Receptor Synthesis Research Articles

Aryl-Extended and Super Aryl-Extended Calix[4]pyrroles: Design, Synthesis, and Applications.

ConspectusProteins exhibit high-binding affinity and selectivity, as well as remarkable catalytic performance. Their binding pockets are hydrophobic but also contain polar and charged groups to contribute to the binding of polar organic molecules in aqueous solution. In the past decades, the synthesis of biomimetic receptors featuring sizable aromatic cavities equipped with converging polar groups has received considerable attention. "Temple" cages, naphthotubes, and aryl-extended calix[4]pyrroles are privileged examples of synthetic scaffolds displaying functionalized hydrophobic cavities capable of binding polar substrates. In particular, calix[4]pyrroles are macrocycles containing four pyrrole rings connected through their pyrrolic 2- and 5-positions by tetra-substituted sp3 carbon atoms (meso-substituents). In 1996, Sessler introduced the meso-octamethyl calix[4]pyrrole as an outstanding receptor for anion binding. Independently, Sessler and Floriani also showed that the introduction of aryl substituents in the meso-positions produced aryl-extended calix[4]pyrroles as a mixture of configurational isomers. In addition, aryl-extended calix[4]pyrroles bearing two and four meso-aryl substituents (walls) were reported. The cone conformation of "two-wall" αα-aryl-extended calix[4]pyrroles features an aromatic cleft with a polar binding site defined by four converging pyrrole NHs. On the other hand, "four-wall" αααα-calix[4]pyrrole isomers possess a deep polar aromatic cavity closed at one end by the converging pyrrole NHs. Because of their functionalized interior, aryl-extended calix[4]pyrroles are capable of binding anions, ion-pairs, and electron-rich neutral molecules in organic solvents. However, in water, they are restricted to the inclusion of neutral polar guests.Since the early 2000s, our research group has been involved in the design and synthesis of "two-wall" and "four-wall" aryl-extended calix[4]pyrroles and their derivatives, such as aryl-extended calix[4]pyrrole cavitands and super aryl-extended calix[4]pyrroles. In this Account, we mainly summarize our own results on the binding of charged and neutral polar guests with these macrocyclic receptors in organic solvents and in water. We also describe the applications of calix[4]pyrrole derivatives in the sensing of creatinine, the facilitated transmembrane transport of anions and amino acids, and the monofunctionalization of bis-isonitriles. Moreover, we explain the use of calix[4]pyrrole receptors as model systems for the quantification of anion-π interactions and the hydrophobic effect. Finally, we discuss the self-assembly of dimeric capsules and unimolecular metallo-cages based on calix[4]pyrrole scaffolds. We comment on their binding properties, as well as on those of bis-calix[4]pyrroles having a fully covalent structure.In molecular recognition, aryl-extended calix[4]pyrroles and their derivatives are considered valuable receptors owing to their ability to interact with a wide variety of electron-rich, neutral, and charged guests. Calix[4]pyrrole scaffolds have also been applied in the development of molecular sensors, ionophores, transmembrane carriers, supramolecular protecting groups and molecular containers modulating chemical reactivity, among others. We believe that the design of new calix[4]pyrrole receptors and the investigation of their binding properties may lead to promising applications in many research areas, such as supramolecular catalysis, chemical biology and materials science. We hope that this Account will serve to spread the knowledge of the supramolecular chemistry of calix[4]pyrroles among supramolecular and nonsupramolecular chemists alike.

Development of a multigram synthesis of the bradykinin receptor 2 agonist FR-190997 and analogs thereof.

Using Fujisawa's B2R agonist FR-190997, we recently demonstrated for the first time that agonism at the bradykinin receptor type 2 (B2R) produces substantial antiproliferative effects. FR-190997 elicited an EC50 of 80 nM in the triple-negative breast cancer cell line MDA-MB-231, a much superior performance to that exhibited by most approved breast cancer drugs. Consequently, we initiated a program aiming primarily at synthesizing adequate quantities of FR-190997 to support further in vitro and in vivo studies toward its repurposing for various cancers and, in parallel, enable the generation of novel FR-190997 analogs for an SAR study. Prerequisite for this endeavor was to address the synthetic challenges associated with the FR-190997 scaffold, which the Fujisawa chemists had constructed in 20 steps, 13 of which required chromatographic purification. We succeeded in developing a 17-step synthesis amenable to late-stage diversification that eliminated all chromatography and enabled access to multigram quantities of FR-190997 and novel derivatives thereof, supporting further anticancer research based on B2R agonists.

