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Transdermal rotigotine (RTG) therapy is prescribed to manage Parkinson's disease (Neupro® patch). However, its use is suffered from application site reactions. Herein, drug nanocrystalline suspension (NS)-loaded hydrogel (NS-HG) employing polysaccharides simultaneously as suspending agent and hydrogel matrix was constructed for transdermal delivery, with alleviated skin irritation. RTG-loaded NS-HG was prepared using a bead-milling technique, employing sodium carboxylmethyl cellulose (Na.CMC) as nano-suspending agent (molecular weight 90,000 g/mol) and hydrogel matrix (700,000 g/mol), respectively. NS-HG was embodied as follows: drug loading: ≤100 mg/mL; shape: rectangular crystalline; crystal size: <286.7 nm; zeta potential: -61 mV; viscosity: <2.16 Pa·s; and dissolution rate: >90 % within 15 min. Nuclear magnetic resonance analysis revealed that the anionic polymers bind to RTG nanocrystals via charge interaction, affording uniform dispersion in the matrix. Rodent transdermal absorption of RTG from NS-HG was comparable to that from microemulsions, and proportional to drug loading. Moreover, NS-HG was skin-friendly; erythema and epidermal swelling were absent after repeated application. Further, NS-HG was chemically stable; >95 % of the drug was preserved up to 4 weeks under long term (25 °C/RH60%), accelerated (40 °C/RH75%), and stress (50 °C) storage conditions. Therefore, this novel cellulose derivative-based nanoformulation presents a promising approach for effective transdermal RTG delivery with improved tolerability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Andrographis paniculata (AP) has been approved by the Thai government for the treatment of mild cases of COVID-19 patients. Increasing use of AP products requires quality control to ensure efficacy and safety. At present, there is no requirement for dissolution test of AP products in the Thai Herbal Pharmacopoeia (THP)., Objective: This work aimed to examine the contents and dissolution profiles of active diterpenoids, andrographolide (AP1), 14-deoxy-11,12-didehydroandrographolide (AP3), neoandrographolide (AP4), and 14-deoxyandrographolide (AP6) in AP capsules available in Thai markets., Materials and Methods: Four extract products (EXT. A-D) and three crude powder products (CRD. A-C) were tested for contents by using HPLC-DAD. Dissolution profiles of four diterpenoids were investigated in different media (pH 1.2, 4.5, 6.8, and 0.01 N HCl + SLS) with apparatus II (paddle type)., Results: The AP1 contents were 1.99%-2.90% w/w for crude capsules and 2.84%-16.27% w/w for extract capsules. In the dissolution test, the dissolution percentages of four diterpenoids from crude capsules were higher than those from extract capsules except EXT. A. AP1 in most extract products (EXT. B, C, D) was dissolved in all dissolution media at a lower percentage than the other three diterpenoids. EXT. A (aqueous extract) was the only extract capsule showing the amounts of all diterpenoids dissolved in all media >80% in 45 min., Conclusion: The study demonstrated that AP1 content in AP products complied with the acceptance criteria in the THP (80%-120%), and the weight variation also met the United States Pharmacopeia (USP) requirements. However, different dissolution profiles of AP products may lead to different bioavailability of diterpenoids and further affect their efficacy., (© 2024 John Wiley & Sons Ltd.)

Parkinson's disease (PD), affecting about ten million people globally, presents a significant health challenge. Rotigotine (RTG), a dopamine agonist, is currently administered as a transdermal patch (Neupro®) for PD treatment, but the daily application can be burdensome and cause skin irritation. This study introduces a combinatorial approach of dissolving microarray patch (MAP) and nanosuspension (NS) for the transdermal delivery of RTG, offering an alternative to Neupro®. The RTG-NS was formulated using a miniaturized media milling method, resulting in a nano-formulation with a mean particle size of 274.09 ± 7.43 nm, a PDI of 0.17 ± 0.04 and a zeta potential of -15.24 ± 2.86 mV. The in vitro dissolution study revealed an enhanced dissolution rate of the RTG-NS in comparison to the coarse RTG powder, under sink condition. The RTG-NS MAPs, containing a drug layer and a 'drug-free' supporting baseplate, have a drug content of 3.06 ± 0.15 mg/0.5 cm 2 and demonstrated greater amount of drug delivered per unit area (∼0.52 mg/0.5 cm 2 ) than Neupro® (∼0.20 mg/1 cm 2 ) in an ex vivo Franz cell study using full-thickness neonatal porcine skin. The in vivo pharmacokinetic studies demonstrated that RTG-NS MAPs, though smaller (2 cm 2 for dissolving MAPs and 6 cm 2 for Neupro®), delivered drug levels comparable to Neupro®, indicating higher efficiency per unit area. This could potentially avoid unnecessarily high plasma levels after the next dose at 24 h, highlighting the benefits of dissolving MAPs over conventional transdermal patches in PD treatment., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Rotigotine (RTG) is a dopamine agonist used in the treatment of Parkinson's disease. As it is susceptible to oxidation, stability studies must be carefully designed for the identification and characterization of all possible degradation products. Here, RTG degradation was evaluated according to the International Conference on Harmonization guidelines under various stress conditions, including acidic and basic hydrolysis, oxidative, metallic, photolytic, and thermal conditions. Additionally, more severe stress conditions were applied to induce RTG degradation. Significant degradation was only observed under oxidative and photolytic conditions. The samples were analyzed by high performance liquid chromatography coupled to photodiode array detectors, charged aerosol, and high-resolution mass spectrometry. Chromatographic analyses revealed the presence of eight substances related to RTG, four of which were already described and were qualified impurities (impurities B, C, K and E) and four new degradation products (DP-1 - DP-4), whose structures were characterized by high-resolution mass spectrometry through Q-Orbitrap and electrospray ionization. In the stress testing of the active pharmaceutical ingredient in solid form, significant RTG degradation was observed in the presence of the oxidative matrix. The results corroborate the literature that confirm the high susceptibility of RTG to oxidation and the importance of using different detectors to detect degradation products in forced degradation studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

A short and chemoenzymatic synthesis of rotigotine using an IR-36-M5 mutant is reported. Focusing on the residues that directly contact the 2-tetralone moiety, we applied structure-guided semi-rational design to obtain a double-mutant F260W/M147Y, which showed a good isolated yield and S -stereoselectivity >99% toward 2-aminotetralin synthesis. Furthermore, the utility of this biocatalytic protocol was successfully demonstrated in the enantioselective synthesis of rotigotine via enzymatic reductive amination as the key step.

Compound 1 is a potent rexinoid that is highly effective in cancer chemoprevention but elevates serum triglycerides. In an effort to separate the lipid toxicity from the anticancer activity of 1 , we synthesized four new analogs of rexinoid 1 , of which three rexinoids did not elevate serum triglycerides. Rexinoids 3 and 4 are twice as potent as rexinoid 1 in binding to Retinoid X receptor (RXR). All-trans retinoic acid (ATRA) plays a key role in maintaining skin homeostasis, and rexinoids 3-6 are highly effective in upregulating the genes responsible for the biosynthesis of ATRA. Inflammation plays a key role in skin cancer, and rexinoids 3 and 4 are highly effective in diminishing LPS-induced inflammation. Rexinoids 3 and 4 are highly effective in preventing UVB-induced nonmelanoma skin cancer (NMSC) without displaying any overt toxicities. Biophysical studies of rexinoids 3 and 5 bound to hRXRα-ligand binding domain (LBD) reveal important conformational and dynamical differences in the ligand binding domain.

