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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]

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 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]