The PPARα/CYP4A14 bile acid pathway is associated with lipid metabolism disorders caused by low birth weight with high-fat diet.

To investigate possible mechanisms underlying the greater susceptibility of lipid metabolism disorders in low birth weight (LBW) mice fed with high-fat diets (HFDs). LBW mice model was established by using the pregnancy malnutrition method. Male pups were selected from LBW and normal-birth weight (NBW) offspring at random. After 3 weeks of weaning, all offspring mice were fed with HFD. Serum triglycerides (TGs), cholesterol (TC), low density lipoprotein (LDL-C), total bile acid (TAB), non-esterified fatty acid (NEFA), and mice fecal bile acid profiles were measured. Lipid deposition in liver sections was visualized by Oil Red O staining. The weight ratio of liver, muscle, and adiposity was calculated. Tandem mass tag (TMT) combined with LC-MS/MS was used to determine the differentially expressed proteins (DEPs) of liver tissue in two groups. Bioinformatics was used for further analysis of DEPs to screen key target proteins, and then Western Blot (WB) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were performed to validate the expressions of DEPs. LBW mice fed with HFD showed more severe lipid metabolism disorders in the childhood. In contrast to the NBW group, the serum bile acids and fecal ω-muricholic acid (ω-MCA) levels in the LBW group were significantly lower. LC-MS/MS analysis showed that downregulated proteins were associated with lipid metabolism, and further analysis found that these proteins are mainly concentrated in peroxisome proliferation-activated receptor (PPAR) and primary bile acid synthesis signaling pathways and are involved in cellular processes and metabolic processes through binding and catalytic functions. Bioinformatics analysis indicated that the level of Cytochrome P450 Family 46 Subfamily A Member 1 (CYP46A1), PPARα, key factors of cholesterol metabolism and bile acid synthesis, as well as downstream molecules Cytochrome P450 Family 4 Subfamily A Member 14 (CYP4A14), and Acyl-Coenzyme A Oxidase 2 (ACOX2) are markedly different in the liver of LBW individuals fed with HFD, and confirmed by WB and RT-qPCR. LBW mice are more prone to dyslipidemia probably due to downregulated bile acid metabolism-related PPARα/CYP4A14 pathway, resulting in insufficient metabolism of cholesterol to bile acids, which, in turn, leads to elevated blood cholesterol.

Synthesis of fluorescent artificial receptors with high specificity for simultaneous detection of non-steroidal anti-inflammatory drugs

Development of multiple detection methods to monitor non-steroidal anti-inflammatory drugs (NSAIDs) in food is an effective way to protect human health. Here, we aimed to synthesize fluorescent artificial receptors by molecular imprinting technique to construct a simultaneous detection system targeting NSAIDs. Rhodamine B and fluorescein-functionalized silanes were employed as the fluorescence signal reporters for naproxen and ketoprofen, respectively. Two fluorescent molecularly imprinted polymers (FMIPs) were obtained with high specificity, giving cross-reactivity factors of 6.4–15.8 (naproxen) and 2.6–25.6 (ketoprofen). Both FMIPs also displayed rapid response time (5 min) and high sensitivity (detection limit at ∼ nM level). A simultaneous detection system was constructed based on the FMIPs and applied for sensing the spiked NSAIDs in real samples, showing recoveries of 71–119 %, comparable with the HPLC methods (70–113 %). In summary, use of different FMIPs to construct simultaneous detection systems is practicable, and provides a flexible way for sensing multiple hazards in food samples.

Endocytosis of AMPA receptors: Role in neurological conditions.