A novel series of 1-amino-tetralin derivatives were designed and synthesized based on the putative binding mode of the naphthalene-type orexin receptor agonist 5 and their agonist activities against orexin receptors were evaluated. The introduction of N-methyl-(3-methoxyphenyl)acetamide unit onto the 1-amino-tetralin skeleton remarkably enhanced the potency of the agonist. The asymmetric synthesis of 6 revealed that (-)-6 having a (S)-1-amino-tetralin skeleton showed a OX 2 R selective agonist activity (EC 50  = 2.69 nM for OX 2 R, OX 1 R/OX 2 R = 461) yet its enantiomer (R)-(+)-6 showed a potent OX 1/2 R dual agonist activity (EC 50  = 13.5 nM for OX 1 R, 0.579 nM for OX 2 R, OX 1 R/OX 2 R = 23.3). These results suggested that upward orientation of the amide side chain against the tetralin scaffold (S-configuration) would be selective for OX 2 R activation, and the downward orientation (R-configuration) would be significant for dual agonist activity. To our best knowledge, there have been no reports thus far that the stereochemistry of one carbon center on the agonist structure regulates the orexin receptor selectivity. Our results would provide important information for the development of OX 1 R selective agonists., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Rotigotine is a non-ergoline dopamine agonist that has been licensed for the treatment of Parkinson's disease. Cardiovascular diseases are the world's leading cause of death. Ox-LDL- induced endothelial damages are involved in the initiation and progression of cardiovascular diseases. In this study, we assessed the beneficial properties of Rotigotine on ox-LDL-induced insults to HUVECs to highlight its potential use in the treatment of cardiovascular diseases. Our findings show that Rotigotine suppresses the expressions of low-density lipoprotein receptor (LDL-R), proprotein convertase subtilisin/kexin type 9 (PCSK-9), and sterol regulatory element-binding protein (SREBP-2). It also inhibits ox-LDL-induced cholesterol accumulation in endothelial cells (ECs), improves U937 monocytes adhesion, and decreases the representation of NADPH oxidase (NOX-4) and generation of reactive oxygen species (ROS) in endothelial cells (ECs). Furthermore, Rotigotine inhibited the expressions of both vascular cellular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in HUVECs and had anti-inflammatory efficacy in ox-LDL-induced cells by inhibiting the expressions of pro-inflammatory cytokines. Notably, Rotigotine inhibits the activation of nuclear factor-kappaB (NF-κB) by preventing nuclear translocation of NF-κB p65 and reducing the luciferase activity of NF-κB reporter. We, therefore, conclude that these effects of Rotigotine on HUVECs suggest that it may play a therapeutic role in cardiovascular diseases.

In this study, the antioxidant and antiradical properties of some phyto lignans (nordihydroguaiaretic acid, secoisolariciresinol, secoisolariciresinol diglycoside, and α-(-)-conidendrin) and mammalian lignans (enterodiol and enterolactone) were examined by different antioxidant assays. For this purpose, radical scavenging activities of phyto and mammalian lignans were realized by 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) radical (ABTS •+ ) scavenging assay and 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) scavenging assay. Additionally, the reducing ability of phyto and mammalian lignans were evaluated by cupric ions (Cu 2+ ) reducing (CUPRAC) ability, and ferric ions (Fe 3+ ) and [Fe 3+ -(TPTZ)2] 3+ complex reducing (FRAP) abilities. Also, half maximal inhibitory concentration (IC 50 ) values were determined and reported for DPPH • and ABTS •+ scavenging influences of all of the lignan molecules. The absorbances of the lignans were found in the range of 0.150-2.320 for Fe 3+ reducing, in the range of 0.040-2.090 for Cu 2+ reducing, and in the range of 0.360-1.810 for the FRAP assay. On the other hand, the IC 50 values of phyto and mammalian lignans were determined in the ranges of 6.601-932.167 µg/mL for DPPH • scavenging and 13.007-27.829 µg/mL for ABTS •+ scavenging. In all of the used bioanalytical methods, phyto lignans, as secondary metabolites in plants, demonstrated considerably higher antioxidant activity compared to that of mammalian lignans. In addition, it was observed that enterodiol and enterolactone exhibited relatively weaker antioxidant activities when compared to phyto lignans or standard antioxidants, including butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), Trolox, and α-tocopherol.

Aims: Dezocine and pentazocine, widely prescribed in China for postoperative pain, were initially considered as mixed agonist/antagonist targeting μ-opioid receptors (MORs) and κ-opioid receptors (KORs). However, dezocine has been revealed to alleviate chronic neuropathic pain through MOR activation and norepinephrine reuptake inhibition (NRI). This study investigated dezocine- and pentazocine-induced antinociception and physical dependence development, compared to the typical MOR-NRI opioid tapentadol., Main Methods: Calcium mobilization assay was conducted to assess the potency of the drugs while hot-plate test was performed to compare the antinociception. Physical dependence development was compared with morphine., Key Findings: Treatment with dezocine, pentazocine and tapentadol stimulated calcium mobilization in HEK293 cells stably expressed MORs but not KORs, whereas dezocine and pentazocine inhibited KOR activities. Subcutaneously injected dezocine-, tapentadol- and pentazocine-induced antinociception dose-dependently, in hot-plate test. Intrathecally injected MOR antagonist CTAP, norepinephrine depletor 6-OHDA and α 2 -adrenoceptor (α 2 -AR) antagonist yohimbine partially antagonized dezocine, pentazocine and tapentadol antinociception. Whereas specific KOR antagonist GNTI did not alter their antinociception, the putative inverse KOR agonist nor-BNI reduced dezocine and pentazocine antinociception. Moreover, combined CTAP and 6-OHDA or yohimbine blocked dezocine and tapentadol antinociception but displayed the same partial inhibition on pentazocine antinociception as CTAP alone. Furthermore, compared to morphine and pentazocine, long-term treatment with dezocine and tapentadol produced much less physical dependence-related withdrawal signs, which were restored by spinal 6-OHDA or yohimbine treatment., Significance: Our findings illustrated that dezocine and tapentadol, but not pentazocine, exert remarkable antinociception in nociceptive pain with less abuse liability via dual mechanisms of MOR activation and NRI., (Copyright © 2021 Elsevier Inc. All rights reserved.)

2-Aminotetralin and 3-aminochroman derivatives are key structural motifs present in a wide range of pharmaceutically important molecules. Herein, we report an effective biocatalytic approach towards these molecules through the enantioselective reductive coupling of 2-tetralones and 3-chromanones with a diverse range of primary amine partners. Metagenomic imine reductases (IREDs) were employed as the biocatalysts, obtaining high yields and enantiocomplementary selectivity for >15 examples at preparative scale, including the precursors to Ebalzotan, Robalzotan, Alnespirone and 5-OH-DPAT. We also present a convergent chemo-enzymatic total synthesis of the Parkinson's disease therapy Rotigotine in 63 % overall yield and 92 % ee., (© 2021 Wiley-VCH GmbH.)

