Synthetic Approach Research Articles

Porous Organic Nanotubes: Chemistry of One-Dimensional Space.

ConspectusOne-dimensional organic nanotubes feature unique properties, such as confined chemical environments and transport channels, which are highly desirable for many applications. Advances in synthetic methods have enabled the creation of different types of organic nanotubes, including supramolecular, hydrogen-bonded, and carbon nanotube analogues. However, challenges associated with chemical and mechanical stability along with difficulties in controlling aspect ratios remain a significant bottleneck. The fascination with structured porous materials has paved the way for the emergence of reticular solids such as metal-organic frameworks (MOFs), covalent organic frameworks (COFs), and organic cages. Reticular materials with tubular morphology promise architectural stability with the additional benefit of permeant porosity. Despite this, the current synthetic approaches to these reticular nanotubes focus more on structural design resulting in less reliable morphological uniformity. This Account, highlights the design motivation behind various classes of organic nanotubes, emphasizing their porous interior space. We explore the strategic assembly of organic nanotubes based on their bonding characteristics, from weak supramolecular to robust covalent interactions. Special attention is given to reticular nanotubes, which have gained prominence over the past two decades due to their distinctive micro and mesoporous structures. We examine the synergy of covalent and noncovalent interactions in constructing assembly of these nanotube structures.This Account furnishes a comprehensive overview of our efforts and advancements in developing porous covalent organic nanotubes (CONTs). We describe a general synthetic approach for creating robust imine-linked nanotubes based on the reticular chemistry principles. The use of spatially oriented tetratopic triptycene-based amine and linear ditopic aldehyde building blocks facilitates one-dimensional nanotube growth. The interplay between directional covalent bonds and solvophobic interactions is crucial for forming uniform, well-defined, and high aspect ratio nanotubes. The nanotubes derive their permeant porosity and thermal and chemical stability from their covalent architecture. We also highlight the adaptability of our synthetic methodology to guide the transformation of one-dimensional nanotubes to toroidal superstructures and two-dimensional thin fabrics. Such morphological transformation can be directed by tuning the reaction time or incorporating additional intermolecular interactions to control the intertwining behavior of individual nanotubes. The cohesion of covalent and noncovalent interactions in the tubular nanostructures manifests superior viscoelastic mechanical properties in the assembled CONT fabrics. We establish a strong correlation between structural framework design and nanostructures by translating reticular synthesis to morphological space and gaining insights into the assembly processes. We anticipate that the present Account will lay the foundation for exploring new designs and chemistry of organic nanotubes for many application platforms.

Nirmatrelvir: From Discovery to Modern and Alternative Synthetic Approaches

The global urgency in response to the COVID-19 pandemic has catalyzed extensive research into discovering efficacious antiviral compounds against SARS-CoV-2. Among these, Nirmatrelvir (PF-07321332) has emerged as a promising candidate, exhibiting potent antiviral activity by targeting the main protease of SARS-CoV-2, and has been marketed in combination with ritonavir as the first oral treatment for COVID-19 with the name of PaxlovidTM. This review outlines the synthetic approaches to Nirmatrelvir, ranging from Pfizer’s original method to newer, more sustainable strategies, such as flow chemistry strategies and multicomponent reactions. Each approach’s novelty and contributions to yield and purification processes are highlighted. Additionally, the synthesis of key fragments comprising Nirmatrelvir and innovative optimization strategies are discussed.

Medicinal perspective of a promising scaffold – dihydropyrimidinones: A review

AbstractDihydropyrimidinones (DHMPs) are the most important pharmacophore in Medicinal Chemistry. The synthetic approach for deriving DHMPs involves the Biginelli reaction or a combination of it with other multi‐component reactions (MCRs). The scaffold has received considerable attention due to its diverse therapeutic activity. This review delves into the exploration of the biological characteristics of DHMPs, which play a pivotal role in various therapeutic areas including “anti‐inflammatory, anti‐HIV, anticancer, antitubercular, antifungal, antibacterial, antihyperglycemic, antihypertensive, anticonvulsant, antimalarial, antioxidant,” reverse transcriptase (RT) inhibitor, antispasmodic, calcium channel blockers, antiproliferative, urease inhibitor, cyclooxygenase (COX‐2), and β‐glucuronidase inhibitor activities. The insights provided in this review have the potential to aid researchers in the formulation of novel drugs, facilitating creation of more resilient, efficient, and safer therapeutic agents with reduced toxicity and minimized adverse effects.

