Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane.

Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly found para-substituted benzene rings in drug design1. The utility of these cage structures derives from their superior pharmacokinetic properties compared with their parent aromatics, including improved solubility and reduced susceptibility to metabolism2,3. A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesized by ring-opening of the interbridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions4. By contrast, scaffolds mimicking meta-substituted arenes are lacking because of the challenge of synthesizing saturated isosteres that accurately reproduce substituent vectors5. Here we show that bicyclo[3.1.1]heptanes (BCHeps), which are hydrocarbons for which the bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on a multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of the absorption, distribution, metabolism and excretion (ADME) properties of these analogues reveals enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta-arene analogue as an sp3-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a new surrogate for meta-substituted benzene rings for implementation in drug discovery programmes.

Intravenous iron therapy results in rapid and sustained rise in myocardial iron content through a novel pathway.

BACKGROUND AND AIMS: Intravenous iron therapies contain iron-carbohydrate complexes, designed to ensure iron becomes bioavailable via the intermediary of spleen and liver reticuloendothelial macrophages. How other tissues obtain and handle this iron remains unknown. This study addresses this question in the context of the heart. METHODS: A prospective observational study was conducted in 12 patients receiving ferric carboxymaltose (FCM) for iron deficiency. Myocardial, spleen, and liver magnetic resonance relaxation times and plasma iron markers were collected longitudinally. To examine the handling of iron taken up by the myocardium, intracellular labile iron pool (LIP) was imaged in FCM-treated mice and cells. RESULTS: In patients, myocardial relaxation time T1 dropped maximally 3 h post-FCM, remaining low 42 days later, while splenic T1 dropped maximally at 14 days, recovering by 42 days. In plasma, non-transferrin-bound iron (NTBI) peaked at 3 h, while ferritin peaked at 14 days. Changes in liver T1 diverged among patients. In mice, myocardial LIP rose 1 h and remained elevated 42 days after FCM. In cardiomyocytes, FCM exposure raised LIP rapidly. This was prevented by inhibitors of NTBI transporters T-type and L-type calcium channels and divalent metal transporter 1. CONCLUSIONS: Intravenous iron therapy with FCM delivers iron to the myocardium rapidly through NTBI transporters, independently of reticuloendothelial macrophages. This iron remains labile for weeks, reflecting the myocardium's limited iron storage capacity. These findings challenge current notions of how the heart obtains iron from these therapies and highlight the potential for long-term dosing to cause cumulative iron build-up in the heart.

Stereoselective Alder-Ene Reactions of Bicyclo[1.1.0]butanes: Facile Synthesis of Cyclopropyl- and Aryl-Substituted Cyclobutenes.

Bicyclo[1.1.0]butanes (BCBs), strained carbocycles comprising two fused cyclopropane rings, have become well-established building blocks in organic synthesis, medicinal chemistry, and chemical biology due to their diverse reactivity profile with radicals, nucleophiles, cations, and carbenes. The constraints of the bicyclic ring system confer high p-character on the interbridgehead C-C bond, leading to this broad reaction profile; however, the use of BCBs in pericyclic processes has to date been largely overlooked in favor of such stepwise, non-concerted additions. Here, we describe the use of BCBs as substrates for ene-like reactions with strained alkenes and alkynes, which give rise to cyclobutenes decorated with highly substituted cyclopropanes and arenes. The former products are obtained from highly stereoselective reactions with cyclopropenes, generated in situ from vinyl diazoacetates under blue light irradiation (440 nm). Cyclobutenes featuring a quaternary aryl-bearing carbon atom are prepared from equivalent reactions with arynes, which proceed in high yields under mild conditions. Mechanistic studies highlight the importance of electronic effects in this chemistry, while computational investigations support a concerted pathway and rationalize the excellent stereoselectivity of reactions with cyclopropenes.

Beyond Strain Release: Delocalization-Enabled Organic Reactivity.