A hollow fiber liquid phase microextraction (HF-LPME) based on a reversed lipid micelle as the extraction phase was proposed and combined with high performance liquid chromatography (HPLC) for the determination of rotigotine in biological matrix. In the proposed procedure, pieces of hollow fibers were fastened on a magnetic stir bar using a thread to provide better precision. Rotigotine was extracted from 5 mL of diluted plasma sample phase with pH 6 into reversed lipid micelle (5 mmol/L of dipalmitoyl phosphatidyl choline in n-octanol/water) impregnated in both the wall pores and the lumen of the hollow fiber. After the extraction at 900 rpm and room temperature for 30 min, the acceptor phase of reversed lipid micelle was collected for HPLC analysis. Various parameters affecting the extraction efficiency, such as type of surfactant and organic solvent, surfactant concentration, sample phase pH, salt amount, extraction time, stirring rate, and dilution factor of the plasma sample, were investigated and optimized. Furthermore, the formed reversed lipid micelle was characterized by fluorescence method. Under the optimal conditions, the linear range of rotigotine was between 2 ng/mL and 100 ng/mL with determination coefficient (r 2 ) ≥ 0.9913. It is shown from results of method validation that the satisfactory accuracy (the relative errors between -8.5% and 3.3%), precision (the relative standard deviations from 3.8% to 8.9%), stability and matrix effect were obtained. The enrichment factor (EF) of the reversed lipid micelle-based HF-LPME for rotigotine reached 126. And the feasibility of the proposed method was confirmed by the application to the pharmacokinetic study of rotigotine in rat plasma., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In the present study diterpene lactones were quantified in leaves and stem of different species of Andrographis collected from Western Ghats of India using reverse phase high performance liquid chromatography (RP-HPLC) method. Different populations of AA ( Andrographis alata ), AE ( Andrographis echioides ), ALn ( Andrographis lineata var. lineata ), ALw ( Andrographis lineata var. lawii ), AM ( Andrographis macrobotrys ), AO ( Andrographis ovata ), AP ( Andrographis paniculata ), APr ( Andrographis producta ) and AS ( Andrographis serphyllifolia ) were assessed for the amount of AG (andrographolide), NAG (neoandrographolide) and DDAG (14-deoxy-11, 12-didehydroandrographolide) in leaves and stem. The most abundant diterpenoid was AG and highest amount of 68.35 mg/g DW was recorded in a population of AP. AG was also present in leaves of ALw at considerable level (40.85 mg/g DW). NAG was optimum in the leaves of AM (98.43 to 102.03 mg/g DW). DDAG was higher in the leaves of AP (16.01 mg/g DW).

Background: Endocrine therapy remains the mainstay of treatment for estrogen receptor-positive (ER+) breast cancer. Constitutively active mutations in the ligand binding domain of ERα render tumors resistant to endocrine agents. Breast cancers with the two most common ERα mutations, Y537S and D538G, have low sensitivity to fulvestrant inhibition, a typical second-line endocrine therapy. Lasofoxifene is a selective estrogen receptor modulator with benefits on bone health and breast cancer prevention potential. This study investigated the anti-tumor activity of lasofoxifene in breast cancer xenografts expressing Y537S and D538G ERα mutants. The combination of lasofoxifene with palbociclib, a CDK4/6 inhibitor, was also evaluated., Methods: Luciferase-GFP tagged MCF7 cells bearing wild-type, Y537S, or D538G ERα were injected into the mammary ducts of NSG mice (MIND model), which were subsequently treated with lasofoxifene or fulvestrant as single agents or in combination with palbociclib. Tumor growth and metastasis were monitored with in vivo and ex vivo luminescence imaging, terminal tumor weight measurements, and histological analysis., Results: As a monotherapy, lasofoxifene was more effective than fulvestrant at inhibiting primary tumor growth and reducing metastases. Adding palbociclib improved the effectiveness of both lasofoxifene and fulvestrant for tumor suppression and metastasis prevention at four distal sites (lung, liver, bone, and brain), with the combination of lasofoxifene/palbociclib being generally more potent than that of fulvestrant/palbociclib. X-ray crystallography of the ERα ligand binding domain (LBD) shows that lasofoxifene stabilizes an antagonist conformation of both wild-type and Y537S LBD. The ability of lasofoxifene to promote an antagonist conformation of Y537S, combined with its long half-life and bioavailability, likely contributes to the observed potent inhibition of primary tumor growth and metastasis of MCF7 Y537S cells., Conclusions: We report for the first time the anti-tumor activity of lasofoxifene in mouse models of endocrine therapy-resistant breast cancer. The results demonstrate the potential of using lasofoxifene as an effective therapy for women with advanced or metastatic ER+ breast cancers expressing the most common constitutively active ERα mutations.

The development of practical C-H/C-H coupling reactions remains a challenging yet appealing synthetic venture because it circumvents the need to prefunctionalize both coupling partners for the generation of C-C bonds. Herein we report a cyclative C(sp 3 )-H/C(sp 2 )-H coupling reaction of free aliphatic acids enabled by a cyclopentane-based mono-N-protected β-amino acid ligand. This reaction uses inexpensive sodium percarbonate (Na 2 CO 3 ·1.5H 2 O 2 ) as the sole oxidant and generates water as the only byproduct. A range of biologically important scaffolds, including tetralins, chromanes, and indanes, can be easily prepared by this protocol. Finally, the synthetic application of this methodology is demonstrated by the concise total synthesis of (±)-russujaponol F in a four-step sequence starting from readily available phenylacetic acid and pivalic acid through sequential functionalizations of four C-H bonds.

Rotigotine-loaded microspheres (RoMS) are sustained-release formulations with prolonged anti-Parkinson's effects. Given that pain is a non-motor symptom of Parkinson's disease, this study investigated the antinociceptive effects of RoMS and their synergistic effects with analgesics on inflammatory pain. A model of inflammatory pain was prepared by intraplantarly injecting male Sprague-Dawley rats with carrageenan. The antinociceptive effects of RoMS, acetaminophen, and tramadol, both alone and in combination, were evaluated using the hind paw withdrawal latency in the hot plate test and Randall-Selitto test. The rotigotine concentrations in serum and tissues were assayed using ultra-performance liquid chromatography-tandem mass spectrometry. Isobolographic analysis was performed to evaluate the nature of the interactions of RoMS with acetaminophen or tramadol. The results showed that hind paw withdrawal latency to thermal and mechanical stimuli was significantly increased on day 3 and 7 after administered RoMS. Rotigotine could be detected in serum and tissues 3 and 7 days after an intramuscular injection of RoMS. However, the rotigotine concentration fell the detection limit of the assay on day 14 after administration. RoMS produced synergistic antinociceptive effects in the inflammatory pain model when RoMS is combined with acetaminophen or tramadol. These findings suggest that RoMS can relieve inflammatory pain in rats. Furthermore, the combination of RoMS with acetaminophen or tramadol produces synergistic antinociception, which may be clinically worthy because combination therapies may reduce the drug doses required for antinociception., (Copyright © 2020. Published by Elsevier B.V.)

Effective drugs are needed for lung cancer, as this disease remains the leading cause of cancer-related deaths. Rexinoids are promising drug candidates for cancer therapy because of their ability to modulate genes involved in inflammation, cell proliferation or differentiation, and apoptosis through activation of the retinoid X receptor (RXR). The only currently FDA-approved rexinoid, bexarotene, is ineffective as a single agent for treating epithelial cancers and induces hypertriglyceridemia. Here, we used a previously validated screening paradigm to evaluate 23 novel rexinoids for biomarkers related to efficacy and safety. These biomarkers include suppression of inducible nitric oxide synthase (iNOS) and induction of sterol regulatory element-binding protein (SREBP). Because of its potent iNOS suppression, low SREBP induction, and activation of RXR, MSU-42011 was selected as our lead compound. We next used MSU-42011 to treat established tumors in a clinically relevant Kras-driven mouse model of lung cancer. KRAS is one of the most common driver mutations in human lung cancer and correlates with aggressive disease progression and poor patient prognosis. Ultrasound imaging was used to detect and monitor tumor development and growth over time in the lungs of the A/J mice. MSU-42011 markedly decreased the tumor number, size, and histopathology of lung tumors compared to the control and bexarotene groups. Histological sections of lung tumors in mice treated with MSU-42011 exhibited reduced cell density and fewer actively proliferating cells compared to the control and bexarotene-treated tumors. Although bexarotene significantly (p < 0.01) elevated plasma triglycerides and cholesterol, treatment with MSU-42011 did not increase these biomarkers, demonstrating a more favorable toxicity profile in vivo. The combination of MSU-42011 and carboplatin and paclitaxel reduced macrophages in the lung and increased activation markers of CD8+T cells compared to the control groups. Our results validate our screening paradigm for in vitro testing of novel rexinoids and demonstrate the potential for MSU-42011 to be developed for the treatment of KRAS-driven lung cancer.

