Search

One new aspidosperma-type alkaloid, melotenine A (1), together with five known ones (2-6), was isolated from the leaves of Melodinus axillaris. Their structures were elucidated by detailed spectroscopic analysis and quantum chemical ECD calculation. The isolated aspidosperma-type alkaloids were evaluated for their cytotoxicity against four human cancer cell lines and melotenine A showed significant cytotoxicity against all cells with IC50 values ranging from 0.6 to 1.5 μM. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • New IAA-tacrine hybrids were synthesized as potent dual AChE/BChE inhibitors. • This series of hybrids targeted both CAS and PAS of AChE and BChE. • Compound 5e could increase the frequency of the network oscillation. • Compound 5e could decrease the duration of synchronized firing. Abstract A series of new indole-3-acetic acid (IAA)-tacrine hybrids as dual acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibitors were designed and prepared based on the molecular docking mode of AChE with an IAA derivative (1a), a moderate AChE inhibitor identified by screening our compound library for anti-Alzheimer's disease (AD) drug leads. The enzyme assay results revealed that some hybrids, e.g. 5d and 5e , displayed potent dual in vitro inhibitory activities against AChE/BChE with IC 50 values in low nanomolar range. Molecular modeling studies in tandem with kinetic analysis suggest that these hybrids target both catalytic active site and peripheral anionic site of cholinesterase (ChE). Molecular dynamic simulations and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) calculations indicate that 5e has more potent binding affinity than hit 1a , which may explain the stronger inhibitory effect of 5e on AChE. Furthermore, their predicted pharmacokinetic properties and in vitro influences on mouse brain neural network electrical activity were discussed. Taken together, compound 5e can be highlighted as a lead compound worthy of further optimization for designing new anti-AD drugs. [ABSTRACT FROM AUTHOR]

All eight stereoisomers ( 1–8 ) of a neosecurinane-type Securinega alkaloid were isolated and identified from a Chinese medicinal plant, Flueggea virosa . Structures of the four pairs of enantiomers were characterized and differentiated from one another based on comprehensive spectroscopic analyses especially specific optical rotation and electronic circular dichroism measurements. While clarifying some historical ambiguities, the discovery of these molecules also brings new puzzles to the natural products community, which will be surely leading to further attention and studies. This case investigation also reminds that future researchers who work with natural products should pay more attention to the enantiomeric purity of their samples. [ABSTRACT FROM AUTHOR]

Flueggether A (I), the first example of Securinega alkaloid oligomers with an ether bridge, and virosinine A (II), possessing a novel heterocyclic backbone, exhibit weak in vitro anti-HIV activity. [ABSTRACT FROM AUTHOR]

Protein arginine methyltransferase 5 (PRMT5) and epidermal growth factor receptor (EGFR) are both involved in the regulation of various cancer-related processes, and their dysregulation or overexpression has been observed in many types of tumors. In this study, we designed and synthesized a series of 1-phenyl-tetrahydro-β-carboline (THβC) derivatives as the first class of dual PRMT5/EGFR inhibitors. Among the synthesized compounds, 10p showed the most potent dual PRMT5/EGFR inhibitory activity, with IC 50 values of 15.47 ± 1.31 and 19.31 ± 2.14 μM, respectively. Compound 10p also exhibited promising antiproliferative activity against A549, MCF7, HeLa, and MDA-MB-231 cell lines, with IC 50 values below 10 μM. Molecular docking studies suggested that 10p could bind to PRMT5 and EGFR through hydrophobic, π-π, and cation-π interactions. Furthermore, 10p displayed favorable pharmacokinetic properties and oral bioavailability (F = 30.6%) in rats, and administrated orally 10p could significantly inhibit the growth of MCF7 orthotopic xenograft tumors. These results indicate that compound 10p is a promising hit compound for the development of novel and effective dual PRMT5/EGFR inhibitors as potential anticancer agents. [Display omitted] • Novel 1-phenyl-THβC derivatives were evaluated as first dual PRMT5/EGFR inhibitors. • Some derivatives significantly inhibited the proliferation of several cancer cell lines. • Compound 10p showed the best dual inhibition on PRMT5 and EGFR, and promising antiproliferative activity. • Compound 10p displayed favorable in vivo PK and PD properties. [ABSTRACT FROM AUTHOR]

