Related Analogues Research Articles

A third generation PSMA-targeted agent [211At]YF2: Synthesis and in vivo evaluation

IntroductionTargeted α-particle therapy agents have shown promising responses in patients who have developed resistance to β-particle emitting radionuclides, albeit off-target toxicity remains a concern. Astatine-211 emits only one α-particle per decay and may alleviate the toxicity from α-emitting daughter radionuclides. Previously, we developed the low-molecular-weight PSMA-targeted agent [211At]L3-Lu that showed suitable therapeutic efficacy and was well tolerated in mice. Although [211At]L3-Lu had good characteristics, we now have evaluated a closely related analogue, [211At]YF2, to determine the better molecule for clinical translation. MethodsThe tin precursors and unlabeled iodo standards for [211At]YF2 and [211At]L3-Lu each were synthesized and a new one-step labeling method was developed to produce [211At]YF2 and [211At]L3-Lu from the respective tin precursor. RCY and RCP were determined using RP-HPLC. Cell uptake, internalization and in vitro cell-killing (MTT) assays were performed on PSMA+ PC-3 PIP cells in parallel experiments to compare [211At]YF2 and [211At]L3-Lu directly. A paired-label biodistribution study was performed in athymic mice with subcutaneous PSMA-positive PC-3 PIP xenografts as a head-to-head comparison of [131I]YF2 and [125I]L3-Lu. The tissue distribution of [211At]YF2 and [211At]L3-Lu were determined individually in the same animal model. Finally, the effect of co-injecting unlabeled iodinated YF2 on the biodistribution of [211At]YF2 was evaluated in the same animal model. ResultsThe syntheses of tin precursors and unlabeled iodo standards were accomplished in reasonable yields. A streamlined and scalable radiolabeling method (1 h total synthesis time) was developed for the radiosynthesis of both [211At]YF2 and [211At]L3-Lu with 86 ± 7 % (n = 10) and 87 ± 5 % (n = 7) RCY, respectively, and > 95 % RCP for both. The maximum activity of [211At]YF2 produced to date was 666 MBq. An alternative method that did not involve HPLC purification was developed that provided similar RCY and RCP. Significantly higher cell uptake, internalization and cytotoxicity was seen for [211At]YF2 compared with [211At]L3-Lu. Significantly higher uptake and longer retention in tumor was seen for [131I]YF2 than for co-administered [125I]L3-Lu, while considerably higher renal uptake was seen for [131I]YF2. The biodistribution of [211At]YF2 was consistent with that of [131I]YF2. Co-injection of 2 nmole iodinated YF2 reduced renal uptake of [211At]YF2 by 6-fold without significantly changing tumor uptake. Conclusion[211At]YF2 exhibited higher cellular uptake, internalization and cytotoxicity than [211At]L3-Lu on PSMA-positive PC3 PIP cells. Likewise, higher uptake and longer retention in tumor was seen for [211At]YF2. Experiments to evaluate the dosimetry and therapeutic efficacy of [211At]YF2 are under way.

It Depends

While Comic-Con is a celebration of popular culture, it is also a launching pad for new properties in film and television. In recent years, the conventional thought about how to approach this has changed from handing out free memorabilia such as tee shirts and posters to providing an actual experience in the properties world. This type of advertising is the immersive activation. The goal of the activation is an analogous relationship between the live experience and the mediated, neither serving as the precedent to the other. In embracing this analogous relationship, mediatized and live performances move forward, establishing new entanglements with their audience. The clearest example of this analogous relationship exists in activations. An immersive activation is a live-action event where the spectator is tasked with the moniker of both audience and participant. The shift from “viewer” to “collaborator” is, as Clair Bishop (2012) and so many others have noted, manifested in fascinating and new creations. I take an approach following neuroscientific discoveries, which support this shift through different means joining the brain’s function with philosophy, as I explore the immersive activation.

Anti-inflammatory Steroids from the South China Sea Sponge Spongia officinalis.