(-)-Epigallocatechin gallate (EGCG), the main component of green tea extract, displays multiple biological activities. However, it cannot be used as a drug due to its low cellular absorption, instability and metabolic degradation. Therefore, there is a need to provide analogs that can overcome the limitations of EGCG. In this work, six synthetic analogs of EGCG sharing a common tetralindiol dibenzoate core were synthesized and fully characterized by 1 H NMR, 13 C NMR, HRMS and IR spectroscopies, and X-ray crystallography. These are (2R,3S)-1,2,3,4-tetrahydronaphthalene-2,3-diyl bis[3,4,5-tris(benzyloxy)benzoate], C 66 H 56 O 10 , and the analogous esters bis(3,4,5-trimethoxybenzoate), C 30 H 32 O 10 , bis(3,4,5-trifluorobenzoate), C 24 H 14 F 6 O 4 , bis[4-(benzyloxy)benzoate], C 38 H 32 O 6 , bis(4-methoxybenzoate), C 26 H 24 O 6 , and bis(2,4,6-trifluorobenzoate), C 24 H 14 F 6 O 4 . Structural analysis revealed that the molecular shapes of these dibenzoate esters of tetralindiol are significantly different from that of previously reported dimandelate esters or monobenzoate esters, as the acid moieties extend far from the bicyclic system without folding back over the tetralin fragment. Compounds with small fluorine substituents take a V-shape, whereas larger methoxy and benzyloxy groups determine the formation of an L-shape or a cavity. Intermolecular interactions are dominated by π-π stacking and C-H...π interactions involving the arene rings in the benzoate fragment and the arene ring in the tetrahydronaphthalene moiety. All six crystal structures are determined in centrosymmetric space groups (either P-1, P2 1 /n, C2/c or I2/a).

All eight stereoisomers of conidendrin were synthesized from (1  R ,2  S ,3  S )-1-(4-benzyloxy-3-methoxyphenyl)-3-(4-benzyloxy-3-methoxybenzyl)-2- hydroxymethyl-1,4-butanediol ((+)- 4 ) and its enantiomer with high optical purity. The configurations at 4-positions of the conidendrin stereoisomers were constructed by intramolecular Friedel-Crafts reaction of protected 4 . After conversion to tetrahydronaphthalene intermediate 7a , the 2- and 3-position of tetrahydronaphthalene structure 7a were converted to 3a- and 9a-position of (+)-α-conidendrin ( 3a ), respectively. By the epimerization process of 2- or 3-position of 7a , the other diastereomers were obtained. All enantiomers were also synthesized from (-)- 4 .

The volatile components emitted from two scale insects, Ceroplastes japonicus and Ceroplastes rubens , were identified using GC-MS analysis. The major volatile components of the solvent extract from C. japonicus were α-humulene (35.8%) and δ-cadinene (17.0%), while those of C. rubens were β-selinene (10.3%) and β-elemene (5.1%). In GC/olfactometry, linalool, butyric acid, 3-methylbutyric acid, 2-methylbutyric acid, and vanillin were identified as the odor-active components of the extract from C. japonicus , in addition to trace amounts of trans -4,5-epoxy-(2 E )-decenal, 4-methyl-(3 E )-hexenoic acid, and phenylacetic acid. With regard to C. rubens, trans -4,5-epoxy-(2 E )-decenal, 3-methylbutyric acid, and phenylacetic acid were identified as the odor-active components. Besides, decan-1,4-olide (γ-decalactone) with milky cherry-like note and 3-hydroxy-4,5-dimethylfuran-2(5 H )-one (sotolone) with brown sugar-like note were also detected as the characteristic cherry-like sweet-and-sour note of these two scale insects., Abbreviations: GC: Gas chromatography; GC/O: gas chromatography/olfactometry.

A racemic spirohydantoin derivative with two aromatic substituents, a tetralin and a 4-methoxybenzyl unit, was synthesized and its crystal structure was determined. To define the relationship between molecular stereochemistry and spatial association modes, development of the crystal packing was analyzed through cooperativity of intermolecular interactions. Homo and heterochiral dimeric motifs were stabilized by intermolecular N-H⋅⋅⋅O, C-H⋅⋅⋅O, C-H⋅⋅⋅π interactions and parallel interactions at large offsets (PILO), thus forming alternating double layers. The greatest contribution to the total stabilization came from a motif of opposite enantiomers linked by N-H⋅⋅⋅O bonds (interaction energy=-13.72 kcal/mol), followed by a homochiral motif where the 4-methoxybenzyl units allowed C-H⋅⋅⋅π, C-H⋅⋅⋅O interactions and PILO (interaction energy=-11.56 kcal/mol). The number of the contact fragments in the environment of the tetralin unit was larger, but the 4-methoxybenzyl unit had greater contribution to the total stabilization. The statistical analysis of the data from the Cambridge Structural Database (CSD) showed that this is a general trend. The compound is a potential inhibitor of kinase enzymes and antigen protein-coupled receptors. A correlation between the docking study and the results of the CSD analysis can be drawn. Due to a greater flexibility, the 4-methoxybenzyl unit is more adaptable for interactions with the biological targets than the tetralin unit., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The serotonin 5-HT 7 G protein-coupled receptor (GPCR) is a proposed pharmacotherapeutic target for a variety of central and peripheral indications, albeit, there are no approved drugs selective for binding 5-HT 7 . We previously reported that a lead analog based on the 5-substituted-N,N-disubstituted-1,2,3,4-tetrahydronaphthalen-2-amine (5-substituted-2-aminotetralin, 5-SAT) scaffold binds with high affinity at the 5-HT 7 GPCR, and can treat symptoms of autism in mouse models; subsequently, the lead was found to have high affinity at the 5-HT 1A GPCR. Herein, we report the synthesis of novel 5-SAT analogs to develop a 3-dimensional quantitative structure-affinity relationship (3D-QSAR) at the human 5-HT 7 receptor for comparison with similar studies at the highly homologous 5-HT 1A receptor. We report 35 new 5-SAT ligands, some with very high affinity (K i  ≤ 1 nM) and stereoselectivity at 5-HT 7 + or 5-HT 1A receptors, several with modest selectivity (up to 12-fold) for binding at 5-HT 7 , and, several ligands with high selectivity (up to 40-fold) at the 5-HT 1A receptor. 3D-QSAR results indicate that steric extensions at the C(5)-position improve selectivity for the 5-HT 7 over 5-HT 1A receptor, while steric and hydrophobic extensions at the chiral C(2)-amino position impart 5-HT 1A selectivity. In silico receptor homology modeling studies, supplemented with molecular dynamics simulations and binding free energy calculations, were used to rationalize experimentally-determined receptor selectivity and stereoselective affinity results. The data from these studies indicate that the 5-SAT chemotype, previously shown to be safe and efficacious in rodent paradigms of neurodevelopmental and neuropsychiatric disorders, is amenable to structural modification to optimize affinity at serotonin 5-HT 7 vs. 5-HT 1A GPCRs, as may be required for successful clinical translation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The aim of present study was to develop a rotigotine (ROT) transdermal patch by converting ROT to a form of deep eutectic 'liquid co-crystal'. Formulation factors including the type of ROT-organic acid deep eutectics, pressure sensitive adhesives (PSAs), drug-loading and patch thickness were investigated by in vitro skin permeation study and the optimized patch was evaluated by pharmacokinetics study. It was particularly concerned about the drug-polymer miscibility and skin permeability of ROT-lactic acid deep eutectics (ROT-LA). FTIR study, thermal analysis and molecular modeling were conducted to investigate the drug-PSA interaction. Multiple linear regression was performed to investigate the mechanism of the promoted skin permeability. The results showed that strong interaction was observed between ROT-LA and hydroxyl PSA, which inhibited the formation of ROT crystals. Skin permeability of ROT-organic acids deep eutectics were improved by the variations of apparent partition coefficient and glass transition temperature. AUC 0-t and C max of optimized patch were 1290.6 ± 102.7 h ng/mL and 60.7 ± 12.0 ng/mL, respectively, which had no significant difference with commercial product. In conclusion, a reduced administration area (75%) and low risk of crystallization were introduced by the ROT deep eutectics, which demonstrated the feasibility of improving drug-polymer miscibility and skin permeability of transdermal drug., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The selective estrogen receptor downregulators (SERDs) are the new emerging class of drugs that are used for the treatment of endocrine resistance breast cancer. Elacestrant (ELA) is a new SERD, currently it is in phase II clinical trial. To understand the ELA-ERα interactions, the molecular docking analysis has been carried out. The ELA molecule binds with the helices H3, H5, H6, and H11 and forms important intermolecular interactions. In addition to this, the tetrahydronapthalene and phenyl rings of ELA are forming T-shaped π···π interactions with the Phe404 and Trp383 residues. Further to understand the stability and flexibility of ELA molecule in the active site of wild and mutated L536S ERα, 100ns molecular dynamics (MD) simulation was performed for both complexes. Interestingly, the MD analysis of wild complex revealed an interaction between ELA and the Asn532 of H11, which is an essential interaction for the downregulation/degradation of ERα, whereas this interaction is not observed in the mutated complex. The drug binding mechanism and H12 dynamics have been elucidated from the analysis of hydrogen bonding interactions and the secondary structure analysis. To explore the binding affinity of ELA molecule, the binding free energy and normal mode analyses were carried out. The per residue decomposition analysis also performed, which shows the contribution of individual amino acids. The principal component analysis and residue interaction network analysis were used to identify the modifications and the interaction between the residues. From the results of different analysis, the inhibition mechanism and downregulation of ERα-ELA complex has been investigated. © 2019 Wiley Periodicals, Inc., (© 2019 Wiley Periodicals, Inc.)