AMPA receptors are glutamate-gated ion channels, present in a wide range of neuron types and in glial cells. Their main role is to mediate fast excitatory synaptic transmission, and therefore, they are critical for normal brain function. In neurons, AMPA receptors undergo constitutive and activity-dependent trafficking between the synaptic, extrasynaptic and intracellular pools. The kinetics of AMPA receptor trafficking is crucial for the precise functioning of both individual neurons and neural networks involved in information processing and learning. Many of the neurological diseases evoked by neurodevelopmental and neurodegenerative malfunctions or traumatic injuries are caused by impaired synaptic function in the central nervous system. For example, attention-deficit/hyperactivity disorder (ADHD), Alzheimer's disease (AD), tumors, seizures, ischemic strokes, and traumatic brain injury are all characterized by impaired glutamate homeostasis and associated neuronal death, typically caused by excitotoxicity. Given the important role of AMPA receptors in neuronal function, it is not surprising that perturbations in AMPA receptor trafficking are associated with these neurological disorders. In this book chapter, we will first introduce the structure, physiology and synthesis of AMPA receptors, followed by an in-depth description of the molecular mechanisms that control AMPA receptor endocytosis and surface levels under basal conditions or synaptic plasticity. Finally, we will discuss how impairments in AMPA receptor trafficking, particularly endocytosis, contribute to the pathophysiology of various neurological disorders and what efforts are being made to therapeutically target this process.

Recent Advancements in Ion-Pair Receptors.

Over the past two decades, non-covalent chemistry has introduced various promising artificial receptors and revolutionized the host-guest chemistry. These versatile receptors have particularly been entertained in sensing and recognizing of diverse neutral molecules and/or ionic entities (e. g. anions, cations and ion-pair) of particular interest. Notably, supramolecular chemistry had given birth to a plethora of important molecules, explored in the chemical, biological, environmental, and pharmacological world to resolve the critical issues related to the human health while keeping environmental concerns in mind. Amongst the various types of supramolecular monotopic receptors (anions, cations, and neutral molecules), heteroditopic receptors (ion-pair receptors) consisting of distinct binding sites in one system for both cation and anion, have gained much interest from the scientific community in recent past because of their unique binding abilities. Interestingly, these promising artificial receptors have shown potential applications in sensing, recognition, transport and extraction processes besides their uses in salt/waste purification. Bearing the importance of these systems in mind, we intended to report the recent developments in ion-pair chemistry. Herein, we divided the whole document into three main sections; first one describes the introduction and history of the ion-pairs receptors. The second portion highlights the synthesis and applications of ion-pair receptors in sensing, recognition, molecular machines, photoswitching behaviour, extraction and transport properties, whereas the last part of this manuscript provides concluding remarks as well as future prospects of ion-pair receptors. We hope that this manuscript will be helpful to stimulating researchers around the globe to find out the hidden opportunities in this and related areas.

Potentiometric sensor based on a computationally designed molecularly imprinted receptor

Molecularly imprinted polymer (MIP)-based polymeric membrane potentiometric sensors are ideal candidates for detection of organic species. The development of such sensors has opened new attractive horizons for potentiometric sensing. However, it should be noted that in the preparation of these MIP receptors, the selection of the functional monomer usually depends on empirical trial- and error-based optimization, which involves tedious and time-consuming experiments. In this work, the computer-aided design and synthesis of an MIP receptor are applied in the fabrication of an MIP-based potentiometric sensor. The density functional theory calculation with the B3LYP model and 6-31G(d) basis set is used to study the interactions between the functional monomer and template molecules. The binding energies of the complexations between the template molecule and different functional monomers are used as a criterion for the selection of the proper monomer. The designed MIP is then synthesized and employed as the receptor for the fabrication of the potentiometric sensor. As a proof-of-concept experiment, the antibiotic sulfadiazine has been selected as a model and 4 functional monomers, 2-hydroxyethyl methacrylate, methyl methacrylate, N-isopropylacrylamide and N-phenylacrylamide, have been chosen. The designed MIP-based sensor exhibits excellent sensitivity with a linear range of 1–10 μM and also shows a good selectivity. We believe that the proposed computer-aided synthesis technique for the MIP receptor selection can provide a general and facile way to replace the traditional empirical MIP preparation method in the fabrication of MIP-based electrochemical and optical sensors.