One new highly degraded steroid, namely 21-nor-4-ene-chaxine A (1) furnishing a 5/6/5-tricyclic, along with one known related analogue (2), were isolated from the South China Sea sponge Spongia officinalis. Their structures including absolute configurations were established by extensive spectroscopic data analysis, TDDFT-ECD calculation, and comparison with the spectral data previously reported in the literature. Compound 1 represent the new member of incisterols family with a highly degradation in ring B. In vitro bioassays revealed compound 2 exhibited significant anti-microglial inflammatory effect on lipopolysaccharide (LPS)-induced inflammation in BV-2 microglial cells.

Novel enzyme-resistant pancreatic polypeptide analogs evoke pancreatic beta-cell rest, enhance islet cell turnover, and inhibit food intake in mice.

Pancreatic polypeptide (PP) is a postprandial hormone secreted from pancreatic islets that activates neuropeptide Y4 receptors (NPY4Rs). PP is known to induce satiety but effects at the level of the endocrine pancreas are less well characterized. In addition, rapid metabolism of PP by dipeptidyl peptidase-4 (DPP-4) limits the investigation of the effects of the native peptide. Therefore, in the present study, five novel amino acid substituted and/or fatty acid derivatized PP analogs were synthesized, namely [P3]PP, [K13Pal]PP, [P3,K13Pal]PP, [N-Pal]PP, and [N-Pal,P3]PP, and their impact on pancreatic beta-cell function, as well as appetite regulation and glucose homeostasis investigated. All PP analogs displayed increased resistance to DPP-4 degradation. In addition, all peptides inhibited alanine-induced insulin secretion from BRIN-BD11 beta cells. Native PP and related analogs (10-8 and 10-6 M), and especially [P3]PP and [K13Pal]PP, significantly protected against cytokine-induced beta-cell apoptosis and promoted cellular proliferation, with effects dependent on the NPY4R for all peptides barring [N-Pal,P3]PP. In mice, all peptides, except [N-Pal]PP and [N-Pal,P3]PP, evoked a dose-dependent (25, 75, and 200 nmol/kg) suppression of appetite, with native PP and [P3]PP further augmenting glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) induced reductions of food intake. The PP peptides had no obvious detrimental effect on glucose tolerance and they did not noticeably impair the glucose-regulatory actions of GLP-1 or CCK. In conclusion, Pro3 amino acid substitution of PP, either alone or together with mid-chain acylation, creates PP analogs with benefits on beta-cell rest, islet cell turnover, and energy regulation that may be applicable to the treatment of diabetes and obesity.

PH-Tolerant Wet Adhesion of Catechol Analogs.

The need for improved wet adhesives has driven research on mussel-inspired materials incorporating dihydroxyphenylalanine (DOPA) and related analogs of the parent catechol, but their susceptibility to oxidation limits practical application of these functionalities. Here, we investigate the molecular-level adhesion of the catechol analogs dihydroxybenzamide (DHB) and hydroxypyridinone (HOPO) as a function of pH. We find that the molecular structure of the catechol analogs influences their susceptibility to oxidation in alkaline conditions, with HOPO emerging as a particularly promising candidate for pH-tolerant adhesives for diverse environmental conditions.

Synthesis and Functional Evaluation of Synthetic Cannabinoid Receptor Agonists Related to ADB-HEXINACA.

ADB-HEXINACA has been recently reported as a synthetic cannabinoid receptor agonist (SCRA), one of the largest classes of new psychoactive substances (NPSs). This compound marks the entry of the n-hexyl tail group into the SCRA landscape, which has continued in the market with recent, newly detected SCRAs. As such, a proactive characterization campaign was undertaken, including the synthesis, characterization, and pharmacological evaluation of ADB-HEXINACA and a library of 41 closely related analogues. Two in vitro functional assays were employed to assess activity at CB1 and CB2 cannabinoid receptors, measuring Gβγ-coupled agonism through a fluorescence-based membrane potential assay (MPA) and β-arrestin 2 (βarr2) recruitment via a live cell-based nanoluciferase complementation reporter assay. ADB-HEXINACA was a potent and efficacious CB1 agonist (CB1 MPA pEC50 = 7.87 ± 0.12 M; Emax = 124 ± 5%; βarr2 pEC50 = 8.27 ± 0.14 M; Emax = 793 ± 42.5), as were most compounds assessed. Isolation of the heterocyclic core and alkyl tails allowed for the comprehensive characterization of structure-activity relationships in this compound class, which were rationalized in silico via induced fit docking experiments. Overall, most compounds assessed are possibly emerging NPSs.