TREK2 (KCNK10, K 2P 10.1) is a two-pore domain potassium (K2P) channel and a potential target for the treatment of pain. Like the majority of the K2P superfamily, there is currently a lack of useful pharmacological tools to study TREK2. Here we present a strategy for identifying novel TREK2 activators. A cell-based thallium flux assay was developed and used to screen a library of drug-like molecules, from which we identified the CysLT1 antagonist Pranlukast as a novel activator of TREK2. This compound was selective for TREK2 versus TREK1 and showed no activity at TRAAK. Pranlukast was also screened against other members of the K2P superfamily. Several close analogues of Pranlukast and other CysLT1 antagonists were also tested for their ability to activate K2P channels. Consistent with previous work, structure activity relationships showed that subtle structural changes to these analogues completely attenuated the activation of TREK2, whereas for TREK1, analogues moved from activators to inhibitors. Pranlukast's activity was also confirmed using whole-cell patch clamp electrophysiology. Studies using mutant forms of TREK2 suggest Pranlukast does not bind in the K2P modulator pocket or the BL-1249 binding site. Pranlukast therefore represents a novel tool by which to study the mechanism of TREK2 activation., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction : Restless Legs Syndrome/Willis-Ekbom disease (RLS/WED) is a common sensory-motor neurological disorder that impairs nocturnal rest causing decreased alertness, depressed mood, reduced job performance and poor quality of life. In patients affected by moderate to severe RLS/WED, a pharmacological treatment is mandatory. Areas covered : The present review is based on an extensive Internet and PubMed search from 1996 to 2019. It is focused on drugs currently used and under development (phase III and beyond) for the treatment of RLS/WED. Expert opinion : The drugs currently available for the treatment of the disease do not always allow for obtaining the optimal control of symptoms, in particular in the long-term treatment. Although initially effective, long-term dopaminergic treatment tends to wane over time and augmentation can occur. Updated international guidelines now recommend α2δ calcium channel ligand medications as the initial drug of choice. Oxycodone-naloxone demonstrated a significant and sustained treatment effect for patients with severe RLS/WED insufficiently controlled with previous treatments. Head-to-head trials of different drugs, as well as more studies on nondopaminergic agents and combination therapy, are greatly needed. Monoamine oxidase B inhibitors could be good candidates for the initial treatment of RLS/WED, sparing stronger dopaminergic agents for later stages of the disease.

Ligands for retinoid X receptors (RXRs), "rexinoids", are attracting interest as candidates for therapy of type 2 diabetes and Alzheimer's and Parkinson's diseases. However, current screening methods for rexinoids are slow and require special apparatus or facilities. Here, we created 7-hydroxy-2-oxo-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2 H -chromene-3-carboxylic acid ( 10 , CU-6PMN) as a new fluorescent RXR agonist and developed a screening system of rexinoids using 10 . Compound 10 was designed based on the fact that umbelliferone emits strong fluorescence in a hydrophilic environment, but the fluorescence intensity decreases in hydrophobic environments such as the interior of proteins. The developed assay using 10 enabled screening of rexinoids to be performed easily within a few hours by monitoring changes of fluorescence intensity with widely available fluorescence microplate readers, without the need for processes such as filtration.

Neuroblastoma (NB) is a neuroendocrine tumor derived from neural crest cells. Approximately 90% of cases occur in children less than 5 years old. The amplification of MYCN correlates with high-risk neuroblastoma and patients with MYCN amplified showed poorer prognosis than those without MYCN amplification. In this study, three compounds isolated from Juniperus oblonga showed anti-proliferative activity against NB cell lines with and without tetracycline inducible MYCN over-expression which were identified as (-)-deoxypodophyllotoxin (1), (-)-matairesinol (2) and (+)-isocupressic acid (3). The effects of compounds 2 and 3 in NB cells included a decrease in NB cell viability and induction of apoptosis. Compound 1 was more effective in NB cells over-expressing MycN. Compound 1 also showed almost 2-fold induction of intracellular free calcium levels in M2(+) cells, which may indicate a different mechanism of action for this compound. Cytotoxicity studies against the human embryonic kidney cell (HEK-293) showed compounds 1, 2 and 3 were ineffective in the non-cancer cells at concentrations approximating their IC 50 against the NB cell lines. These results may lead to safer and more effective treatment options for NB patients especially for those with high-risk NB., (Copyright © 2019 Elsevier Inc. All rights reserved.)