The release of strain energy is a fundamental driving force for organic reactions. However, absolute strain energy alone is an insufficient predictor of reactivity, evidenced by the similar ring strain but disparate reactivity of cyclopropanes and cyclobutanes. In this work, we demonstrate that electronic delocalization is a key factor that operates alongside strain release to boost, or even dominate, reactivity. This delocalization principle extends across a wide range of molecules containing three-membered rings such as epoxides, aziridines, and propellanes and also applies to strain-driven cycloaddition reactions. Our findings lead to a "rule of thumb" for the accurate prediction of activation barriers in such systems, which can be easily applied to reactions involving many of the strained building blocks commonly encountered in organic synthesis, medicinal chemistry, polymer science, and bioconjugation. Given the significance of electronic delocalization in organic chemistry, for example in aromatic π-systems and hyperconjugation, we anticipate that this concept will serve as a versatile tool to understand and predict organic reactivity.

Gold-Catalyzed Cyclization of Yndiamides with Isoxazoles via α-Imino Gold Fischer Carbenes.

Gold catalysis is an important method for alkyne functionalization. Here we report the gold-catalyzed formal [3+2] aminative cyclization of yndiamides and isoxazoles in a direct synthesis of polysubstituted diaminopyrroles, which are important motifs in drug discovery. Key to this process is the formation, and subsequent cyclization, of an α-imino gold Fischer carbene, which represents a new type of gold carbene intermediate. The reaction proceeds rapidly under mild conditions, with high regioselectivity being achieved by introducing a subtle steric bias between the nitrogen substituents on the yndiamide. DFT calculations revealed that the key to this regioselectivity was the interconversion of isomeric gold keteniminiun ions via a low-barrier π-complex transition state, which establishes a Curtin-Hammett scenario for isoxazole addition. By using benzisoxazoles as substrates, the reaction outcome could be switched to a formal [5+2] cyclization, leading to 1,4-oxazepines.

Synthetic Study toward Triterpenes from the Schisandraceae Family of Natural Products.

Triterpenoid natural products from the Schisandraceae family have long presented a significant synthetic challenge. Lancifodilactone I, a member of the family not previously synthesized, was identified as a key natural product target, from which many other members could be synthesized. We envisaged that the core ring system of lancifodilactone I could be accessed by a strategy involving palladium-catalysed cascade cyclisation of a bromoenynamide, via carbopalladation, Suzuki coupling and 8π-electrocyclisation, to synthesize the core 7,8-fused ring system. Exploration of this strategy on model systems resulted in efficient syntheses of 5,6- and 5,8-fused systems in high yields, which represent the first such cyclisation where the ynamide nitrogen atom is 'external' to the forming ring system. The enamide functionality resident in the cascade cyclisation product was found to be less nucleophilic than the accompanying tri-/tetrasubstituted alkene(s), enabling regioselective oxidations. Application of this strategy to 7,6-, and 7,8-fused systems, and ultimately the 'real' substrate, was ultimately thwarted by the difficulty of 7-membered ring closure, leading to side product formation. Nevertheless, a tandem bromoenynamide carbopalladation, Suzuki coupling and 6/8π-electrocyclisation was shown to be a highly efficient tactic for the formation of bicyclic enamides, which may find applications in other synthetic contexts.

Rapid and Scalable Halosulfonylation of Strain-Release Reagents.

Sulfonylated aromatics are commonplace motifs in drugs and agrochemicals. However, methods for the direct synthesis of sulfonylated non-classical arene bioisosteres, which could improve the physicochemical properties of drug and agrochemical candidates, are limited. Here we report a solution to this challenge: a one-pot halosulfonylation of [1.1.1]propellane, [3.1.1]propellane and bicyclo[1.1.0]butanes that proceeds under practical, scalable and mild conditions. The sulfonyl halides used in this chemistry feature aryl, heteroaryl and alkyl substituents, and are conveniently generated in situ from readily available sulfinate salts and halogen atom sources. This methodology enables the synthesis of an array of pharmaceutically and agrochemically relevant halogen/sulfonyl-substituted bioisosteres and cyclobutanes, on up to multidecagram scale.

Collective Synthesis of Illudalane Sesquiterpenes via Cascade Inverse Electron Demand (4 + 2) Cycloadditions of Thiophene S,S-Dioxides.