CREBB repression of protein synthesis in mushroom body gates long-term memory formation in Drosophila

Learned experiences are not necessarily consolidated into long-term memory (LTM) unless they are periodic and meaningful. LTM depends on de novo protein synthesis mediated by cyclic AMP response element-binding protein (CREB) activity. In Drosophila, two creb genes (crebA, crebB) and multiple CREB isoforms have reported influences on aversive olfactory LTM in response to multiple cycles of spaced conditioning. How CREB isoforms regulate LTM effector genes in various neural elements of the memory circuit is unclear, especially in the mushroom body (MB), a prominent associative center in the fly brain that has been shown to participate in LTM formation. Here, we report that i) spaced training induces crebB expression in MB α-lobe neurons and ii) elevating specific CREBB isoform levels in the early α/βsubpopulation of MB neurons enhances LTM formation. By contrast, learning from weak training iii) induces 5-HT1A serotonin receptor synthesis, iv) activates 5-HT1A in early α/βneurons, and v) inhibits LTM formation. vi) LTM is enhanced when this inhibitory effect is relieved by down-regulating 5-HT1A or overexpressing CREBB. Our findings show that spaced training-induced CREBB antagonizes learning-induced 5-HT1A in early α/βMB neurons to modulate LTM consolidation.

Design and Synthesis of Fibroblast Growth Factor Receptor (FGFR) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Cancer.

The activation of the STAT signal after incubation with the HDAC inhibitor represents a key mechanism causing resistance to HDAC inhibitors in some solid tumor cells, while the FGFR inhibitor could downregulate the level of pSTAT3. Inspired by the therapeutic prospect of FGFR/HDAC dual inhibitors, we designed and synthesized a series of quinoxalinopyrazole hydroxamate derivatives as FGFR/HDAC dual inhibitors. Among them, compound 10e potently inhibited FGFR1-4 and HDAC1/2/6/8 and presented improved antiproliferative effects of tumor cells. Further studies indicated that 10e also downregulated the expression of pSTAT3, potentially overcoming resistance to HDAC inhibitors. What's more, 10e significantly inhibited the tumor growth in HCT116 and SNU-16 xenograft models with favorable pharmacokinetic profiles. Collectively, these results supported that 10e could be a new drug candidate for malignant tumors.

GRP94 Inhabits the Immortalized Porcine Hepatic Stellate Cells Apoptosis under Endoplasmic Reticulum Stress through Modulating the Expression of IGF-1 and Ubiquitin.

Endoplasmic reticulum stress (ERS) is closely related to the occurrence and progression of metabolic liver disease. The treatment targeting glucose-regulated protein 94 (GRP94) for liver disease has gotten much attention, but the specific effect of GRP94 on hepatocyte apoptosis is still unclear. So far, all the studies on GRP94 have been conducted in mice or rats, and little study has been reported on pigs, which share more similarities with humans. In this study, we used low-dose (LD) and high-dose (HD) tunicamycin (TM) to establish ERS models on piglet livers and immortalized porcine hepatic stellate cells (HSCs). On the piglet ERS model we found that ERS could significantly (p < 0.01) stimulate the secretion and synthesis of insulin-like growth factor (IGF-1), IGF-1 receptor (IGF-1R), and IGF-binding protein (IGFBP)-1 and IGFBP-3; however, with the increase in ERS degree, the effect of promoting secretion and synthesis significantly (p < 0.01) decreased. In addition, the ubiquitin protein and ubiquitination-related gene were significantly increased (p < 0.05) in the LD group compared with the vehicle group. The protein level of Active-caspase 3 was significantly increased (p < 0.01) in the HD group, however, the TUNEL staining showed there was no significant apoptosis in the piglet liver ERS model. To explore the biofunction of ER chaperone GRP94, we used shRNA to knock down the expression of GRP94 in porcine HSCs. Interestingly, on porcine HSCs, the knockdown of GRP94 significantly (p < 0.05) decreased the secretion of IGF-1, IGFBP-1 and IGFBP-3 under ERS, but had no significant effect on these under normal condition, and knockdown GRP94 had a significant (p < 0.01) effect on the UBE2E gene and ubiquitin protein from the analysis of two-way ANOVA. On porcine HSCs apoptosis, the knockdown of GRP94 increased the cell apoptosis in TUNEL staining, and the two-way ANOVA analysis shows that knockdown GRP94 had a significant (p < 0.01) effect on the protein levels of Bcl-2 and Caspase-3. For CCK-8 assay, ERS had a significant inhibitory(p < 0.05) effect on cell proliferation when treated with ERS for 24 h, and both knockdown GRP94 and ERS had a significant inhibitory(p < 0.05) effect on cell proliferation when treated with ERS for 36 h and 48 h. We concluded that GRP94 can protect the cell from ERS-induced apoptosis by promoting the IGF-1 system and ubiquitin. These results provide valuable information on the adaptive mechanisms of the liver under ERS, and could help identify vital functional genes to be applied as possible diagnostic biomarkers and treatments for diseases induced by ERS in the future.