A Spherical Superhydrophobic Activated Carbon Catalyst for Biodiesel Production ‐Exploring Process Efficiency, Kinetics, Thermodynamics and Life Cycle Cost Analysis

AbstractEngineering the wettability of functional materials holds significant interest, focusing on the need for superhydrophobic catalysts, crucial for their ability to prevent the poisoning of active sites by water, produced in situ or as a by‐product. Herein, for the first time, a superhydrophobic spherical activated carbon (SSAC@PhSO3H) is engineered as a catalyst via a novel synthetic approach and tailored in Jatropha curcas oil (JCO) biodiesel synthesis. With a large surface area (1461 m2 g−1), high acid density (6.26 mmol g−1), and water contact angle (163.4°), the catalyst demonstrates superior performance and remarkable water repellency, firmly establishing its superhydrophobic characteristics. Response Surface Methodology based on the Central Composite Design (RSM‐CCD) approach predicted a maximal biodiesel yield of 98.8% (80 °C, 5 wt%, 15:1 methanol to oil molar ratio (MOMR), and 40 min). Life cycle cost analysis (LCCA) estimates biodiesel production cost of 0.37 USD ($) per kg emphasizing high commercial viability. Compared with H2SO4‐sulfonated biochar, SSAC@PhSO3H retains its inherent activity (86.8 ± 0.4% yield in 10th run) and spherical morphology even after nine successive reaction cycles indicating high stability. Nevertheless, JCO biodiesel's fuel properties met European Norm, EN 14 212 and American Society for Testing and Materials, ASTM D6757 standards, highlighting its potential for industrial biodiesel production.

Helically Chiral π-Expanded Azocines Through Regioselective Beckmann Rearrangement and Their Charged States.

We report a synthetic approach to π-expanded [6]helicenes incorporating tropone and azocine units in combination with a 5-membered ring, which exhibit intriguing structural, electronic, and chiroptical properties. The regioselective Beckmann rearrangement allows the isolation of helical scaffolds containing 8-membered lactam, azocine, and amine units. As shown by X-ray crystallographic analysis, the incorporation of tropone or azocine units leads to highly distorted [6]helicene moieties, with distinct packing motifs in the solid state. The compounds exhibit promising optoelectronic properties with considerable photoluminescence quantum yields and tunable emission wavelengths depending on the relative position of the nitrogen center within the polycyclic framework. Separation of the enantiomers by chiral high-performance liquid chromatography (HPLC) allowed characterization of their chiroptical properties by circular dichroism (CD) and circularly polarized luminescence (CPL) spectroscopy. The azocine compounds feature manifold redox chemistry, allowing for the characterization of the corresponding radical anions and cations as well as the dications and dianions, with near-infrared (NIR) absorption bands extending beyond 3000 nm. Detailed theoretical studies provided insights into the aromaticity evolution upon reduction and oxidation, suggesting that the steric strain prevents the azocine unit from undergoing aromatization, while the indene moiety dominates the observed redox chemistry.

Helically Chiral π‐Expanded Azocines Through Regioselective Beckmann Rearrangement and Their Charged States

AbstractWe report a synthetic approach to π‐expanded [6]helicenes incorporating tropone and azocine units in combination with a 5‐membered ring, which exhibit intriguing structural, electronic, and chiroptical properties. The regioselective Beckmann rearrangement allows the isolation of helical scaffolds containing 8‐membered lactam, azocine, and amine units. As shown by X‐ray crystallographic analysis, the incorporation of tropone or azocine units leads to highly distorted [6]helicene moieties, with distinct packing motifs in the solid state. The compounds exhibit promising optoelectronic properties with considerable photoluminescence quantum yields and tunable emission wavelengths depending on the relative position of the nitrogen center within the polycyclic framework. Separation of the enantiomers by chiral high‐performance liquid chromatography (HPLC) allowed characterization of their chiroptical properties by circular dichroism (CD) and circularly polarized luminescence (CPL) spectroscopy. The azocine compounds feature manifold redox chemistry, allowing for the characterization of the corresponding radical anions and cations as well as the dications and dianions, with near‐infrared (NIR) absorption bands extending beyond 3000 nm. Detailed theoretical studies provided insights into the aromaticity evolution upon reduction and oxidation, suggesting that the steric strain prevents the azocine unit from undergoing aromatization, while the indene moiety dominates the observed redox chemistry.