Thiophene S,S-dioxides are underutilized tools for the de novo construction of benzene rings in organic synthesis. We report a collective synthesis of nine illudalane sesquiterpenes using bicyclic thiophene S,S-dioxides as generalized precursors to the indane core of the natural products. Exploiting furans as unusual dienophiles in this inverse electron demand Diels-Alder cascade, this concise and convergent approach enables the synthesis of these targets in as little as five steps. Theoretical studies rationalize the reactivity of thiophene S,S-dioxides with both electron-poor and electron-rich dienophiles and reveal reaction pathways involving either nonpolar pericyclic or bifurcating ambimodal cycloadditions. Overall, this work demonstrates the wider potential of thiophene S,S-dioxides as convenient and flexible precursors to polysubstituted arenes.

Multiple approaches to repurposing drugs for neuroblastoma.

Neuroblastoma (NB) is the second leading extracranial solid tumor of early childhood with about two-thirds of cases presenting before the age of 5, and accounts for roughly 15 percent of all pediatric cancer fatalities in the United States. Treatments against NB are lacking, resulting in a low survival rate in high-risk patients. A repurposing approach using already approved or clinical stage compounds can be used for diseases for which the patient population is small, and the commercial market limited. We have used Bayesian machine learning, in vitro cell assays, and combination analysis to identify molecules with potential use for NB. We demonstrated that pyronaridine (SH-SY5Y IC50 1.70 µM, SK-N-AS IC50 3.45 µM), BAY 11-7082 (SH-SY5Y IC50 0.85 µM, SK-N-AS IC50 1.23 µM), niclosamide (SH-SY5Y IC50 0.87 µM, SK-N-AS IC50 2.33 µM) and fingolimod (SH-SY5Y IC50 4.71 µM, SK-N-AS IC50 6.11 µM) showed cytotoxicity against NB. As several of the molecules are approved drugs in the US or elsewhere, they may be repurposed more readily for NB treatment. Pyronaridine was also tested in combinations in SH-SY5Y cells and demonstrated an antagonistic effect with either etoposide or crizotinib. Whereas when crizotinib and etoposide were combined with each other they had a synergistic effect in these cells. We have also described several analogs of pyronaridine to explore the structure-activity relationship against cell lines. We describe multiple molecules demonstrating cytotoxicity against NB and the further evaluation of these molecules and combinations using other NB cells lines and in vivo models will be important in the future to assess translational potential.

2'-Alkynyl spin-labelling is a minimally perturbing tool for DNA structural analysis.

The determination of distances between specific points in nucleic acids is essential to understanding their behaviour at the molecular level. The ability to measure distances of 2-10 nm is particularly important: deformations arising from protein binding commonly fall within this range, but the reliable measurement of such distances for a conformational ensemble remains a significant challenge. Using several techniques, we show that electron paramagnetic resonance (EPR) spectroscopy of oligonucleotides spin-labelled with triazole-appended nitroxides at the 2' position offers a robust and minimally perturbing tool for obtaining such measurements. For two nitroxides, we present results from EPR spectroscopy, X-ray crystal structures of B-form spin-labelled DNA duplexes, molecular dynamics simulations and nuclear magnetic resonance spectroscopy. These four methods are mutually supportive, and pinpoint the locations of the spin labels on the duplexes. In doing so, this work establishes 2'-alkynyl nitroxide spin-labelling as a minimally perturbing method for probing DNA conformation.

Advances in polycyclization cascades in natural product synthesis.

Cascade reactions (also known as domino reactions) are arguably the most powerful means to achieve the construction of multiple ring systems in a single step. In this Tutorial Review, highlights in cascade polycyclizations applied to natural product syntheses over the last five years are discussed, including pericyclic, ionic, metal-catalyzed, organocatalytic, and radical processes. Significant developments in each of these fields that have advanced the state-of-the-art are a particular focus, including photochemical and electrochemical methods, novel biomimetic routes, and enantioselective cascades.

Impact of the COVID-19 lockdown on liver transplant recipients. A single center observational study.