Abstract LB173: Discovery of ALTA-2618, the first allosteric, mutant-selective targeted therapy for AKT1 E17K driven cancers

Abstract BACKGROUND: AKT1 E17K is a clinically validated oncogenic driver mutated in ~1-2% of all cancers and is enriched in several solid tumors including breast (~5%), endometrial (~3%) and prostate (~1.5%) cancer. Over half of AKT1 E17K mutant breast and gynecologic cancers are homozygous for the mutant oncogene with loss of the wildtype (WT) AKT1 allele via copy-neutral loss-of-heterozygosity (CN-LOH), suggesting uniquely potent oncogene addiction in these tumor types. While inhibitors of WT PI3K or AKT have demonstrated clinical efficacy in HR+/HER2- metastatic breast cancers with PI3K/AKT pathway mutations, on-target adverse events - most commonly hyperglycemia, diarrhea, and rash - have hindered the tolerability and durability of these agents. We aimed to exploit the mutant lysine of the E17K variant to develop a covalent, highly mutant-selective inhibitor that would avoid the toxicities associated with WT AKT inhibition. METHODS: Structure-based design was guided by proprietary co-crystal structures, enabling a refined pharmacophore consensus model, which fueled novel small molecule covalent design iterations using an in-house computational chemistry cluster. Lead molecules were identified from cellular signaling assays assessing pAKT S473 suppression and selectivity over WT AKT1 and AKT2. Rapid PK assessments were performed in mice, rats, dogs, and cynomolgus monkeys. Molecules with low clearance and high oral bioavailability were advanced directly to breast and endometrial PDX models driven by AKT1 E17K mutations. RESULTS: We identified ALTA-2618, a potent (7nM EC50) inhibitor of AKT1 E17K with 22x selectivity over WT AKT1 and 140x selectivity over WT AKT2. ALTA-2618 and related analogues demonstrated covalent attachment to the AKT1 E17K protein via intact mass spectrometry, and electron density analysis of co-crystal structures of highly similar family members of ALTA-2618 reveals unambiguous covalent attachment to the K17 side chain. Based on favorable exposure-response relationships and ideal cross-species PK, ALTA-2618 was tested in once daily oral dosing and induced tumor regressions in AKT1 E17K mutant HR+/HER2low breast cancer, TNBC, and endometrial cancer PDXs at doses as low as 10 mg/kg/d. Complete responses were observed with 30 mg/kg/d in the HR+/HER2low breast PDX model that were sustained for 60 days of dosing without significant body weight loss or hyperglycemia. CONCLUSIONS: ALTA-2618 is a potent, highly mutant-selective AKT1 E17K inhibitor that demonstrates favorable PK and tolerability with oral once-daily dosing that enables prolonged tumor regressions in multiple AKT1 E17K-mutant PDX models. These data support a mid-2024 IND submission to investigate ALTA-2618 in patients with AKT1 E17K mutant cancers. Citation Format: Eric A. Murphy, Michael D. Bartberger, Maureen Ibanez, Troy T. Smith, Nicole Alvarez, Noel Timple, Xuefeng Zhu, Kevin Fan, Kevin Yu. Discovery of ALTA-2618, the first allosteric, mutant-selective targeted therapy for AKT1 E17K driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB173.

The mechanism of covalent inhibition of LAR phosphatase by illudalic acid

Leukocyte antigen-related (LAR) phosphatase is a receptor-type protein tyrosine phosphatase involved in cellular signaling and associated with human disease including cancer and metabolic disorders. Selective inhibition of LAR phosphatase activity by well characterized and well validated small molecules would provide key insights into the roles of LAR phosphatase in health and disease, but identifying selective inhibitors of LAR phosphatase activity has been challenging. Recently, we described potent and selective inhibition of LAR phosphatase activity by the fungal natural product illudalic acid. Here we provide a detailed biochemical characterization of the adduct formed between LAR phosphatase and illudalic acid. A mass spectrometric analysis indicates that two cysteine residues are covalently labeled by illudalic acid and a related analog. Mutational analysis supports the hypothesis that inhibition of LAR phosphatase activity is due primarily to the adduct with the catalytic cysteine residue. A computational study suggests potential interactions between the illudalic acid moiety and the enzyme active site. Taken together, these data offer novel insights into the mechanism of inhibition of LAR phosphatase activity by illudalic acid.