Design and Discovery of a Potent and Selective Inhibitor of Integrin αvβ1.

Selective inhibition of the RGD (Arg-Gly-Asp) integrin αvβ1 has been recently identified as an attractive therapeutic approach for the treatment of liver fibrosis given its function, target expression, and safety profile. Our identification of a non-RGD small molecule lead followed by focused, systematic changes to the core structure utilizing a crystal structure, in silico modeling, and a tractable synthetic approach resulted in the identification of a potent small molecule exhibiting a remarkable affinity for αvβ1 relative to several other integrin isoforms measured. Azabenzimidazolone 25 demonstrated antifibrotic efficacy in an in vivo rat liver fibrosis model and represents a tool compound capable of further exploring the biological consequences of selective αvβ1 inhibition.

Synthetic approach to Bell's inequalities and a fundamental Bell-type theorem

A fundamental Bell-type inequality is derived by referring solely to laws of logic, tertium non datur and the transitivity axiom, that are used to express the local realism assumption. The general form of the achieved inequality makes it a root of other more specific Bell-type theorems involving additional mathematical formalism and experimental conditions. Its universality is demonstrated explicitly by showing that the most famous theorems provided by Bell, Clauser, Horne, Shimony and Holt (CHSH), Clauser and Horne (CH), Eberhard, d'Espagnat and Maccone are direct corollaries of the general inequality. The method to retrieve Bell's inequalities of different kinds, as being based on a single scheme of reasoning, unifies diversity of proofs presented in the literature. Additionally, some of the known inequalities can be easily achieved in a more general form compared to their original versions and still suitable, or possibly even more convenient, for experimental investigations. By extracting local realism in the form of an explicit logical propositions and making it a cornerstone of a systematic reasoning leading to the universal Bell's inequality, the paper offers a synthetic perspective on Bell-type theorems and their logical basis.

Patents on PARP-1 Inhibitors for the Management of Cancer from 2017-2023.

There are eighteen members of the Poly (ADP-ribose) polymerases (PARPs) family, which oversee various cellular processes such as maintaining the integrity of the genome, regulating transcription, cell cycle progression, initiating the DNA damage response, and apoptosis. PARP1 is an essential member of the PARP family and plays a crucial role in repairing single-strand breaks in eukaryotic cells through a process called BER (base excision repair). It is the most extensively studied and commonly found member of this family. This article discusses the advancements in developing PARP inhibitors for human cancers. It covers the discovery of new PARP1 inhibitors with chemical classification that selectively target multiple areas using cancer models in vitro and in vivo and evaluates them critically. The focus is on patents that have been published from 2017 to 2023, except tankyrase inhibitors. PARP1 inhibitors were developed by various companies and academic groups from the 1990s to enhance the effectiveness of chemo and radiotherapy. However, their progress was hindered due to their severe toxicity when combined with these treatments. Therefore, on finding PARP1 inhibitors that can amplify the ability of chemotherapy agents to kill tumors while causing minimal toxicity, these substances can either be used alone as part of the synthetic lethality approach or in conjunction with radiotherapy or chemotherapy, resulting in a mutually beneficial outcome.

Pricing for a cooler planet: An empirical analysis of the effect of taxing carbon

Finland introduced the planet’s first carbon tax in 1990 to experiment with, to most economists, the best policy to reverse carbon emissions. I estimate the causal effect of taxing carbon on Finnish emissions using the Synthetic Control Approach (Abadie, 2021). The results suggest that taxing carbon reduces emissions by big margins. Finnish emissions are 16% lower in 1995, 25% lower in 2000, and 30% lower in 2004 than emissions in the counterfactual consistent with carbon taxes whose value increasing by 20 fold in 1990–2005. The estimates suggest that the carbon tax’s abatement elasticity is about 9%.