BACKGROUND: the impact of the COVID-19 outbreak and lockdown on liver transplant (LT) patients remains unknown. The aim of this cross-sectional study was to assess the consequences of the COVID-19 pandemic on the physical and mental health of LT patients during the lockdown period. METHODS: a web-based questionnaire was emailed to 238 LT patients undergoing regular follow-up at our unit between August and October 2020. This pseudonymized survey explored demographic and lifestyle variables (i.e., eating and physical habits), disruptions in routine medical care, different dimensions of mental health, COVID-19-related mood and coping (worries/anxiety, depression, insomnia, fear of COVID, resilience, etc.) and health perception using different validated instruments. RESULTS: altogether, 48.7 % (116 of 238) LT recipients accepted to participate in the study, 104 of whom gave their consent to publish the data. The median age was 63 years. Up to 39.4 % presented worrying scores indicating moderate/severe generalized anxiety disorder (GAD), whereas 25.5 % exhibited moderate/severe insomnia and only 10.5 % moderate/severe depression. Forty patients (38.5 %) gained weight, 24 % experienced a worsening in their eating habits and 63.4 % referred to practicing less or much less exercise during the lockdown. Only 25 % perceived a worsening in the control of their chronic comorbidities. Missed medical appointments (0.9 %) or poor adherence to therapy (1.9 %) were exceptional. CONCLUSIONS: COVID-19 lockdown has negatively impacted the mental and physical health of LT patients. Long-term consequences remain unclear.

Synthesis and Applications of Polysubstituted Bicyclo[1.1.0]butanes.

Bicyclo[1.1.0]butanes (BCBs) are valuable substrates in the "strain release" synthesis of polysubstituted four-membered ring systems, with applications including bioconjugation agents. The introduction of substituents onto the BCB bridges is challenging due to limitations in current methods for the preparation of this bicyclic scaffold, typically necessitating linear syntheses with limited functional group tolerance and/or substituent scope. Here, we report the synthesis of tri- and tetrasubstituted BCBs via directed metalation of readily accessed BCB amides; this straightforward "late stage" approach generates a wide variety of bridge-substituted BCBs that can be easily converted into other useful small ring building blocks. Access to a monodeuterated BCB afforded unprecedented insight into the mechanism of dihalocarbene insertion into BCBs to afford bicyclo[1.1.1]pentanes (BCPs).

Twofold Radical-Based Synthesis of N,C-Difunctionalized Bicyclo[1.1.1]pentanes.

Bicyclo[1.1.1]pentylamines (BCPAs) are of growing importance to the pharmaceutical industry as sp3-rich bioisosteres of anilines and N-tert-butyl groups. Here we report a facile synthesis of 1,3-disubstituted BCPAs using a twofold radical functionalization strategy. Sulfonamidyl radicals, generated through fragmentation of α-iodoaziridines, undergo initial addition to [1.1.1]propellane to afford iodo-BCPAs; the newly formed C-I bond in these products is then functionalized via a silyl-mediated Giese reaction. This chemistry also translates smoothly to 1,3-disubstituted iodo-BCPs. A wide variety of radical acceptors and iodo-BCPAs are accommodated, providing straightforward access to an array of valuable aniline-like isosteres.

Marine alkaloids as bioactive agents against protozoal neglected tropical diseases and malaria.

Covering: 2000 up to 2021Natural products are an important resource in drug discovery, directly or indirectly delivering numerous small molecules for potential development as human medicines. Among the many classes of natural products, alkaloids have a rich history of therapeutic applications. The extensive chemodiversity of alkaloids found in the marine environment has attracted considerable attention for such uses, while the scarcity of these natural materials has stimulated efforts towards their total synthesis. This review focuses on the biological activity of marine alkaloids (covering 2000 to up to 2021) towards Neglected Tropical Diseases (NTDs) caused by protozoan parasites, and malaria. Chemotherapy represents the only form of treatment for Chagas disease, human African trypanosomiasis, leishmaniasis and malaria, but there is currently a restricted arsenal of drugs, which often elicit severe adverse effects, show variable efficacy or resistance, or are costly. Natural product scaffolds have re-emerged as a focus of academic drug discovery programmes, offering a different resource to discover new chemical entities with new modes of action. In this review, the potential of a range of marine alkaloids is analyzed, accompanied by coverage of synthetic efforts that enable further studies of key antiprotozoal natural product scaffolds.

Synthesis of Sulfonamide-Based Ynamides and Ynamines in Water.

Ynamides, though relatively more stable than ynamines, are still moisture-sensitive and prone to hydration especially under acidic and heating conditions. Here we report an environmentally benign, robust protocol to synthesize sulfonamide-based ynamides and arylynamines via Sonogashira coupling reactions in water, using a readily available quaternary ammonium salt as the surfactant.

Race and Gender Disparity in the Surgical Management of Hepatocellular Cancer: Analysis of the Surveillance, Epidemiology, and End Results (SEER) Program Registry.