Biogenesis inspired chemical investigation of a Chinese folk medicine, Flueggea virosa, returned three unprecedented C,C-linked trimeric Securinegaalkaloids, fluevirosines A–C (1–3). Their absolute structures were characterized on the basis of spectroscopic data and computational analysis. Compounds 2and 3showed inhibition against the splicing of XBP1 mRNA. [ABSTRACT FROM AUTHOR]

Trace amine-associated receptor 1 (TAAR1) senses a spectrum of endogenous amine-containing metabolites (EAMs) to mediate diverse psychological functions and is useful for schizophrenia treatment without the side effects of catalepsy. Here, we systematically profiled the signaling properties of TAAR1 activation and present nine structures of TAAR1-Gs/Gq in complex with EAMs, clinical drugs, and synthetic compounds. These structures not only revealed the primary amine recognition pocket (PARP) harboring the conserved acidic D3.32 for conserved amine recognition and "twin" toggle switch for receptor activation but also elucidated that targeting specific residues in the second binding pocket (SBP) allowed modulation of signaling preference. In addition to traditional drug-induced Gs signaling, Gq activation by EAM or synthetic compounds is beneficial to schizophrenia treatment. Our results provided a structural and signaling framework for molecular recognition by TAAR1, which afforded structural templates and signal clues for TAAR1-targeted candidate compounds design. [Display omitted] • Activation profiles of m/hTAAR1 in response to a variety of EAM and pre-clinical drugs • Structures of m/hTAAR1-Gs/Gq in complex with EAMs, SEP, or synthetic compounds • Two pockets, PARP and SBP, enabled small EAM recognition and potent agonist design • Preferential Gq or Gs/Gq agonist of TAAR1 alleviated schizophrenia-like phenotypes Structural basis for the molecular recognition and signaling diversity of TAAR1 has been revealed, which facilitates structure-based preferential Gq or dual Gs/Gq pathway agonist design to alleviate MK-801-induced schizophrenia-like phenotypes. [ABSTRACT FROM AUTHOR]

Protein arginine methyltransferase 5 (PRMT5) is an epigenetics related enzyme that has been validated as an important therapeutic target for treating various types of cancer. Upregulation of tumor suppressor hnRNP E1 has also been considered as an effective antitumor therapy. In this study, a series of tetrahydroisoquinolineindole hybrids were designed and prepared, and compounds 3m and 3s4 were found to be selective inhibitors of PRMT5 and upregulators of hnRNP E1. Molecular docking studies indicated that compounds 3m occupied the substrate site of PRMT5 and formed essential interactions with amino acid residues. Furthermore, compounds 3m and 3s4 exerted antiproliferative effects against A549 cells by inducing apoptosis and inhibiting cell migration. Importantly, silencing of hnRNP E1 eliminated the antitumor effect of 3m and 3s4 on the apoptosis and migration in A549 cells, suggesting a regulatory relationship between PRMT5 and hnRNP E1. Additionally, compound 3m exhibited high metabolic stability on human liver microsomes (T 1/2 = 132.4 min). In SD rats, the bioavailability of 3m was 31.4%, and its PK profiles showed satisfactory AUC and C max values compared to the positive control. These results suggest that compound 3m is the first class of dual PRMT5 inhibitor and hnRNP E1 upregulator that deserves further investigation as a potential anticancer agent. [Display omitted] • Tetrahydroisoquinolineindoles were screened as PRMT5 inhibitors/hnRNP E1 promoters. • Some compounds exhibited significant antitumor activities. • Compounds 3m and 3s4 significant up-regulate hnRNP E1 protein level. • The study firstly indicates the regulatory relationship between PRMT5 and hnRNP E1. • Compound 3m was observed a 31.4% F and quite satisfying T 1/2 , AUC and Cmax values. [ABSTRACT FROM AUTHOR]