(-)-Podophyllotoxin is one of the most potent microtubule depolymerizing agents and has served as an important lead compound in antineoplastic drug discovery. Reported here is a short chemoenzymatic total synthesis of (-)-podophyllotoxin and related aryltetralin lignans. Vital to this approach is the use of an enzymatic oxidative C-C coupling reaction to construct the tetracyclic core of the natural product in a diastereoselective fashion. This strategy allows gram-scale access to (-)-deoxypodophyllotoxin and is readily adaptable to the preparation of related aryltetralin lignans., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The cubane phenyl ring bioisostere paradigm was further explored in an extensive study covering a wide range of pharmaceutical and agrochemical templates, which included antibiotics (cefaclor, penicillin G) and antihistamine (diphenhydramine), a smooth muscle relaxant (alverine), an anaesthetic (ketamine), an agrochemical instecticide (triflumuron), an antiparasitic (benznidazole) and an anticancer agent (tamibarotene). This investigation highlights the scope and limitations of incorporating cubane into bioactive molecule discovery, both in terms of synthetic compatibility and physical property matching. Cubane maintained bioisosterism in the case of the Chagas disease antiparasitic benznidazole, although it was less active in the case of the anticancer agent (tamibarotenne). Application of the cyclooctatetraene (COT) (bio)motif complement was found to optimize benznidazole relative to the benzene parent, and augmented anticancer activity relative to the cubane analogue in the case of tamibarotene. Like all bioisosteres, scaffolds and biomotifs, however, there are limitations (e.g. synthetic implementation), and these have been specifically highlighted herein using failed examples. A summary of all templates prepared to date by our group that were biologically evaluated strongly supports the concept that cubane is a valuable tool in bioactive molecule discovery and COT is a viable complement.

The effects of time, temperature, and salinity on the adsorption of Tonalide (AHTN), Musk Xylene (MX), Galaxolide (HHCB), and Musk Ketone (MK) by microplastics of polyethylene (PE) and polyvinyl chloride (PVC) are studied. Results indicate that the equilibrium sorption time was about 10 h and the adsorption kinetics model conformed to the first-order adsorption kinetic model and pseudo-second order kinetic model, this indicates that the main adsorption mechanism might be chemical adsorption and physical absorption. Adsorption reached a nadir at 15 °C and 14% salinity. The adsorption capacity gradually increases, and then decreases, finally increases with an increase in NaCl concentration. Due to the specific surface area and the pore volume of PVC was larger than PE, the adsorption capacity of PVC was higher than that of PE in the equal conditions., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P 1 receptor modulator. In comparison to fingolimod (1), a full agonist of S1P 1 currently marketed for the treatment of relapse remitting multiple sclerosis (RRMS), 2 offers several potential advantages having demonstrated improved safety multiples in preclinical evaluations against undesired pulmonary and cardiovascular effects. In clinical trials, 2 was found to exhibit a pharmacokinetic half-life ( T 1/2 ) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P 1 . Herein, we describe our efforts to discover highly potent, partial agonists of S1P 1 with a shorter T 1/2 and increased in vivo phosphate metabolite formation. These efforts culminated in the discovery of BMS-986166 (14a), which was advanced to human clinical evaluation. The pharmacokinetic/pharmacodynamic (PK/PD) relationship as well as pulmonary and cardiovascular safety assessments are discussed. Furthermore, efficacy of 14a in multiple preclinical models of autoimmune diseases are presented.

Potassium (K + ) channels have been evolutionarily tuned for activation by diverse biological stimuli, and pharmacological activation is thought to target these specific gating mechanisms. Here we report a class of negatively charged activators (NCAs) that bypass the specific mechanisms but act as master keys to open K + channels gated at their selectivity filter (SF), including many two-pore domain K + (K 2P ) channels, voltage-gated hERG (human ether-à-go-go-related gene) channels and calcium (Ca 2+ )-activated big-conductance potassium (BK)-type channels. Functional analysis, x-ray crystallography, and molecular dynamics simulations revealed that the NCAs bind to similar sites below the SF, increase pore and SF K + occupancy, and open the filter gate. These results uncover an unrecognized polypharmacology among K + channel activators and highlight a filter gating machinery that is conserved across different families of K + channels with implications for rational drug design., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Viruses are obligate intracellular microbes that exploit the host metabolic machineries to meet their biosynthetic demands, making these host pathways potential therapeutic targets. Here, by exploring a lipid library, we show that AM580, a retinoid derivative and RAR-α agonist, is highly potent in interrupting the life cycle of diverse viruses including Middle East respiratory syndrome coronavirus and influenza A virus. Using click chemistry, the overexpressed sterol regulatory element binding protein (SREBP) is shown to interact with AM580, which accounts for its broad-spectrum antiviral activity. Mechanistic studies pinpoint multiple SREBP proteolytic processes and SREBP-regulated lipid biosynthesis pathways, including the downstream viral protein palmitoylation and double-membrane vesicles formation, that are indispensable for virus replication. Collectively, our study identifies a basic lipogenic transactivation event with broad relevance to human viral infections and represents SREBP as a potential target for the development of broad-spectrum antiviral strategies.

1-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino]benzotriazole-5-carboxylic acid (CBt-PMN), a partial agonist of retinoid X receptor (RXR), has attracted attention due to its potential to treat type 2 diabetes and central nervous system diseases with reduced adverse effects of existing full agonists. Herein, we report the crystal structure of CBt-PMN-bound ligand-binding domain of human RXRα (hRXRα) and its biochemical characterization. Interestingly, the structure is a tetramer in nature, in which CBt-PMNs are clearly found binding in two different conformations. The dynamics of the hRXRα/CBt-PMN complex examined using molecular dynamics simulations suggest that the flexibility of the AF-2 interface depends on the conformation of the ligand. These facts reveal that the dual conformation of CBt-PMN in the complex is probably the reason behind its partial agonistic activity., (© 2018 Federation of European Biochemical Societies.)

The methods described in this chapter concern procedures for the design, synthesis, and in vitro biological evaluation of an array of potent retinoid-X-receptor (RXR) agonists employing 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN), and recently reported NEt-TMN analogs, as a case study. These methods have been extensively applied beyond the present case study to generate several analogs of other potent RXR agonists (rexinoids), particularly the RXR agonist known as bexarotene (Bex), a Food and Drug Administration (FDA) approved drug for cutaneous T-cell lymphoma that is also often prescribed, off-label, for breast, lung, and other human cancers. Common side effects with Bex treatment include hypertriglyceridemia and hypothyroidism, because of off-target activation or inhibition of other nuclear receptor pathways impacted by RXR. Because rexinoids are often selective for RXR, versus the retinoic-acid-receptor (RAR), cutaneous toxicity is often avoided as a side effect for rexinoid treatment. Several other potent RXR agonists, and their analogs, have been reported in the literature and rigorously evaluated (often in comparison to Bex) as potential cancer therapeutics with unique activity and side-effect profiles. Some of the more prominent examples include LGD100268, CD3254, and 9-cis-UAB30, to name only a few. Hence, the methods described herein are more widely applicable to a diverse array of RXR agonists.In terms of design, the structure-activity relationship (SAR) study is usually performed by modifying three distinct areas of the rexinoid base structure, either of the nonpolar or polar sides of the rexinoid and/or the linkage that joins them. For the synthesis of the modified base-structure analogs, often identical synthetic strategies used to access the base-structure are applied; however, reasonable alternative synthetic routes may need to be explored if the modified analog intermediates encounter bottlenecks where yields are negligible for a given step in the base-structure route. In fact, this particular problem was encountered and successfully resolved in our case study for generating an array of NEt-TMN analogs.

Fusarium solani H915 is a fungus derived from mangrove sediments. From its ethyl acetate extract, a new alkenoic acid, fusaridioic acid A (1), three new bis-alkenoic acid esters, namely, fusariumester A₁ (2), A₂ (3) and B (4), together with three known compounds (5⁻7), were isolated. The structures of the new compounds were comprehensively characterized by high resolution electrospray ionization-mass spectrometry (HR-ESI-MS), 1D and 2D nuclear magnetic resonance (NMR). Additionally, the antifungal activities against tea pathogenic fungi Pestalotiopsis theae and Colletotrichum gloeosporioides were studied. The new compound, 4, containing a β-lactone ring, exhibited moderate inhibitory activity against P. theae, with an MIC of 50 μg/disc. Hymeglusin ( 6 ), a typical β-lactone antibiotic and a terpenoid alkaloid, equisetin (7), exhibited potent inhibitory activities against both fungal species. The isolated compounds were evaluated for their effects on zebrafish embryo development. Equisetin clearly imparted toxic effect on zebrafish even at low concentrations. However, none of the alkenoic acid derivatives exhibited significant toxicity to zebrafish eggs, embryos, or larvae. Thus, the β-lactone containing alkenoic acid derivatives from F. solani H915 are low in toxicity and are potent antifungal agents against tea pathogenic fungi., Competing Interests: The authors have no conflict of interest to declare. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript and in the decision to publish the results.