Electrical/piezoresistive effects in bent Alpide MAPS

The ITS3 upgrade baseline design employs MAPS (Monolithic Active Pixel Sensor) in bent state. Bending experiments with the existing ITS2 MAPS (=Alpide chip) show it remains functional but with relative large analog supply current changes. It is shown that by the piezoresistive effect, rotation of current mirror FETs can be responsible which was confirmed after validating the layout. Measured Gauge Factor has proper sign but is 3 times lower than typical values derived from literature. The magnitude of the measured strain induced PMOS V th shift is as expected but the sign differs for compressive strain with some of the literature.

Synthesis of obovatol and related neolignan analogues as α-glucosidase and α-amylase inhibitors

Diabetes mellitus is a metabolic disease characterized by hyperglycemia, which can be counteracted by the inhibition of α-glucosidase (α-Glu) and α-amylase (α-Amy), enzymes responsible for the hydrolysis of carbohydrates. In recent decades, many natural compounds and their bioinspired analogues have been studied as α-Glu and α-Amy inhibitors. However, no studies have been devoted to the evaluation of α-Glu and α-Amy inhibition by the neolignan obovatol (1). In this work, we report the synthesis of 1 and a library of new analogues. The synthesis of these compounds was achieved by implementing methodologies based on: phenol allylation, Claisen/Cope rearrangements, methylation, Ullmann coupling, demethylation, phenol oxidation and Michael-type addition. Obovatol (1) and ten analogues were evaluated for their in vitro inhibitory activity towards α-Glu and α-Amy. Our investigation highlighted that the naturally occurring 1 and four neolignan analogues (11, 22, 26 and 27) were more effective inhibitors than the hypoglycemic drug acarbose (α-Amy: 34.6 µM; α-Glu: 248.3 µM) with IC5O value of 6.2–23.6 µM toward α-Amy and 39.8–124.6 µM toward α-Glu. Docking investigations validated the inhibition outcomes, highlighting optimal compatibility between synthesized neolignans and both the enzymes. Concurrently circular dichroism spectroscopy detected the conformational changes in α-Glu induced by its interaction with the studied neolignans. Detailed studies through fluorescence measurements and kinetics of α-Glu and α-Amy inhibition also indicated that 1, 11, 22, 26 and 27 have the greatest affinity for α-Glu and 1, 11 and 27 for α-Amy. Surface plasmon resonance imaging (SPRI) measurements confirmed that among the compounds studied, the neolignan 27 has the greater affinity for both enzymes, thus corroborating the results obtained by kinetics and fluorescence quenching. Finally, in vitro cytotoxicity of the investigated compounds was tested on human colon cancer cell line (HCT-116). All these results demonstrate that these obovatol-based neolignan analogues constitute promising candidates in the pursuit of developing novel hypoglycemic drugs.

Synthesis and Biological Activity of Penaresidins A and B, Penazetidine A, and Related Analogues

AbstractSince the first reports of their isolation, penaresidins A and B together with penazetidine A and related analogues have attracted interest from the synthetic community for their unique structural features, specifically the highly functionalized azetidine core. This review provides a comprehensive overview of the biological activity of the penaresidins, penazetidine, and their analogues together with reported synthetic strategies developed since their isolation.1 Introduction2 Biological Activity of Penaresidin A, Penaresidin B, and Penazetidine A and Related Analogues3 Retrosynthetic Analysis4 Penaresidin A Analogue (Kamikawa, 1995)5 15-epi-Penaresidin A (Mori, 1995)6 16-epi-Penazetidine A (Mori, 1996)7 Penaresidin B (Yoda, 1997)8 15-epi-Penaresidin B and Penaresidin B (Mori, 1997)9 Penaresidin A and 16-nor-Penazetidine A (Knapp, 1997)10 Substituted Penaresidin Core (Beauhaire and Ducrot, 1998)11 Substituted Penaresidin Core (Ducrot, 1999)12 Penaresidin A (Lin, 1999)13 Penaresidin B (Yoda, 2003)14 Penaresidin Structure-Reactivity Relationship (Kobayashi, 2007)15 Penaresidin A (Raghavan, 2010)16 Penaresidin A (Reddy, 2014)17 Penaresidin B (Liu, 2015)18 Penaresidin B (Yakura, 2018)19 Penaresidin B (DuBois, 2020)20 Penaresidin Analogues (Bodnár, 2021)