Metallaphotoredox deuteroalkylation utilizing thianthrenium salts

Deuterium labeling compounds play a crucial role in organic and pharmaceutical chemistry. The synthesis of such compounds typically involves deuterated building blocks, allowing for the incorporation of deuterium atoms and functional groups into a target molecule in a single step. Unfortunately, the limited availability of synthetic approaches to deuterated synthons has impeded progress in this field. Here, we present an approach utilizing alkyl-substituted thianthrenium salts that efficiently and selectively introduce deuterium at the α position of alkyl chains through a pH-dependent HIE process, using D2O as the deuterium source. The resulting α-deuterated alkyl thianthrenium salts, which bear two deuterium atoms, exhibit excellent selectivity and deuterium incorporation in electrophilic substitution reactions. Through in situ formation of isotopically labelled alkyl halides, these thianthrenium salts demonstrate excellent compatibility in a series of metallaphotoredox cross-electrophile coupling with (hetero)aryl, alkenyl, alkyl bromides, and other alkyl thianthrenium salts. Our technique allows for a wide range of substrates, high deuterium incorporation, and precise control over the site of deuterium insertion within a molecule such as the benzyl position, allylic position, or any alkyl chain in between, as well as neighboring heteroatoms. This makes it invaluable for synthesizing various deuterium-labeled compounds, especially those with pharmaceutical significance.

Rutaecarpine-inspired scaffold-hopping strategy and Ullmann cross-coupling based synthetic approach: Identification of pyridopyrimidinone-indole based novel anticancer chemotypes

Natural products as starting templates have shown historically major contribution to development of drugs. Inspired by the structure–function of an anticancer natural alkaloid Rutaecarpine, the Scaffold-hopped Acyclic Analogues of Rutaecarpine (SAAR) with ‘N’-atom switch (1°-hop) and ring-opening (2°-hop) were investigated. A new synthetic route was developed for an effective access to the analogues, i.e. 2-indolyl-pyrido[1,2-a]pyrimidinones, which involved preparation of N-Boc-N’-phthaloyltryptamine/mexamine-bromides and pyridopyrmidinon-2-yl triflate, a nickel/palladium-catalysed Ullmann cross-coupling of these bromides and triflate, deprotection of phthalimide followed by N-aroylation, and Boc-deprotection. Fourteen novel SAAR-compounds were prepared, and they showed characteristic antiproliferative activity against various cancer cells. Three most active compounds (11a, 11b, and 11c) exhibited good antiproliferative activity, IC50 7.7–15.8 µM against human breast adenocarcinoma cells (MCF-7), lung cancer cells (A549), and colon cancer cells (HCT-116). The antiproliferative property was also observed in the colony formation assay. The SAAR compound 11b was found to have superior potency than original natural product Rutaecarpine and an anticancer drug 5-FU in antiproliferative activities with relatively lower cytotoxicity towards normal breast epithelial cells (MCF10A) and significantly higher inhibitory effect on cancer cells’ migration. The compound 11b was found to possess favourable in silico physicochemical characteristics (lipophilicity-MLOGP, TPSA, and water solubility-ESOL, and others), bioavailability score, and pharmacokinetic properties (GI absorption, BBB non-permeant, P-gp, and CYP2D6). Interestingly, the compound 11b did not show any medicinal chemistry structural alert of PAINS and Brenk filter. The study represents for the first time the successful discovery of new potent anticancer chemotypes using Rutaecarpine natural alkaloid as starting template and reaffirms the significance of natural product-inspired scaffold-hopping technique in drug discovery research.

Synthesis and Cheminformatics-Directed Antibacterial Evaluation of Echinosulfonic Acid-Inspired Bis-Indole Alkaloids.