Phytochemical investigation of the ethyl acetate soluble part, generated from the ethanol extract of the roots of Dipsacus asper , led to the separation and identification of three undescribed triterpenoids including one arborinane type, one ursane type and one oleanane type, two unreported oleanane type triterpenoid arabinoglycosides, and 18 known analogues. Structures of these compounds were determined by comprehensive spectroscopic analyses, with the absolute configurations of 25-acetoxy-28-dehydroxyrubiarbonone E and 2 α ,3 β -dihydroxy-23-norurs-4(24),11,13(18)-trien-28-oic acid being established by evaluation of their experimental and calculated ECD spectra. 25-Acetoxy-28-dehydroxyrubiarbonone E features an oxygenated C-25 that is the first case among arborinane type triterpenoids, while 2 α ,3 β ,24-trihydroxy-23-norurs-12-en-28-oic acid incorporates a sp3 C-24 that is a rare structural feature of 23-norursane type triterpenoids. Of these isolates, 2′,4′- O -diacetyl-3- O - α - l -arabinopyranosyl-23-hydroxyolea-12-en-28-oic acid and hederagonic acid exhibited moderate antibacterial activity against Staphylococcus aureus with IC 50 values of 12.3 and 10.3 μ M, respectively, while those with either a feruloyloxy group or an arabinosyl moiety at C-3 displayed potent cytotoxic activities against four tumor cell lines A549, H157, HepG2 and MCF-7. Twenty-three compounds including five undescribed ones were isolated from the roots of Dipsacus asper and their cytotoxic evaluation with SAR discussion was presented. Image 1 • Five undescribed compounds were isolated from the roots of Dipsacus asper. • TDDFT calculations of ECD spectra were used to determine the absolute configurations. • Some compounds exhibited moderate antibacterial activities. • Some isolates displayed potent cytotoxic activities with IC 50 values below 10 μ M. • The structure-activity relationship (SAR) for cytotoxic evaluation was well discussed. [ABSTRACT FROM AUTHOR]

Two polyketides, stemonones A ( 1 ) and B ( 2 ) with new skeletons, were isolated from the roots of Stemona tuberosa . Their absolute structures were fully characterized by comprehensive spectroscopic analyses and comparison of experimental electronic circular dichroism (ECD) spectra with calculated ones. The plausible biosynthetic pathways for 1 and 2 were also proposed. Anti-inflammatory assay confirmed that the two compounds showed moderate inhibitory effects on β -glucuronidase release in rat polymorphonuclear leukocytes (PMNs) induced by platelet-activating factor. [ABSTRACT FROM AUTHOR]

Twenty-five novel pregnenolone/2-cyanoacryloyl conjugates ( 6 – 30 ) were designed and prepared, with the aim of developing novel anticancer drugs with dual NF-κB inhibitory and anti-proliferative activities. Compounds 22 and 27 – 30 showed inhibition against TNF-α-induced NF-κB activation in luciferase assay, which was confirmed by Western blotting. Among them, compound 30 showed potent NF-κB inhibitory activity (IC 50 = 2.5 μM) and anti-proliferative against MCF-7, A549, H157, and HL-60 cell lines (IC 50 = 6.5–36.2 μM). The present study indicated that pregnenolone/2-cyanoacryloyl conjugate I can server as a novel scaffold for developing NF-κB inhibitors and anti-proliferative agents in cancer chemotherapy. [ABSTRACT FROM AUTHOR]