OR27-4 Placebo-Controlled and Open-Label Extension Study of a Novel Hepatic-Targeted Antisense Cimdelirsen (IONIS-GHR-LRx) Under Investigation in Acromegaly Patients

Abstract Cimdelirsen (IONIS-GHR-LRx; ISIS 766720) is a novel, ligand-conjugated, hepatic-targeted investigative antisense molecule designed to reduce growth hormone receptor (GHr) synthesis, thereby inhibiting deleterious effects of growth hormone (GH) hypersecretion and reducing circulating insulin-like growth factor-1 (IGF-1) levels in acromegaly patients. Methods Cimdelirsen was evaluated in a 4-month double-blind, placebo-controlled phase 2 study (DBL) in uncontrolled acromegaly patients (IGF-1>1.3-<5xULN) treated with stable long-acting somatostatin receptor ligand (SRL) injections (NCT03548415). Due to COVID-19 pandemic, the study closed early resulting in smaller cohorts than planned. While no longer powered to assess Day 141 primary endpoint (PE), the study permitted placebo-controlled evaluation of safety and efficacy. The final analysis included 41 patients in the cimdelirsen low dose (60 and 80 mg; n=22), high dose (120 and 160 mg; n=7) or placebo (n=12) cohorts. 39 of these patients subsequently entered an open label extension (OLE) safety study where all patients were treated with cimdelirsen and at the time of interim analysis, 23 patients were treated for ≥ 1 year (NCT03967249).Patient reported outcomes were assessed using the validated ACROQoL and an acromegaly symptoms questionnaire. Results Cimdelirsen treatment resulted in a significant, dose dependent reduction in GH-binding protein (GHBP), a biomarker of hepatic GHR reduction: -2% placebo, -43% low dose, -64% high dose; p<0.001. Importantly, GHBP reductions were not associated with fasting GH increases. The GH mean change from baseline to PE was 1 ng/mL placebo, 0 ng/mL low dose and 1 ng/mL high dose (p>0.5). GHBP reductions without GH increases were maintained for up to 1 year of treatment in all patients.Integrated AUC for IGF-1 calculated after GHBP had reached near-maximal reductions (Day 57 to PE) demonstrated dose-dependent reductions that were significant at the high dose (+692%*day placebo, -460 low dose, and -1378 high dose; p=0.21 and 0.05 for the low dose and high dose groups, respectively). A greater reduction in IGF-1 AUC was observed in patients who had higher IGF-1 levels at baseline.Patients with higher IGF-1 levels showed significant improvements in ACROQoL at the PE; all patients demonstrated improvements after 1 year. Importantly, high-dose cimdelirsen improved sweating and headaches at PE.In both studies, there were no drug-related SAEs. The most frequently reported TEAE were UTI (16.1%) and COVID-19 (12.8%) in DBL and OLE, respectively. No safety signals were observed including no ALT elevation >3×ULN and no thrombocytopenia (<100 10^3/uL). Glycemic control remained stable and showed no worsening of HbA1c. Conclusion Once monthly SC cimdelirsen injections demonstrated long-term safety, were well-tolerated, and resulted in significant reductions in GHBP and IGF-1 AUC without increased GH levels. Cimdelirsen also improved PRO, collectively supporting further development of this novel, liver-directed potential therapy for uncontrolled acromegaly. Presentation: Tuesday, June 14, 2022 10:30 a.m. - 10:45 a.m.

