RÉSUMÉ
Topoisomerase (Top) inhibitors used in clinical cancer treatments are limited because of their toxicity and severe side effects. Noteworthily, Top1/2 dual inhibitors overcome the compensatory effect between Top1 and 2 inhibitors to exhibit stronger antitumor efficacies. In this study, a series of indolo[3,2-c]isoquinoline derivatives were designed as Top1/2 dual inhibitors possessing apparent antiproliferative activities. Mechanistic studies indicated that the optimal compounds 23 and 31 with increasing reactive oxygen species levels damage DNA, inducing both cancer cell apoptosis and cycle arrest. Importantly, the results of the toxicity studies showed that compounds 23 and 31 possessed good oral safety profiles. In xenograft models, compound 23 exhibited remarkable antitumor potency, which was superior to the clinical Top inhibitors irinotecan and etoposide. Overall, this work highlights the therapeutic potential and safety profile of compound 23 as a Top1/2 dual inhibitor in tumor therapy and provides valuable lead compounds for further development of Top inhibitors.
Sujet(s)
Antinéoplasiques , ADN topoisomérases de type II , Isoquinoléines , Inhibiteurs de la topoisomérase-I , Inhibiteurs de la topoisomérase-II , Humains , Animaux , Isoquinoléines/pharmacologie , Isoquinoléines/composition chimique , Isoquinoléines/usage thérapeutique , Isoquinoléines/synthèse chimique , Isoquinoléines/pharmacocinétique , Antinéoplasiques/pharmacologie , Antinéoplasiques/composition chimique , Antinéoplasiques/usage thérapeutique , Antinéoplasiques/synthèse chimique , Inhibiteurs de la topoisomérase-II/pharmacologie , Inhibiteurs de la topoisomérase-II/usage thérapeutique , Inhibiteurs de la topoisomérase-II/composition chimique , Inhibiteurs de la topoisomérase-II/synthèse chimique , Inhibiteurs de la topoisomérase-I/pharmacologie , Inhibiteurs de la topoisomérase-I/usage thérapeutique , Inhibiteurs de la topoisomérase-I/composition chimique , Inhibiteurs de la topoisomérase-I/synthèse chimique , Administration par voie orale , ADN topoisomérases de type II/métabolisme , Lignée cellulaire tumorale , Relation structure-activité , Souris , Apoptose/effets des médicaments et des substances chimiques , Prolifération cellulaire/effets des médicaments et des substances chimiques , ADN topoisomérases de type I/métabolisme , Tests de criblage d'agents antitumoraux , Tests d'activité antitumorale sur modèle de xénogreffe , Indoles/pharmacologie , Indoles/composition chimique , Indoles/usage thérapeutique , Souris nude , Découverte de médicament , Espèces réactives de l'oxygène/métabolismeRÉSUMÉ
Multidrug resistance (MDR) of human tumors has resulted in an immediate need to develop appropriate new drugs. This work outlines the development of 20 potent IQQ N-oxide derivatives in two isomeric families, both exhibiting nanomolar GI50 against human tumor cell lines. Preliminary NCI-60 tumor screening sees the C(6) isomers achieve a mean GI50 > 2 times lower than the corresponding C(7) isomers. MDR evaluation of nine selected compounds reveals that each presents lower GI50 concentrations in two MDR tumor cell lines. Four of the series display nanomolar GI50 values against MDR cells, having selectivity ratios up to 2.7 versus the sensitive (parental) cells. The most potent compound 25 inhibits the activity of drug efflux pumps in MDR cells, causes significant ROS accumulation, and potently inhibits cell proliferation, causing alterations in the cell cycle profile. Our findings are confirmed by 3D spheroid models, providing new candidates for studies against MDR cancers.
Sujet(s)
Antinéoplasiques , Prolifération cellulaire , Multirésistance aux médicaments , Résistance aux médicaments antinéoplasiques , Tests de criblage d'agents antitumoraux , Humains , Antinéoplasiques/pharmacologie , Antinéoplasiques/composition chimique , Antinéoplasiques/synthèse chimique , Cycle cellulaire/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Découverte de médicament , Multirésistance aux médicaments/effets des médicaments et des substances chimiques , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Isoquinoléines/pharmacologie , Isoquinoléines/composition chimique , Isoquinoléines/synthèse chimique , Espèces réactives de l'oxygène/métabolisme , Relation structure-activité , Fluorescéines/synthèse chimique , Fluorescéines/composition chimique , Fluorescéines/pharmacologieRÉSUMÉ
The total synthesis of 1,4a-di-epi-ent-pancratistatin, a novel stereoisomer of the anti-tumor Amaryllidaceae alkaloid pancratistatin, was achieved in 14 steps starting from D-mannitol. The construction of the pancratistatin skeleton involved conjugate addition of organocuprate to a nitrosoolefin, which was generated in situ from inosose oxime. This was followed by stereoselective reduction of the oxime to an amine and site-selective formylation. Biological evaluations revealed that the newly synthesized compounds exhibit cytotoxicity toward cancer cells and significant ferroptosis inhibitory activity. These compounds constitute a promising small-molecule library for the development of potent bioactive agents.