Tropisetron is an adjuvant for dezocine used in intravenous patient-controlled analgesia (PCA) and has been reported to provide superior pain control. It is efficacious in reducing the institutional incidence of postoperative nausea and vomiting (PONV), which decreases resource utilization and cost. However, no scientific evidence has been reported in the literature demonstrating analytical confirmation of the compatibility and stability of the combination of dezocine and tropisetron. Thus, the present study aimed to investigate the stability of dezocine with tropisetron in 0.9% sodium chloride injection form for PCA administration.Commercial solutions of dezocine and tropisetron were combined and examined for compatibility and stability when diluted with 0.9% sodium chloride injection in polyolefin bags and glass bottles stored at 4°C or 25°C for up to 14 days. The initial concentrations were 40 mg/100 mL dezocine and 5 mg/100 mL tropisetron. For all samples, the compatibility parameters (including precipitation, cloudiness, discoloration, and pH values) were evaluated. Chemical stability was also determined using high-performance liquid chromatographic (HPLC) analysis.After a 14-day period of storage at 4°C or 25°C, the initial concentrations of dezocine and tropisetron were maintained at at least 98%. All of the mixtures remained clear and colorless throughout the observation period, and no color change or precipitation was observed.These results indicated that admixtures of 40 mg/100 mL dezocine and 5 mg/100 mL tropisetron in 0.9% sodium chloride injection were stable for at least 14 days when stored in polyolefin bags or glass bottles at 4°C or 25°C and protected from light.

Type 2 diabetes (T2D) is a severe disease and it is one of the most raising problems worldwide. This study deals with design, synthesis and in vivo determination of a new set of tetralin-sulfonamide derivatives as anti-diabetic and dipeptidyl peptidase-IV (DPP-4) inhibiting agents. Most of the new compounds exhibited significant hypoglycemic effect alongside with DPP-4 suppression potency considering sitagliptin as a reference drug. The most promising compounds 4, 15 showed 2.80 nM DPP-4 IC 50 with 20-40 folds selectivity over DPP-8 and DPP-9. 2D and 3D QSAR models were performed using auto QSAR of Schrödinger, QuaSAR of MOE and 3D Field-based QSAR of Schrödinger, respectively. The experimental results revealed that the alignment-independent descriptors, electrostatic and steric field descriptors were significantly correlated with the antidiabetic activity of the new derivatives. In addition, the new compounds were docked in the active site of DPP-4 in reference to sitagliptin to rationalize the binding modes of the compounds with the amino acid residues of the enzyme. Furthermore, 131 I-compound 4 complex was selected to evaluate the pharmacokinetic behavioral profile of compound 4 and its body organs uptakes alongside its elimination pathway as a representative example for the rest of the analogues. The bio distribution pattern of the tracer proved the selective accumulation of 131 I-substrate in the pancreas and rapid clearance from most of the body organs., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Vesicular acetylcholine transporter (VAChT) is a reliable biomarker for assessing the loss of cholinergic neurons in the brain that is associated with cognitive impairment of patients. 5-Hydrotetralin compound (±)-5-OH-VAT is potent (K i  = 4.64 ± 0.32 nM) and selective for VAChT (>1800-fold and 398-fold for σ 1 and σ 2 receptor, respectively) with favorable hydrophilicity (LogD = 1.78), while (-)-5-OH-VAT originally serves as the radiolabeling precursor of (-)-[ 18 F]VAT, a promising VAChT radiotracer with a logD value of 2.56. To evaluate (-)-5-OH-[ 18 F]VAT as a radiotracer for VAChT, we performed in vitro binding assay to determine the potency of the minus enantiomer (-)-5-OH-VAT and plus enantiomer (+)-5-OH-VAT, indicating that (-)-5-OH-VAT is a more potent VAChT enantiomer. Radiosynthesis of (-)-5-OH-[ 18 F]VAT was explored using three strategies. (-)-5-OH-[ 18 F]VAT was achieved with a good yield (24 ± 6%) and high molar activity (∼37 GBq/µmol, at the end of synthesis) using a microwave assisted two-step one-pot procedure that started with di-MOM protected nitro-containing precursor (-)-6. MicroPET studies in the brain of nonhuman primate (NHP) suggest that (-)-5-OH-[ 18 F]VAT readily penetrated the blood brain barrier and specifically accumulated in the VAChT-enriched striatum with improved washout kinetics from striatum compared to [ 18 F]VAT. Nevertheless, the lower target to non-target ratio may limit its use for in vivo measurement of the VAChT level in the brain., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Ethyl acetate extracts of seaweeds were chromatographically fractionated to yield 14-methyl pentyl tetrahydro-8-hydroxy-10-methylnaphthalene-8-carboxylate (1) and tetrahydro-4-isopropyl-9-(9, 14-dimethyldec-9-enyl)-pyran-1-one (2) from Sargassum ilicifolium, whereas Padina gymnospora afforded dihydro-2-(10-(hydroxymethyl)-7,15-dimethyl-9-oxoundec-11-enyl)-2-methyl-2H-pyran-1(4H)-one (3) and 1-(decahydro-1-hydroxy-7-methyl-8-vinylnaphthalen-2-yl)ethanone (4) as major constituents. Compound 1 displayed significantly higher antioxidant activity (IC 50  < 1 mg/mL, p < 0.05) comparable to other analogues (IC 50  > 1 mg/mL). The C 20-22 polyunsaturated fatty acid (C 20-22 PUFA) concentrate (CFA) prepared from the deep-sea dogfish liver oil was added with the studied compounds and physiochemical properties and fatty acid composition during an accelerated storage were evaluated. No significant reduction in C 20-22 PUFAs (∼6%) in the CFA treated with 1 as compared to that with the control (∼35%) was recorded. A greater induction time was observed for the CFA supplemented with 1 (6.8 h) than other compounds (≤6 h) and control (∼1.6 h), maintaining the oxidation indices of the CFA within desirable limits., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The glycine transporter 1 (GlyT1) has emerged as a key novel target for the treatment of schizophrenia. Herein, we report the synthesis and biological evaluation of aminotetralines and aminochromanes as novel classes of competitive GlyT1 inhibitors. Starting from a high-throughput screening hit, structure-activity relationship studies led first to the discovery of aminotetralines displaying high GlyT1 potency and selectivity, with favorable pharmacokinetic properties. Systematic investigations of various parameters (e.g., topological polar surface area, number of hydrogen bond donors) guided by ex vivo target occupancy evaluation resulted in lead compounds possessing favorable brain penetration properties as for (7 S,8 R)-27a. Further optimization revealed compounds with reduced efflux liabilities as for aminochromane 51b. In an in vivo efficacy model (7 S,8 R)-27a, dose-dependently reversed L-687,414 induced hyperlocomotion in mice with an ED 50 of 0.8 mg/kg. All these results suggest (7 S,8 R)-27a and 51b as new GlyT1 inhibitors worthy of further profiling.