Synthesis, Biological Activity and Molecular Docking of Chimeric Peptides Targeting Opioid and NOP Receptors.

Recently, mixed opioid/NOP agonists came to the spotlight for their favorable functional profiles and promising outcomes in clinical trials as novel analgesics. This study reports on two novel chimeric peptides incorporating the fragment Tyr-c[D-Lys-Phe-Phe]Asp-NH2 (RP-170), a cyclic peptide with high affinity for µ and κ opioid receptors (or MOP and KOP, respectively), conjugated with the peptide Ac-RYYRIK-NH2, a known ligand of the nociceptin/orphanin FQ receptor (NOP), yielding RP-170-RYYRIK-NH2 (KW-495) and RP-170-Gly3-RYYRIK-NH2 (KW-496). In vitro, the chimeric KW-496 gained affinity for KOP, hence becoming a dual KOP/MOP agonist, while KW-495 behaved as a mixed MOP/NOP agonist with low nM affinity. Hence, KW-495 was selected for further in vivo experiments. Intrathecal administration of this peptide in mice elicited antinociceptive effects in the hot-plate test; this action was sensitive to both the universal opioid receptor antagonist naloxone and the selective NOP antagonist SB-612111. The rotarod test revealed that KW-495 administration did not alter the mice motor coordination performance. Computational studies have been conducted on the two chimeras to investigate the structural determinants at the basis of the experimental activities, including any role of the Gly3 spacer.

Urinary Levels of miR-491-5p and miR-592 as Potential Diagnostic Biomarkers in Female Aging Patients with OAB: A Pilot Study

Women with overactive bladder syndrome (OAB) have a lower urinary ratio of nerve growth factor (NGF) to its precursor (proNGF) compared to healthy controls. MicroRNAs related to NGF and proNGF metabolism and to their receptors may be present in urine and may possess diagnostic value. Urine and blood samples from 20 control and 20 OAB women (50–80 years) were obtained, together with validated questionnaires and other clinical parameters. The relative expression of urinary microRNAs was measured with RT-qPCR. MiR-491-5p, which negatively controls the translation of the matrix metalloproteinase-9 (MMP-9), the main enzyme degrading NGF, was significantly decreased in OAB. Similarly, miR-592, which represses p75NTR receptor synthesis, was down-regulated in OAB. Age, renal function and insulin resistance did not affect these results. ROC curves confirmed the high sensitivity of miR-491-5p and miR-592 for diagnosis. On the other hand, miRNAs involved in the expression of proNGF, of survival receptor TrkA and of markers of nerve integrity were similar between groups. The detection of miR-491-5p and miR-592 in urine could be a useful and non-invasive tool for the diagnosis of OAB syndrome in aging women.

Superfast desulfurization for protein chemical synthesis and modification

Superfast desulfurization for protein chemical synthesis and modification

Perfluorooctane sulfonic acid (PFOS) exposures interfere with behaviors and transcription of genes on nervous and muscle system in zebrafish embryos

Perfluorooctane sulfonic acid (PFOS) has been widely detected in environment and organisms. PFOS has been identified as the driving agent for the behavioral changes of zebrafish larvae, while the underlying molecular mechanism remains unclear. In this study, zebrafish embryos/larvae were exposed to 0, 0.04, 0.1, 0.4 and 1 μM PFOS for 166 h. The locomotor behaviors and the mRNA transcription of genes in neuromuscular system were detected. Exposure to PFOS did not affect the hatching/death rates and body length, but increased the heart beat rates and frequency of spontaneous tail coiling. Locomotor behavior in zebrafish larvae of 0.4 and 1 μM PFOS groups were increased in the light condition. Additionally, the levels of acetylcholine (Ach) in 0.4 μM PFOS group and dopamine (DA) in 0.1, 0.4 and 1 μM PFOS groups were found to be significantly increased. The expression of genes related to the synthesis and decomposition of ACh，the synthesis and receptor of DA, and fosab was increased in the different PFOS treatment groups, while the expression of all the other genes of the neuromuscular system were significantly reduced. The findings of this investigation demonstrated that PFOS exposure may alter the locomotor behavior of zebrafish through disrupting the expressions of genes in neuromuscular system. The disturbed process of neurotransmitter transmission and muscle contraction caused by PFOS may be the dominant mechanism of hyperactivity in zebrafish.