Experimental analysis of the melt fraction - mechanical strength relationship for iron ore sinter analogues

This study examined the strength of sinter analogue tablets for different types of iron ore under varying sintering conditions. A steel tamper was designed to quantify strength based on the percentage of 1 mm retained size after a drop weight test. The study found a linear relationship between total melt fraction M and strength index S quantified by mass fraction of the +1 mm retained size: S=0.88M. Importantly, a relationship was found between the total melt and a combined F factor incorporating the thermodynamic liquid fraction (α, representing sintering conditions) and the mineralogical factor loss on ignition (LOI ratio, β, representing ore types), where F=6.5α+β−1. This factor F was found well correlated the total melt via an asymptotic exponential relationship as M=1−2.6e−F. The results also suggested that, to achieve an acceptable strength of 80% +1 mm for a typical basicity B = 2, a sintering temperature range between 1273 and 1370 °C is required for the LOI range between 1.6% to 10.7% respectively. Finally, an analogous analysis was also carried out which proposed a similar trend between sinter yield obtained in a kilogram-scale by lab-scale studies and the present 0.6-g analogue scale.

Abstract 5928: Structure-activity relationships for the pan-quadruplex experimental drug QN-302 and two analogs probed with comparative transcriptome profiling and molecular modeling

Abstract The tetrasubstituted naphthalene diimide compound QN-302 binds to G-quadruplex DNA structures. It inhibits the transcription of cancer-related genes in pancreatic ductal adenocarcinoma (PDAC) cells, shows high potency in PDAC cells in vitro and in PDAC animal models. It is currently in Phase 1 clinical evaluation as an anticancer drug for advanced, metastatic solid tumors. A study of structure-activity relationships of QN-302 and two related analogs (CM03 and SOP1247) is reported here. These have been probed using comparisons of transcriptional profiles from whole-genome RNA-seq analyses, together with qualitative molecular modelling. Compounds CM03 and SOP1247 differ by the presence of a methoxy substituent in the former: these two have closely similar transcriptional profiles, whereas that of QN-302, although showing effects in the same cancer-related pathways, highlights the down regulation of distinct genes, for example in the hedgehog pathway. The distinct pattern of genes affected by QN-302 is hypothesized to contribute to its superior potency compared to CM03 and SOP1247. Its superior ability to stabilize quadruplex structures has been attributed to its benzyl-pyrrolidine substituent fitting into and filling most of the space in a quadruplex groove compared to the hydrogen atom in CM03 or the methoxy group in SOP1247. Citation Format: Ahmed A. Ahmed, Shozeb Haider, Tariq Arshad, Stephen Neidle. Structure-activity relationships for the pan-quadruplex experimental drug QN-302 and two analogs probed with comparative transcriptome profiling and molecular modeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5928.

Structural basis of ligand recognition and design of antihistamines targeting histamine H4 receptor

The histamine H4 receptor (H4R) plays key role in immune cell function and is a highly valued target for treating allergic and inflammatory diseases. However, structural information of H4R remains elusive. Here, we report four cryo-EM structures of H4R/Gi complexes, with either histamine or synthetic agonists clobenpropit, VUF6884 and clozapine bound. Combined with mutagenesis, ligand binding and functional assays, the structural data reveal a distinct ligand binding mode where D943.32 and a π-π network determine the orientation of the positively charged group of ligands, while E1825.46, located at the opposite end of the ligand binding pocket, plays a key role in regulating receptor activity. The structural insight into H4R ligand binding allows us to identify mutants at E1825.46 for which the agonist clobenpropit acts as an inverse agonist and to correctly predict inverse agonism of a closely related analog with nanomolar potency. Together with the findings regarding receptor activation and Gi engagement, we establish a framework for understanding H4R signaling and provide a rational basis for designing novel antihistamines targeting H4R.