Phytochemical investigation on the aerial parts of Tabernaemontana bufalina Lour. (Apocynaceae) led to the identification of four undescribed monoterpenoid indole alkaloids named taberbufamines A−D, an undescribed natural product, and fourteen known indole alkaloids. The structures of the undescribed alkaloids were established by spectroscopic and computational methods, and their absolute configurations were further determined by quantum chemical TDDFT calculations and the experimental ECD spectra. Taberbufamines A and B possessed an uncommon skeleton incorporating an indolizidino [8,7- b ]indole motif with a 2-hydroxymethyl-butyl group attached at the pyrrolidine ring. Biosynthetically, Taberbufamines A and B might be derived from iboga-type alkaloid through rearrangement. Vobatensine C showed significant bioactivity against A-549, Bel-7402, and HCT-116 cells with IC 50 values of 2.61, 1.19, and 1.74 μM, respectively. Ervahanine A showed antimicrobial activity against Bacillus subtilis , Mycobacterium smegmatis , and Helicobacter pylori with MIC values of 4, 8, and 16 μg/mL, respectively. 19(S)-hydroxyibogamine was shown as butyrylcholinesterase inhibitor (IC 50 of 20.06 μM) and α-glycosidase inhibitor (IC 50 of 17.18 μM), while tabernamine, ervahanine B, and ervadivaricatine B only showed α-glycosidase inhibitory activities with IC 50 values in the range of 0.95–4.61 μM. Taberbufamines A and B possessed an uncommon skeleton incorporating an indolizidino [8,7-b]indole motif with a 2-hydroxymethyl-butyl group attached at the pyrrolidine ring. [Display omitted] • Taberbufamines A and B had a skeleton with an indolizidino [8,7-b]indole motif. • Some alkaloids showed cytotoxicity, antimicrobial and BChE inhibitory activities. • The mechanisms against BChE were tested by Lineweaver-Burk plot analysis. • A plausible biogenetic pathway for taberbufamines A and B was proposed. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel 2-phenyl-1 H -benzo[ d ]imidazole-based α-glucosidase inhibitors were identified. • Some of derivatives significantly increased α-glucosidase inhibition. • The non-competitive inhibitors 15o and 22d did not have cytotoxicity towards LO2 cells. • Compound 15o showed significant in vivo anti-hyperglycaemic activity. In the present study, a series of 2-phenyl-1 H -benzo[ d ]imidazole-based α-glucosidase inhibitors were synthesized and evaluated for their in vitro and in vivo anti-diabetic potential. Screening of an in-house library revealed a moderated α-glucosidase inhibitor, 6a with 3-(1 H -benzo[ d ]imidazol-2-yl)aniline core, and then the structural optimization was performed to obtain more efficient derivatives. Most of these derivatives showed increased activity than 6a , and the most promising inhibitors were found to be compounds 15o and 22d with IC 50 values of 2.09 ± 0.04 and 0.71 ± 0.02 µM, respectively. Fluorescence quenching experiment confirmed the direct binding of compounds 15o and 22d with α-glucosidase. Kinetic study revealed that both compounds were non-competitive inhibitors, that was consistent with the result of molecular docking studies where they located at the allosteric site of the enzyme. Cell viability evaluation demonstrated the non-cytotoxicity of 15o and 22d against LO2 cells. Furthermore, the in vivo pharmacodynamic study revealed that compound 15o showed significant hypoglycemic activity and improved oral sucrose tolerance, comparable to the positive control acarbose. [ABSTRACT FROM AUTHOR]

