compromising cancer therapies by improving their efficacy.

Discovery of BAY-985, a Highly Selective TBK1/IKKε Inhibitor.

The serine/threonine kinase TBK1 (TANK-binding kinase 1) and its homologue IKKε are noncanonical members of the inhibitor of the nuclear factor κB (IκB) kinase family. These kinases play important roles in multiple cellular pathways and, in particular, in inflammation. Herein, we describe our investigations on a family of benzimidazoles and the identification of the potent and highly selective TBK1/IKKε inhibitor BAY-985. BAY-985 inhibits the cellular phosphorylation of interferon regulatory factor 3 and displays antiproliferative efficacy in the melanoma cell line SK-MEL-2 but showed only weak antitumor activity in the SK-MEL-2 human melanoma xenograft model.

Discovery and SAR of Novel 2,3-Dihydroimidazo[1,2-c]quinazoline PI3K Inhibitors: Identification of Copanlisib (BAY 80-6946).

The phosphoinositide 3-kinase (PI3K) pathway is aberrantly activated in many disease states, including tumor cells, either by growth factor receptor tyrosine kinases or by the genetic mutation and amplification of key pathway components. A variety of PI3K isoforms play differential roles in cancers. As such, the development of PI3K inhibitors from novel compound classes should lead to differential pharmacological and pharmacokinetic profiles and allow exploration in various indications, combinations, and dosing regimens. A screening effort aimed at the identification of PI3Kγ inhibitors for the treatment of inflammatory diseases led to the discovery of the novel 2,3-dihydroimidazo[1,2-c]quinazoline class of PI3K inhibitors. A subsequent lead optimization program targeting cancer therapy focused on inhibition of PI3Kα and PI3Kß. Herein, initial structure-activity relationship findings for this class and the optimization that led to the identification of copanlisib (BAY 80-6946) as a clinical candidate for the treatment of solid and hematological tumors are described.

Amines bearing tertiary substituents by tandem enantioselective carbolithiation-rearrangement of vinylureas.

In the presence of (-)-sparteine or a (+)-sparteine surrogate, organolithiums add to N-alkenyl-N'-arylureas to give benzylic organolithiums in an enantioselective manner. Under the influence of DMPU, these organolithiums undergo rearrangement with migration of the N'-aryl ring from N to C, leading to the urea derivatives of enantiomerically enriched amines bearing tertiary substituents. Basic hydrolysis returns the functionalized amine, providing a new synthetic route to compounds with quaternary stereogenic centers bearing nitrogen.

Quaternary centres bearing nitrogen (α-tertiary amines) as products of molecular rearrangements.

Quaternary centres bearing a nitrogen substituent (α-tertiary amines and their derivatives) are found in a variety of bioactive molecules but pose a major challenge in synthesis, particularly when enantiomeric purity is required. Approaches comparable to those used for tertiary alcohols are typically hampered by the poor electrophilicity of imines, requiring powerful nucleophiles that may also act as bases. A set of powerful alternative approaches make use of the rearrangement of readily available precursors, often (but not always) with formation of a new tertiary carbon to nitrogen bond. In this Feature Article we review the scope, limitations and specificities of some of these rearrangements in order to illuminate their synthetic potential.

Geometry-selective synthesis of E or Z N-vinyl ureas (N-carbamoyl enamines).

N-Vinyl ureas are emerging as a valuable class of compounds with both nucleophilic and electrophilic reactivity. They may be made by capturing the enamine tautomer of an imine with an isocyanate, a reaction which in general leads to the E isomer of the vinyl urea. Deprotonation of such a vinyl urea, or of an allyl urea, generates a dipole stabilized Z-allyl anion which may be protonated to return the Z-vinyl urea. Isomerization of an allyl urea with a Ru complex provides an alternative route to E-vinyl ureas.