Small molecules to regulate the GH/IGF1 axis by inhibiting the growth hormone receptor synthesis.

Growth hormone (GH) and insulin‐like growth factor‐1 (IGF1) play an important role in mammalian development, cell proliferation and lifespan. Especially in cases of tumor growth there is an urgent need to control the GH/IGF1 axis. In this study we screened a 38,480-compound library, and in two consecutive rounds of analogues selection, we identified active lead compounds based on the following criteria: inhibition the GH receptor (GHR) activity and its downstream effectors Jak2 and STAT5, and inhibition of growth of breast and colon cancer cells. The most active small molecule (BM001) inhibited both the GH/IGF1 axis and cell proliferation with an IC50 of 10‐30 nM of human cancer cells. BM001 depleted GHR in human lymphoblasts. In preclinical xenografted experiments, BM001 showed a strong decrease in tumor volume in mice transplanted with MDA‐MB‐231 breast cancer cells. Mechanistically, the drug acts on the synthesis of the GHR. Our findings open the possibility to inhibit the GH/IGF1 axis with a small molecule.

Survival of Patients with Metastatic Prostate Cancer After Disease Progression on an Androgen Receptor Axis–Targeted Therapy Given in the Metastatic Castration-Sensitive Versus Metastatic Castration-Resistant Prostate Cancer Setting

Androgen receptor axis–targeted therapies (ARATs; androgen receptor or androgen synthesis inhibitors) have been approved for the treatment of patients with metastatic castration-sensitive and castration-resistant prostate cancer (mCSPC and mCRPC) on the basis of improved overall survival (OS) in randomized clinical trials. However, it is not clear whether the OS for patients after progression on first-line ARAT differs if the first ARAT was administered in the mCSPC versus mCRPC setting and what its estimates are. We assessed the OS after disease progression on ARAT given as first-line therapy in mCSPC versus mCRPC. Patient-level data were collected retrospectively, and only those treated with first-line ARAT for mCSPC or mCRPC were included. For patients receiving ARAT in the mCRPC setting, no prior ARAT was allowed in the mCSPC setting. The median OS and hazard ratio (HR) were determined via Kaplan-Meier analysis from the time of progression on ARAT. Of 382 patients treated with first-line ARAT, 172 (44 mCSPC and 128 mCRPC) had experienced disease progression and were included in the analysis. Median OS was similar in the mCSPC (23 mo) and mCRPC (17 mo) settings (HR 0.99, 95% confidence interval 0.62–1.56; p = 0.95). A total of 138 patients received subsequent systemic therapy after progression. Our results suggest that median OS is similar after progression on one ARAT, whether given in the first-line mCSPC or first-line mCRPC setting, and is estimated to be <2 yr. These data have implications for patient prognostication and the design of clinical trials in the post-ARAT setting for further drug development. Patient summaryWe investigated whether the survival benefit differs between metastatic castration-sensitive and castration-resistant prostate cancer for patients who have already experienced cancer progression after first-line treatment with one drug targeting the androgen receptor pathway (called ARAT). We found that the median survival benefit was less than 2 years and was similar for the two groups.