Synthetic efforts toward complex natural product (NP) scaffolds are useful ones, particularly those aimed at expanding their bioactive chemical space. Here, we utilised an orthogonal cheminformatics-based approach to predict the potential biological activities for a series of synthetic bis-indole alkaloids inspired by elusive sponge-derived NPs, echinosulfone A (1) and echinosulfonic acids A-D (2-5). Our work includes the first synthesis of desulfato-echinosulfonic acid C, an α-hydroxy bis(3'-indolyl) alkaloid (17), and its full NMR characterisation. This synthesis provides corroborating evidence for the structure revision of echinosulfonic acids A-C. Additionally, we demonstrate a robust synthetic strategy toward a diverse range of α-methine bis(3'-indolyl) acids and acetates (11-16) without the need for silica-based purification in either one or two steps. By integrating our synthetic library of bis-indoles with bioactivity data for 2048 marine indole alkaloids (reported up to the end of 2021), we analyzed their overlap with marine natural product chemical diversity. Notably, the C-6 dibrominated α-hydroxy bis(3'-indolyl) and α-methine bis(3'-indolyl) analogues (11, 14, and 17) were found to contain significant overlap with antibacterial C-6 dibrominated marine bis-indoles, guiding our biological evaluation. Validating the results of our cheminformatics analyses, the dibrominated α-methine bis(3'-indolyl) alkaloids (11, 12, 14, and 15) were found to exhibit antibacterial activities against methicillin-sensitive and -resistant Staphylococcus aureus. Further, while investigating other synthetic approaches toward bis-indole alkaloids, 16 incorrectly assigned synthetic α-hydroxy bis(3'-indolyl) alkaloids were identified. After careful analysis of their reported NMR data, and comparison with those obtained for the synthetic bis-indoles reported herein, all of the structures have been revised to α-methine bis(3'-indolyl) alkaloids.

ZIF-7-NH2 functionalized collagen fibers for effective and selective mercury ion capture

Adsorptive removal of mercury ion from wastewater has become a hot topic due to the toxicity and persistence; acquiring adsorbent materials with high-capacity, rapid-kinetic, super-selective while low-cost features are highly demanded. Herein, based on the full functionality of collagen fiber (CF) from the leather waste, we proposed an innovative synthetic approach through exploiting amino-functionalized ZIF-7 (ZIF-7-NH2) as functional groups to facilely in-situ incorporate with CF, affording low-cost but effective adsorbent materials of CF/ZIF-7-NH2 composite maximizing both functions of CF and ZIF-7-NH2 in the Hg(II) capture. Remarkably, it exhibits an ultra-high capacity as high as 909.09 mg g-1, fast kinetics that could remove 99.01 % of 200 mg·L-1 within 20 min, and significant selectivity of SHg/M (KdHg/KdM) as large as 522–1017 over Mg2+, K+, Ca2+, Cd2+, and Mn2+. We understand such an impressive adsorption is contributed by the synergistic action between functional groups including on the CF and ZIF-7-NH2. This study offers an effective method for removing heavy metal ions, achieving efficient removal of Hg(II) ions for pollution control, and promoting the reuse of waste CF to reduce waste accumulation in various aspects.

Direct Synthesis of Zinc-Blende ZnSe Nanoplatelets.

The distinct optical properties and electronic structures of two-dimensional colloidal nanoplatelets (NPLs) have garnered significant scientific and practical interest. However, concerns regarding the toxicity of cadmium-based NPLs and their limited spectral coverage show the importance of developing nontoxic alternatives. In this study, we devised a new synthetic approach for the direct synthesis of zinc-blende (ZB) ZnSe NPLs. By introducing two different zinc precursors, short-chain metal carboxylate- zinc acetate, and metal halide-zinc chloride, we successfully synthesized two-dimensional ZB ZnSe NPLs. By modifying the reaction parameters, we obtained two different populations of ZnSe NPLs, characterized by the first absorption peak at "343" and "367 nm". Ostwald ripening experiments further confirmed the formation of 2D ZnSe NPLs by the observed discrete growth mechanism. Lastly, we investigated the impact of surface ligands on the excitonic properties of ZB ZnSe NPLs by treating their initially carboxylic acid-capped surface with oleylamine. Remarkably, we observed significant red-shifting in the first excitonic peaks, up to 130 meV, in a reversible manner, demonstrating further tunability of excitonic features in ZnSe NPLs. We anticipate that our findings will serve as a catalyst for further exploration of nontoxic two-dimensional materials, fostering their investigation and application in various fields.

A general strategy for the synthesis of taxane diterpenes.