Sujet(s)
Alcaloïdes des Amaryllidaceae , Alcaloïdes des Amaryllidaceae/composition chimique , Alcaloïdes des Amaryllidaceae/pharmacologie , Alcaloïdes des Amaryllidaceae/synthèse chimique , Humains , Stéréoisomérie , Lignée cellulaire tumorale , Isoquinoléines/composition chimique , Isoquinoléines/pharmacologie , Isoquinoléines/synthèse chimique , Antinéoplasiques/pharmacologie , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Tests de criblage d'agents antitumoraux , Structure moléculaire , Prolifération cellulaire/effets des médicaments et des substances chimiques , Relation structure-activité , Survie cellulaire/effets des médicaments et des substances chimiquesRÉSUMÉ
Bacteria have evolved resistance to nearly all known antibacterials, emphasizing the need to identify antibiotics that operate via novel mechanisms. Here we report a class of allosteric inhibitors of DNA gyrase with antibacterial activity against fluoroquinolone-resistant clinical isolates of Escherichia coli. Screening of a small-molecule library revealed an initial isoquinoline sulfonamide hit, which was optimized via medicinal chemistry efforts to afford the more potent antibacterial LEI-800. Target identification studies, including whole-genome sequencing of in vitro selected mutants with resistance to isoquinoline sulfonamides, unanimously pointed to the DNA gyrase complex, an essential bacterial topoisomerase and an established antibacterial target. Using single-particle cryogenic electron microscopy, we determined the structure of the gyrase-LEI-800-DNA complex. The compound occupies an allosteric, hydrophobic pocket in the GyrA subunit and has a mode of action that is distinct from the clinically used fluoroquinolones or any other gyrase inhibitor reported to date. LEI-800 provides a chemotype suitable for development to counter the increasingly widespread bacterial resistance to fluoroquinolones.
Sujet(s)
Antibactériens , DNA gyrase , Résistance bactérienne aux médicaments , Escherichia coli , Fluoroquinolones , Isoquinoléines , Sulfonamides , Inhibiteurs de la topoisomérase-II , Inhibiteurs de la topoisomérase-II/pharmacologie , Inhibiteurs de la topoisomérase-II/composition chimique , Inhibiteurs de la topoisomérase-II/synthèse chimique , Isoquinoléines/composition chimique , Isoquinoléines/pharmacologie , Isoquinoléines/synthèse chimique , Sulfonamides/pharmacologie , Sulfonamides/composition chimique , Sulfonamides/synthèse chimique , Fluoroquinolones/pharmacologie , Fluoroquinolones/composition chimique , Fluoroquinolones/synthèse chimique , DNA gyrase/métabolisme , Antibactériens/pharmacologie , Antibactériens/composition chimique , Antibactériens/synthèse chimique , Résistance bactérienne aux médicaments/effets des médicaments et des substances chimiques , Escherichia coli/effets des médicaments et des substances chimiques , Escherichia coli/enzymologie , Tests de sensibilité microbienne , Relation structure-activité , Découverte de médicament , Régulation allostérique/effets des médicaments et des substances chimiquesRÉSUMÉ
Neuromuscular blocking agents (NMBAs) are widely used in anesthesia for intubation and surgical muscle relaxation. Novel atracurium and mivacurium derivatives were developed, with compounds 18c, 18d, and 29a showing mivacurium-like relaxation at 27.27 nmol/kg, and 15b, 15c, 15e, and 15h having a shorter duration at 272.7 nmol/kg. The structure-activity and configuration-activity relationships of these derivatives and 29a's binding to nicotinic acetylcholine receptors were analyzed through molecular docking. Rabbit trials showed 29a has a shorter duration compared to mivacurium. This suggests that linker properties, ammonium group substituents, and configuration are crucial for NMBA activity and duration, with compound 29a emerging as a potential ultra-short-acting NMBA.
Sujet(s)
Conception de médicament , Isoquinoléines , Curarisants , Curarisants/pharmacologie , Curarisants/synthèse chimique , Curarisants/composition chimique , Relation structure-activité , Animaux , Isoquinoléines/composition chimique , Isoquinoléines/pharmacologie , Isoquinoléines/synthèse chimique , Lapins , Récepteurs nicotiniques/métabolisme , Simulation de docking moléculaire , Structure moléculaire , Relation dose-effet des médicaments , Mivacurium , Atracurium/analogues et dérivés , Atracurium/pharmacologie , Atracurium/synthèse chimique , Atracurium/composition chimiqueRÉSUMÉ
Isoquinolone is one of the most common heterocyclic core structures in countless natural products and many bioactive compounds. Here, a highly efficient approach to synthesize isoquinolone scaffolds on DNA via rhodium(III)-catalyzed C-H activation has been described. This chemistry transformation is robust and has shown good compatibility with DNA, which is suitable for DNA-encoded library synthesis.