A Low-Power Analog Integrated Euclidean Distance Radial Basis Function Classifier

This study introduces a low-power analog integrated Euclidean distance radial basis function classifier. The high-level architecture is composed of several Manhattan distance circuits in connection with a current comparator circuit. Notably, each implementation was designed with modularity and scalability in mind, effectively accommodating variations in the classification parameters. The proposed classifier’s operational principles are meticulously detailed, tailored for low-power, low-voltage, and fully tunable implementations, specifically targeting biomedical applications. This design methodology materialized within a 90 nm CMOS process, utilizing the Cadence IC Suite for the comprehensive management of both the schematic and layout design aspects. During the verification phase, post-layout simulation results were meticulously cross-referenced with software-based classifier implementations. Also, a comparison study with related analog classifiers is provided. Through the simulation results and comparative study, the design architecture’s accuracy and sensitivity were effectively validated and confirmed.

Molecule auto-correction to facilitate molecular design

Ensuring that computationally designed molecules are chemically reasonable is at best cumbersome. We present a molecule correction algorithm that morphs invalid molecular graphs into structurally related valid analogs. The algorithm is implemented as a tree search, guided by a set of policies to minimize its cost. We showcase how the algorithm can be applied to molecular design, either as a post-processing step or as an integral part of molecule generators.Graphical abstract

Identification of epidermal growth factor receptor-tyrosine kinase inhibitor targeting the VP1 pocket of human rhinovirus.

Screening a library of 1,200 preselected kinase inhibitors for anti-human rhinovirus 2 (HRV-2) activity in HeLa cells identified a class of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) as effective virus blockers. These were based on the 4-anilinoquinazoline-7-oxypiperidine scaffold, with the most potent representative AZ5385 inhibiting the virus with EC50 of 0.35 µM. Several structurally related analogs confirmed activity in the low µM range, while interestingly, other TKIs targeting EGFR lacked anti-HRV-2 activity. To further probe this lack of association between antiviral activity and EGFR inhibition, we stained infected cells with antibodies specific for activated EGFR (Y1068) and did not observe a dependency on EGFR-TK activity. Instead, consecutive passages of HRV-2 in HeLa cells in the presence of a compound and subsequent nucleotide sequence analysis of resistant viral variants identified the S181T and T210A alterations in the major capsid VP1 protein, with both residues located in the vicinity of a known hydrophobic pocket on the viral capsid. Further characterization of the antiviral effects of AZ5385 showed a modest virus-inactivating (virucidal) activity, while anti-HRV-2 activity was still evident when the inhibitor was added as late as 10 h post infection. The RNA copy/infectivity ratio of HRV-2 propagated in AZ5385 presence was substantially higher than that of control HRV indicating that the compound preferentially targeted HRV progeny virions during their maturation in infected cells. Besides HRV, the compound showed anti-respiratory syncytial virus activity, which warrants its further studies as a candidate compound against viral respiratory infections.

Structure-activity relationships for the G-quadruplex-targeting experimental drug QN-302 and two analogues probed with comparative transcriptome profiling and molecular modeling.

The tetrasubstituted naphthalene diimide compound QN-302 binds to G-quadruplex (G4) DNA structures. It shows high potency in pancreatic ductal adenocarcinoma (PDAC) cells and inhibits the transcription of cancer-related genes in these cells and in PDAC animal models. It is currently in Phase 1a clinical evaluation as an anticancer drug. A study of structure-activity relationships of QN-302 and two related analogues (CM03 and SOP1247) is reported here. These have been probed using comparisons of transcriptional profiles from whole-genome RNA-seq analyses, together with molecular modelling and molecular dynamics simulations. Compounds CM03 and SOP1247 differ by the presence of a methoxy substituent in the latter: these two compounds have closely similar transcriptional profiles. Whereas QN-302 (with an additional benzyl-pyrrolidine group), although also showing down-regulatory effects in the same cancer-related pathways, has effects on distinct genes, for example in the hedgehog pathway. This distinctive pattern of genes affected by QN-302 is hypothesized to contribute to its superior potency compared to CM03 and SOP1247. Its enhanced ability to stabilize G4 structures has been attributed to its benzyl-pyrrolidine substituent fitting into and filling most of the space in a G4 groove compared to the hydrogen atom in CM03 or the methoxy group substituent in SOP1247.