BACKGROUND: The existence of race and gender disparity has been described in numerous areas of medicine. The management of hepatocellular cancer is no different, but in no other area of medicine, is the treatment algorithm more complicated by local, regional, and national health care distribution policy. METHODS: Multivariate logistic regression and Cox-regression were utilized to analyze the treatment of patients with hepatocellular cancer registered in SEER between 1999 and 2013 to determine the incidence and effects of racial and gender disparity. Odd ratios (OR) are relative to Caucasian males, SEER region, and tumor characteristics. RESULTS: The analysis of 57,449 patients identified the minority were female (25.31%) and African-American (16.26%). All tumor interventions were protective (p < 0.001) with respect to survival. The mean survival for all registered patients was 13.01 months with conditional analysis, confirming that African-American men were less likely to undergo ablation, resection, or transplantation (p < 0.001). Women were more likely to undergo resection (p < 0.001). African-American women had an equivalent OR for resection but had a significantly lower transplant rate (p < 0.001). CONCLUSIONS: Utilizing SEER data as a surrogate for patient navigation in the treatment of hepatocellular cancer, our study identified not only race but gender bias with African-American women suffering the greatest. This is underscored by the lack of navigation of African-Americans to any therapy and a significant bias to navigate female patients to resection potentially limiting subsequent access to definitive therapy namely transplantation.

Examining the Direct and Indirect Effects of Mothers' Rejection from the Ex-Spouse on Time to Repartnering.

Individuals who feel rejected following relationship dissolution typically experience reductions in their health and wellbeing. Although feelings of rejection can be painful, the acquisition of a new romantic relationship can help to ease this pain. The goal of this study is to examine the direct and indirect effects of divorced residential mothers' rejection from the ex-spouse on their time to entering post-divorce romantic relationships. Results indicate that mothers' rejection from the ex-spouse is significantly associated with delays in repartnering. Results indicated two marginally significant indirect effects, providing some evidence that mothers' rejection from the ex-spouse and delayed repartnering is transmitted through decreases in mothers' depressive symptoms and increases in mothers' barriers to repartnering. These findings demonstrate the importance of promoting divorced mothers' self-perceptions following divorce.

Structure-activity relationship study of cytotoxic neolignan derivatives using multivariate analysis and computation-aided drug design.

Dehydrodieugenol B and five related natural neolignans were isolated from the Brazilian plant species Nectandra leucantha. Three of these compounds were shown to be active against murine (B16F10) and human (A2058) melanoma cells but non-toxic to human fibroblasts (T75). These results stimulated the preparation of a series of 23 semi-synthetic derivatives in order to explore structure-activity relationships and study the biological potential of these derivatives against B16F10 and A2058 cell lines. These structurally-related neolignan derivatives were analyzed by multivariate statistics and machine learning, which indicated that the most important characteristics were related to their three-dimensional structure and, mainly, to the substituents on the neolignan skeleton. The results suggested that the presence of hydroxyl or alkoxyl groups at positions 3, 4 and 5 (with appropriate sidechains) promoted an increase in electropological and charge density, which seem to be important for biological activity against murine (B16F10) and human (A2058) melanoma cells.

Synthesis of All-Carbon Disubstituted Bicyclo[1.1.1]pentanes by Iron-Catalyzed Kumada Cross-Coupling.

1,3-Disubstituted bicyclo[1.1.1]pentanes (BCPs) are important motifs in drug design as surrogates for p-substituted arenes and alkynes. Access to all-carbon disubstituted BCPs via cross-coupling has to date been limited to use of the BCP as the organometallic component, which restricts scope due to the harsh conditions typically required for the synthesis of metallated BCPs. Here we report a general method to access 1,3-C-disubstituted BCPs from 1-iodo-bicyclo[1.1.1]pentanes (iodo-BCPs) by direct iron-catalyzed cross-coupling with aryl and heteroaryl Grignard reagents. This chemistry represents the first general use of iodo-BCPs as electrophiles in cross-coupling, and the first Kumada coupling of tertiary iodides. Benefiting from short reaction times, mild conditions, and broad scope of the coupling partners, it enables the synthesis of a wide range of 1,3-C-disubstituted BCPs including various drug analogues.