The carbon skeleton of any organic molecule serves as the foundation for its three-dimensional structure, playing a pivotal role in determining its physical and biological properties1. As such, taxane diterpenes are one of the most well-known natural product families, primarily owing to the success of their most prominent compound, paclitaxel, an effective anticancer therapeutic for more than 25 years2-6. In contrast to classical taxanes, the bioactivity of cyclotaxanes (also referred to as complex taxanes) remains significantly underexplored. The carbon skeletons of these two groups of taxanes differ significantly, and so would typically their own distinct synthetic approaches. Here we report a versatile synthetic strategy based on the interconversion of complex molecular frameworks, providing general access to the wider taxane diterpene family. A range of classical and cyclotaxane frameworks was prepared including, among others, the total syntheses of taxinine K (2), canataxapropellane (5) and dipropellane C from a single advanced intermediate. The synthetic approach deliberately eschews biomimicry, emphasizing instead the power of stereoelectronic control in orchestrating the interconversion of polycyclic frameworks.

Polymerase theta is a synthetic lethal target for killing Epstein-Barr virus lymphomas.

Treatment options for Epstein-Barr virus (EBV)-cancers are limited, underscoring the need for new therapeutic approaches. We have previously shown that EBV-transformed cells and cancers lack homologous recombination (HR) repair, a prominent error-free pathway that repairs double-stranded DNA breaks; instead, EBV-transformed cells demonstrate genome-wide scars of the error-prone microhomology-mediated end joining (MMEJ) repair pathway. This suggests that EBV-cancers are vulnerable to synthetic lethal therapeutic approaches that target MMEJ repair. Indeed, we have previously found that targeting PARP, an enzyme that contributes to MMEJ, results in the death of EBV-lymphoma cells. With the emergence of clinical resistance to PARP inhibitors and the recent discovery of inhibitors of Polymerase theta (POLθ), the polymerase essential for MMEJ, we investigated the role of POLθ in EBV-lymphoma cells. We report that EBV-transformed cell lines, EBV-lymphoma cell lines, and EBV-lymphomas in AIDS patients demonstrate greater abundance of POLθ, driven by the EBV protein EBNA1, compared to EBV-uninfected primary lymphocytes and EBV-negative lymphomas from AIDS patients (a group that also abundantly expresses POLθ). We also find POLθ enriched at cellular DNA replication forks and exposure to the POLθ inhibitor Novobiocin impedes replication fork progress, impairs MMEJ-mediated repair of DNA double-stranded breaks, and kills EBV-lymphoma cells. Notably, cell killing is not due to Novobiocin-induced activation of the lytic/replicative phase of EBV. These findings support a role for POLθ not just in DNA repair but also DNA replication and as a therapeutic target in EBV-lymphomas and potentially other EBV-cancers as EBNA1 is expressed in all EBV-cancers.IMPORTANCEEpstein-Barr virus (EBV) contributes to ~2% of the global cancer burden. With a recent estimate of >200,000 deaths a year, identifying molecular vulnerabilities will be key to the management of these frequently aggressive and treatment-resistant cancers. Building on our earlier work demonstrating reliance of EBV-cancers on microhomology-mediated end-joining repair, we now report that EBV lymphomas and transformed B cell lines abundantly express the MMEJ enzyme POLθ that likely protects cellular replication forks and repairs replication-related cellular DNA breaks. Importantly also, we show that a newly identified POLθ inhibitor kills EBV-cancer cells, revealing a novel strategy to block DNA replication and repair of these aggressive cancers.

Facile Synthesis of H-Phosphinates from P(OR)3 or ClP(OR)2 via SiO2-Promoted Hydrolysis.

H-Phosphinates represent a valuable class of organophosphorus building blocks and catalytic ligands. The existing synthetic approaches are generally associated with the use of strong acids, the need for meticulous treatment of intermediates, and the limitation of only P-aryl introductions. Following a comprehensive investigation into the unexpected SiO2-promoted hydrolysis observed during the chromatography workup of the crude R'P(OR)2 intermediates, we have developed an extremely simple and general synthetic route to H-phosphinates from commercially available Grignard reagents and P(OR)3. An alternative approach involved the use of ClP(OR)2 in place of P(OR)3, which proved to be a valuable strategy for the preparation of sterically hindered ArMgBr substrates bearing bulky ortho-substituted motifs. A library of 36 structurally diverse P-(cyclo)alkyl and P-(hetero)aryl H-phosphinates was thus obtained in moderate to high yields using this practical protocol. Furthermore, the CuCl2-mediated P(O)-H bond derivations were also examined, resulting in the formation of the corresponding EtOPhP(O)-X (X = O, N, S) compounds in nearly quantitative yields.