β‐Cyclodextrin‐Based Nanocomposite Derivatives: State of the Art in Synthesis, Characterization and Application in Molecular Recognition

AbstractThis review describes the synthesis of nanocomposite derivatives based on β‐cyclodextrin (β‐CD) using silver nanoparticles (NPs), gold NPs, magnetic NPs, carbon nanotubes, nanosheets, carbon dots and graphene oxide NPs. These nanocomposites were prepared by green synthesis method, chemical method, reduction method, thermal reduction, ultrasonication method and hydrothermal method. β‐CD is cyclic oligosaccharide consisting of seven glucose units linked by 1,4‐α‐glycosidic bonds. Its external surface is hydrophilic due to the substantial hydroxyl groups, and the interior is hydrophobic. β‐CD are useful in nanocomposites and metallic NPs because they provide nanoplatforms for biocompatibility. β‐CD is commonly used to change NPs because of their excellent biocompatibility, amphipathic properties and for enhancing the morphological and chemical features of nanocomposites. Thus, nanostructured materials based on β‐CD may enhance the potential for molecular recognition property which is a natural phenomenon and fundamentally important in chemistry and biology. The most important area in molecular recognition research is design and synthesis of model receptors (hosts) to recognize substrates (guests) of biochemical significance to mimic biological events. Because NPs have a high surface‐to‐volume ratio when combined with molecularly imprinted polymers (MIPs). This review briefs the application and characterizations of β‐CD based nanocomposites derivatives in molecular recognition.

A Full Target-Mediated Drug Disposition (TMDD) Model to Explain the Changes in Recombinant Human Erythropoietin (rhEpo) Pharmacokinetics in Patients with Different Bone Marrow Integrity Following Hematopoietic Transplantation

Our aim was to build a mechanistic full target-mediated drug disposition (TMDD) model for rhEpo to better understand rhEpo disposition, Epo receptor (EpoR) synthesis, and degradation in hematopoietic transplant patients with four distinct bone marrow conditions. All PK data were analyzed simultaneously using the nonlinear mixed effect modeling approach with NONMEM. The final model was a two-compartmental full TMDD model, which adequately characterizes rhEpo PK in patients and provides insight into the dynamics of free EpoR, rhEpo-EpoR, and total EpoR. The model predicted association rate constant (kon), dissociation rate constant (koff), and internalization rate constant (kint) were 0.0276 pM−1h−1, 0.647 h−1, and 0.255h−1, respectively, which were supported by experimental data. Also, the EpoR degradation rate constant (kdeg) was estimated to be 0.461 h−1. EpoR production rate was estimated to be 37.5 pM/h for adults at pre-ablation baseline and 5.91 pM/h, and 4.19 pM/h in the early post-transplant post-engraftment, and late post-transplant full engraftment. Our model provides extensive information on the dynamics of free EpoR, total EpoR and rhEpo-EpoR, and proven to be more robust and can provide more physiologically relevant binding parameters than previous models.

Preparation of Fe3O4-Cys-Cu magnetic nanocatalyst for expedient synthesis of tripodal C3 symmetric chromofluorogenic receptor for sensing of fluoride ion selectively: An experimental and computational slant

In this paper, an ecofriendly nanocatalyst (Fe3O4-Cys-Cu) was synthesized by the coordinating copper ions to the l-cysteine functionalized magnetic nanoparticles. The prepared nanocatalyst was characterized by XRD, HRTEM, EDS-SEM, FT-IR, TGA, and DTA techniques. Afterward, the catalytic activity of this magnetic nanocatalyst was explored for the one-pot synthesis of a series of tripodal triazoles (7a-d) as an important class of sensors in the field of sensing and biosensing. This magnetically nanocatalytic methodology is advantageous in terms of high yield of the products, use of non-conventional microwaves, green solvent, reduction of reaction time, low catalyst dosage, and recyclability of catalyst up to six cycles. Further, synthesized triazole 7b was then evaluated as a selective chromofluorogenic receptor for the recognition of duplicitous fluoride ions in DMSO. Receptor upon addition of F− ion shows colorimetric response by displaying naked-eye color change from pale yellow to shiny green with a redshift in the UV–vis spectra and fluorescent green under UV lamp. The 1:3 binding stoichiometry of receptor-fluoride ion was determined by Job's plot and further verified by ESI-HRMS data. 1H NMR and 19F NMR validate the binding of the receptor with F− ion by hydrogen bonding with subsequent deprotonation, and further, theoretical calculations using density functional theory confirm the presence of the same.