Birch reductions of aromatic hydrocarbons by means of single-electron-transfer steps depend on alkali metals, ammonia, and cryogenic reaction conditions. In contrast, 2-naphthoyl-coenzyme A (2-NCoA) and 5,6-dihydro-2-NCoA (5,6-DHNCoA) reductases catalyze two two-electron reductions of the naphthoyl-ring system to tetrahydronaphthoyl-CoA at ambient temperature. Using a number of substrate analogues, we provide evidence for a Meisenheimer complex-analogous intermediate during 2-NCoA reduction, whereas the subsequent reduction of 5,6-dihydro-2-NCoA is suggested to proceed via an unprecedented cationic transition state. Using vibrational circular dichroism (VCD) spectroscopy, we demonstrate that both enzymatic reductions are highly stereoselective in D 2 O, providing an enantioselective pathway to products inaccessible by Birch reduction. Moreover, we demonstrate the power of VCD spectroscopy to determine the absolute configuration of isotopically engendered alicyclic stereocenters., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A new family of melatonin receptor ligands, characterized by a tetrahydroquinoline (THQ) scaffold carrying an amide chain in position 3, was devised as conformationally constrained analogs of flexible N-anilinoethylamides previously developed. Molecular superposition models allowed to identify the patterns of substitution conferring high receptor binding affinity and to support the THQ ring as a suitable scaffold for the preparation of melatonin ligands. The biological activity of 3-acylamino-THQs was compared with that of the corresponding tetralin derivatives. The THQ ring proved to be a versatile scaffold for easy feasible MT 1 and MT 2 ligands, which resulted as more polar bioisosteres of their tetralin analogs. Potent partial agonists, with subnanomolar binding affinity for the MT 2 receptor, were obtained, and a new series of THQ derivatives is presented. The putative binding mode of potent THQs and tetralines was discussed on the basis of their conformational equilibria as inferred from molecular dynamics simulations and experimental NMR data.

CDK4/6 pathway is an attractive chemotherapeutic target for antitumor drug discovery and development. Herein, we reported the structure-based design and synthesis of a series of novel tetrahydronaphthyridine analogues as selective CDK4/6 inhibitors. Compound 5 was identified as a hit and then systematically structure optimization study was conducted. These efforts led to compound 28, which exhibited excellent in vitro potencies against CDK4/6 enzymatic activity with high selectivity over CDK1, and against Colo-205 cell growth. The compound demonstrated favorable in vitro metabolic and robust mice pharmacokinetic properties. In Colo-205 xenograft models, compound 28 showed potent tumor growth inhibition with acceptable toxic effects, which could serve as a novel anticancer agent for further preclinical study., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

A ligand-based virtual screening exercise examining likely bioactive conformations of AM 580 (2) and AGN 193836 (3) was used to identify the novel, less lipophilic RARα agonist 4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid 5, which has good selectivity over the RARβ, and RARγ receptors. Analysis of the medicinal chemistry parameters of the 3,5-substituents of derivatives of template 5 enabled us to design a class of drug-like molecules with lower intrinsic clearance and higher oral bioavailability which led to the novel RARα agonist 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid 56 that has high RARα potency and excellent selectivity versus RARβ (2 orders of magnitude) and RARγ (4 orders of magnitude) at both the human and mouse RAR receptors with improved drug-like properties. This RARα specific agonist 56 has high oral bioavailability (>80%) in both mice and dogs with a good PK profile and was shown to be inactive in cytotoxicity and genotoxicity screens., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Retinoids which are vitamin A (Retinol) derivatives have been suggested to mediate the inhibition of cancer cell growth and apoptosis. It has been reported that all trans retinoic acid (ATRA) exhibited suppressive effects on different types of leukemia including chronic myelogenous leukemia., Objective: In the present study, we aim to find out the effects of 6 synthetic N-(3,5,5,8,8-pentamethyl-5,6,7,8- tetrahydronaphthalene-2-yl)-carboxamide derivatives (compound 6-12) on cell viability and apoptotic pathways in K562 human chronic myelogenous leukemia cell line., Methods: Cell viability and apoptosis were examined by spectrophotometric thiazolyl blue tetrazolium bromide (MTT) and caspase-3 assay, western blot, RT-PCR and flow cytometry., Results: Our results indicated that compound 6 (5-(1,2-Dithiolan-3-yl)-N-(3,5,5,8,8-pentamethyl-5,6,7,8- tetrahydronaphthalen-2-yl)pentanamide), 8 (4-(3,4-Dimethoxyphenyl)-N-(3,5,5,8,8-pentamethyl-5,6,7,8- tetrahydronaphthalen-2-yl)butanamide) and 11 (E-3-(4-Hydroxy-3-methoxyphenyl)-N-(3,5,5,8,8-pentamethyl- 5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide) exhibited apoptotic effects in K562 human chronic myelogenous leukemia cell line and induced caspase 3, PARP cleavage, Bax/Bcl-2 ratio, Bad and Bim gene expressions., Conclusion: Some retinoid derivatives tested in this study induced apoptosis of K562 cells which suggest that these compounds may serve as potential agents in the treatment of chronic myelogenous leukemia., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

This report describes the stereoselective synthesis of 3-azido-tetralins, -chromanes, and -tetrahydroquinolines via a tandem allylic azide rearrangement/Friedel-Crafts alkylation. Exposure of allylic azides with a pendant trichloroacetimidate to catalytic quantities of AgSbF 6 proved optimal for this transformation. This cascade successfully differentiates the equilibrating azide isomers, providing products in excellent yield and selectivity (>25 examples, up to 94% yield and >25:1 dr). In many cases, the reactive isomer is only a trace fraction of the equilibrium mixture, keenly illustrating the dynamic nature of these systems. We demonstrate the utility of this process via a synthesis of hasubanan.

Microplastics and synthetic musks (SMs) are two typical organic pollutants in the marine environment. In this study, the sorption of three SMs to microplastics in a simulated seawater environment was examined. Tonalide (AHTN), musk xylene (MX), and musk ketone (MK) were the musks investigated, while polypropylene (PP) was used as the microplastic. It was found that the equilibrium sorption time was about 10h and the adsorption kinetics model conformed to a Lagergren adsorption model. The adsorption capacity increased with decreasing particle size. Adsorption reached a peak at 25°C, and the adsorption capacity was not sensitive to the concentration of sodium chloride. There is a need for more research and monitoring of microplastics in the marine environment due to their strong ability to absorb organic pollutants., (Copyright © 2017. Published by Elsevier Ltd.)

Rotigotine behenate (RGTB), a long chain alkyl ester of the prodrug of rotigotine (RGT), has been synthesized for use in a sustained delivery system. The aim of the present report was to develop and validate a simple, sensitive and reliable LC-MS/MS method for the simultaneous determination of RGT and its prodrug RGTB in rat plasma samples. Detection was performed on a 1290 Infinity UPLC coupled Triple Quad 4500 mass spectrometer operated in positive MRM mode using an Eclipse XDB-CN chromatography column (2.1mm×100mm, 3.5μm) by isocratic elution using a 0.2% formic acid aqueous solution and acetonitrile, with stable isotope labeled RGT as an internal standard. The sample preparation method employed 50μL of a plasma sample and liquid-liquid extraction with a mixture of diethyl ether-dichloromethane (3:2, v/v) as the extraction solvent. The proposed method was fully validated by assessing its specificity, linearity, precision and accuracy, recovery, matrix effects and stability. Good linearity was found within the range of 0.1-10.0ng/mL for both analytes (r>0.996). This method was successfully applied to a pharmacokinetic study of a slow release RGTB formulation in rats following a single intramuscular injection and biological conversion in vitro., (Copyright © 2017. Published by Elsevier B.V.)