[Display omitted] In this present study, a series of novel (E)-2-benzylidene- N -(3-cyano-4,5,6,7-tetrahydrobenzo[ b ]thiophen-2-yl)hydrazine-1-carboxamide derivatives against α-glucosidase were designed and synthesized, and their biological activities were evaluated in vitro and in vivo. Most of the designed analogues exhibited better inhibitory activity than the marketed acarbose, especially the most potent compound 7 with an IC 50 value of 9.26 ± 1.84 μM. The direct binding of 7 and 8 with α-glucosidase was confirmed by fluorescence quenching experiments, and the kinetic and molecular docking studies revealed that 7 and 8 inhibited α-glucosidase in a non-competitive manner. Cytotoxicity bioassay indicated compounds 7 and 8 were non-toxic towards LO2 and HepG2 at 100 μM. Furthermore, both compounds were demonstrated to have in vivo hypoglycemic activity by reducing the blood glucose levels in sucrose-treated rats. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel tetrahydrobenzo[ b ]thiophen-2-yl)urea derivatives were designed and synthesized. • Tetrahydrobenzo[ b ]thiophen-2-yl)urea derivatives significantly increased α-glucosidase inhibition. • The most potent compounds 8r and 8s showed non-toxicity towards LO2 and HepG2 cells. • Compound 8r showed promising in vivo anti-hyperglycaemic activity. α-Glucosidase inhibitors, which can inhibit the digestion of carbohydrates into glucose, are one of important groups of anti-type 2 diabetic drugs. In the present study, we report our effort on the discovery and optimization of α-glucosidase inhibitors with tetrahydrobenzo[ b ]thiophen-2-yl)urea core. Screening of an in-house library revealed a moderated α-glucosidase inhibitors, 5a , and then the following structural optimization was performed to obtain more efficient derivatives. Most of these derivatives showed increased inhibitory activity against α-glucosidase than the parental compound 5a (IC 50 of 26.71 ± 1.80 μM) and the positive control acarbose (IC 50 of 258.53 ± 1.27 μM). Among them, compounds 8r (IC 50 = 0.59 ± 0.02 μM) and 8s (IC 50 = 0.65 ± 0.03 μM) were the most potent inhibitors, and showed selectivity over α-amylase. The direct binding of both compounds with α-glucosidase was confirmed by fluorescence quenching experiments. Kinetics study revealed that these compounds were non-competitive inhibitors, which was consistent with the molecular docking results that compounds 8r and 8s showed high preference to bind to the allosteric site instead of the active site of α-glucosidase. In addition, compounds 8r and 8s were not toxic (IC 50 > 100 μM) towards LO2 and HepG2 cells. Finally, the in vivo anti-hyperglycaemic activity assay results indicated that compounds 8r could significantly decrease the level of plasma glucose and improve glucose tolerance in SD rats treated with sucrose. The present study provided the tetrahydrobenzo[ b ]thiophen-2-yl)urea chemotype for developing novel α-glucosidase inhibitors against type 2 diabetes. [ABSTRACT FROM AUTHOR]

Eleven new highly oxygenated germacrane-type sesquiterpenoids (1–11) and 16 known analogues (12–27) were isolated from the aerial parts of Sigesbeckia orientalis. Compounds 13 , 21 and 23 possessing an 8-methacryloxy group showed stronger in vitro cytotoxicity against human A549 and MDA-MB-231 cancer cell lines than other co-metabolites, with IC 50 values ranging from 6.02 to 10.77 μM. • 11 new and 16 known sesquiterpenoids were isolated from Sigesbeckia orientalis. • Their structures were elucidated using extensive spectroscopic analysis. • Their cytotoxic activities against A549 and MDA-MB-231 cell lines were evaluated. • Compounds possessing an 8-methacryloxy group showed stronger cytotoxicity. Eleven new highly oxygenated germacrane-type sesquiterpenoids (1–11) and 16 known analogues (12–27) were isolated from the aerial parts of Sigesbeckia orientalis. Their structures, including absolute configurations, were determined by comprehensive spectroscopic methods especially NMR and ECD analyses. Compounds 13 , 21 and 23 possessing an 8-methacryloxy group showed stronger in vitro cytotoxicity against human A549 and MDA-MB-231 cancer cell lines than other co-metabolites, with IC 50 values ranging from 6.02 to 10.77 μM comparable to the positive control adriamycin. [ABSTRACT FROM AUTHOR]