RhI-Catalysed Cycloisomerization Reactions of 1,7-Enynes to Access Cage-like Tricyclo[3.2.2.06,8]nonenes

Cage-like polycycles represent a class of structurally unique and biologically promising molecules. Whereas, efficient synthetic approaches are quite rare. This work disclosed the RhI-catalysed cycloisomerization reactions of 1,7-enynes containing a chelating group at the alkyne terminus, which afforded the unprecedented cage-like tricyclo[3.2.2.06,8]-nonenes via unprecedented 7-endo-dig cyclization. This work not only provides a straightforward approach to this novel cage-like tricycles, but also unveils the underexplored π-acidic reactivity of RhI catalyst with the assistance of secondary chelation.

Abstract PR007: Delineating functional drivers of esophageal adenocarcinoma to identify synthetic lethal interactions

Abstract Application of molecular targeted therapies for esophageal adenocarcinoma (EAC) has been limited by a lack of druggable oncogenic drivers. We propose that synthetic lethal interactions may provide new opportunities for targeted therapies in EAC. We have taken an integrated multi-omics approach incorporating Perturb-Seq (CRISPR editing combined with single cell RNA sequencing) and in vivo tumorigenesis assays to perform high-throughput characterisation of >70 high-confidence EAC driver genes, and genome-wide CRISPR-Cas9 knockout screens in isogenic models of EAC tumorigenesis to identify disease relevant synthetic lethal genetic interactions. MS-based proteomics, reverse phase protein arrays, polysome profiling and bulk RNA-sequencing of isogenic models were utilised to interrogate the biology of bona fide EAC drivers and associated driver specific gene dependencies. The overall goals were to (i) enhance our understanding of EAC tumorigenesis, (ii) identify potential opportunities for therapeutic interventions targeting EAC drivers via synthetic lethal-like approaches, and (iii) reduce the complexity of genetic heterogeneity by categorising EAC drivers with similar phenotypic outcomes. Through our approach we have identified complex crosstalk between the tumor suppressor SMAD4 and regulation of mTOR signaling, with specific downstream effects on translational reprogramming in EAC. Mutation or loss of SMAD4 occurs in up to 20% of EAC, but not pre-malignant tissue (Barrett’s esophagus), and is sufficient to promote transformation of pre-malignant cells in our in vivo tumorigenesis model. In this model, xenotransplanted SMAD4-deficient (via CRISPR-Cas9 knockout or shRNA knockdown) Barrett’s metaplasia cells formed invasive, metastatic tumors after a period of latency. SMAD4 deficient cells had downregulated expression of 4E-BP1, which inhibits EIF4E, the cap-dependent translation initiation factor. This was accompanied by increased mTOR activity, including phosphorylation and inactivation of 4EBP1. Moreover, we found that SMAD4-deficient cells preferentially upregulate cap-dependent translation at the expense of IRES mediated translation. Furthermore, perturbation of additional negative regulators of mTOR signaling in combination with SMAD4 knockout exacerbated these effects and accelerated tumorigenesis in vivo. We have extended these findings to a model of Barrett’s esophagus patient-derived organoids (PDOs) and observed increased proliferative potential of our genetically modified PDOs. Finally, analysing gene ontologies for differentially expressed genes from Perturb-seq revealed that driver-dependent transcriptional changes can be categorized into a smaller number of functional pathways allowing us to potentially consider groups of drivers as functional units. This work advances our understanding of EAC tumorigenesis, provides new mechanistic insights into SMAD4-driven transformation as well as novel potential therapeutic avenues for SMAD4-deficient EAC. Citation Format: Julia V. Milne, Ebtihal Mustafa, Kenji Fujihara, Eric Kusnadi, Anna Trigos, Niko Thio, Maree Pechlivanis, Carlos Cabalag, Twishi Gulati, Kaylene Simpson, Cuong Duong, Luc Furic, Wayne Phillips, Nicholas Clemons. Delineating functional drivers of esophageal adenocarcinoma to identify synthetic lethal interactions [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr PR007.