Enumeration, Nomenclature, and Stability Rules of Carbon Nanobelts.

With recent breakthroughs and advances in synthetic chemistry, carbon nanobelts (CNBs) have become an emerging hot topic in chemistry and materials science. Owing to their unique molecular structures, CNBs have intriguing properties with applications in synthetic materials, host-guest chemistry, optoelectronics, and so on. Although a considerable number of CNBs with diverse forms have been synthesized, no systematic nomenclature is available yet for this important family of macrocycles. Moreover, little is known about the detailed isomerism of CNBs, which, in fact, exhibits greater complexity than that of carbon nanotubes. The copious variety of CNB isomers, along with the underlying structure-property relationships, bears fundamental relevance to the ongoing design and synthesis of novel nanobelts. In this paper, we propose an elegant approach to systematically enumerate, classify, and name all possible isomers of CNBs. Besides the simplest, standard CNBs defined by chiral indices (n, m), the nonstandard CNBs (n, m, l) involve an additional winding index l. Based on extensive quantum chemical calculations, we present a comprehensive study of the relative isomer stability of CNBs containing up to 30 rings. A simple Hückel-based model with a high predictive power reveals that the relative stability of standard CNBs is governed by the π stabilization and the strain destabilization induced by the cylindrical carbon framework, and the former effect prevails over the latter. For nonstandard CNBs, a third stability factor, the H···H repulsion in the benzo[c]phenanthrene-like motifs, is also shown to be important and can be incorporated into the simple quantitative model. In general, lower-energy CNB isomers have a larger HOMO-LUMO gap, suggesting that their thermodynamic stability coincides with kinetic stability. The most stable CNB isomers determined can be considered the optimal targets for future synthesis. These results lay an initial foundation and provide a useful theoretical tool for further research on CNBs and related analogues.

Comparative Pharmacological Effects of Lisuride and Lysergic Acid Diethylamide Revisited.

Lisuride is a non-psychedelic serotonin (5-HT) 2A receptor (5-HT2A) agonist and analogue of the psychedelic lysergic acid diethylamide (LSD). Lisuride also acts as an agonist at the serotonin 1A receptor (5-HT1A), a property known to counter psychedelic effects. Here, we tested whether lisuride lacks psychedelic activity due to a dual mechanism: (1) partial agonism at 5-HT2A and (2) potent agonism at 5-HT1A. The in vitro effects of lisuride, LSD, and related analogues on 5-HT2A signaling were characterized by using miniGαq and β-arrestin 2 recruitment assays. The 5-HT1A- and 5-HT2A-mediated effects of lisuride and LSD were also compared in male C57BL/6J mice. The in vitro results confirmed that LSD is an agonist at 5-HT2A, with high efficacy and potency for recruiting miniGαq and β-arrestin 2. By contrast, lisuride displayed partial efficacy for both functional end points (6-52% of 5-HT or LSD Emax) and antagonized the effects of LSD. The mouse experiments demonstrated that LSD induces head twitch responses (HTRs)(ED50 = 0.039 mg/kg), while lisuride suppresses HTRs (ED50 = 0.006 mg/kg). Lisuride also produced potent hypothermia and hypolocomotion (ED50 = 0.008-0.023 mg/kg) that was blocked by the 5-HT1A antagonist WAY100635 (3 mg/kg). Blockade of 5-HT1A prior to lisuride restored basal HTRs, but it failed to increase HTRs above baseline levels. HTRs induced by LSD were blocked by lisuride (0.03 mg/kg) or the 5-HT1A agonist 8-OH-DPAT (1 mg/kg). Overall, our findings show that lisuride is an ultrapotent 5-HT1A agonist in C57BL/6J mice, limiting its use as a 5-HT2A ligand in mouse studies examining acute drug effects. Results also indicate that the 5-HT2A partial agonist-antagonist activity of lisuride explains its lack of psychedelic effects.