Sujet(s)
ADN , Rhodium , Rhodium/composition chimique , Catalyse , Structure moléculaire , ADN/composition chimique , Isoquinoléines/composition chimique , Isoquinoléines/synthèse chimiqueRÉSUMÉ
Since synovial hypoxic microenvironment significantly promotes the pathological progress of rheumatoid arthritis (RA), hypoxia-inducible factor 1 (HIF-1) has been emerged as a promising target for the development of novel therapeutic agents for RA treatment. In this study, we designed and synthesized a series of diaryl substituted isoquinolin-1(2H)-one derivatives as HIF-1 signaling inhibitors using scaffold-hopping strategy. By modifying the substituents on N-atom and 6-position of isoquinolin-1-one, we discovered compound 17q with the most potent activities against HIF-1 (IC50 = 0.55 µM) in a hypoxia-reactive element (HRE) luciferase reporter assay. Further pharmacological studies revealed that 17q concentration-dependently blocked hypoxia-induced HIF-1α protein accumulation, reduced inflammation response, inhibited cellular invasiveness and promoted VHL-dependent HIF-1α degradation in human RA synovial cell line. Moreover, 17q improved the pathological injury of ankle joints, decreased angiogenesis and attenuated inflammation response in the adjuvant-induced arthritis (AIA) rat model, indicating the promising therapeutic potential of compound 17q as an effective HIF-1 inhibitor for RA therapy.
Sujet(s)
Polyarthrite rhumatoïde , Isoquinoléines , Transduction du signal , Animaux , Humains , Mâle , Rats , Antirhumatismaux/pharmacologie , Antirhumatismaux/composition chimique , Antirhumatismaux/synthèse chimique , Arthrite expérimentale/traitement médicamenteux , Arthrite expérimentale/anatomopathologie , Arthrite expérimentale/métabolisme , Polyarthrite rhumatoïde/traitement médicamenteux , Polyarthrite rhumatoïde/métabolisme , Polyarthrite rhumatoïde/anatomopathologie , Relation dose-effet des médicaments , Découverte de médicament , Sous-unité alpha du facteur-1 induit par l'hypoxie/antagonistes et inhibiteurs , Sous-unité alpha du facteur-1 induit par l'hypoxie/métabolisme , Isoquinoléines/composition chimique , Isoquinoléines/pharmacologie , Isoquinoléines/synthèse chimique , Structure moléculaire , Transduction du signal/effets des médicaments et des substances chimiques , Relation structure-activité , Quinolinone/synthèse chimique , Quinolinone/composition chimique , Quinolinone/pharmacologieRÉSUMÉ
G-quadruplexes are noncanonical four-stranded DNA secondary structures. MYC is a master oncogene and the G-quadruplex formed in the MYC promoter functions as a transcriptional silencer and can be stabilized by small molecules. We have previously revealed a novel mechanism of action for indenoisoquinoline anticancer drugs, dual-downregulation of MYC and inhibition of topoisomerase I. Herein, we report the design and synthesis of novel 7-aza-8,9-methylenedioxyindenoisoquinolines based on desirable substituents and π-π stacking interactions. These compounds stabilize the MYC promoter G-quadruplex, significantly lower MYC levels in cancer cells, and inhibit topoisomerase I. MYC targeting was demonstrated by differential activities in Raji vs CA-46 cells and cytotoxicity in MYC-dependent cell lines. Cytotoxicities in the NCI-60 panel of human cancer cell lines were investigated. Favorable pharmacokinetics were established, and in vivo anticancer activities were demonstrated in xenograft mouse models. Furthermore, favorable brain penetration, brain pharmacokinetics, and anticancer activity in an orthotopic glioblastoma mouse model were demonstrated.
Sujet(s)
Antinéoplasiques , Conception de médicament , G-quadruplexes , Isoquinoléines , Régions promotrices (génétique) , Protéines proto-oncogènes c-myc , Inhibiteurs de la topoisomérase-I , G-quadruplexes/effets des médicaments et des substances chimiques , Humains , Animaux , Antinéoplasiques/pharmacologie , Antinéoplasiques/synthèse chimique , Antinéoplasiques/pharmacocinétique , Antinéoplasiques/composition chimique , Antinéoplasiques/usage thérapeutique , Lignée cellulaire tumorale , Isoquinoléines/pharmacologie , Isoquinoléines/composition chimique , Isoquinoléines/pharmacocinétique , Isoquinoléines/synthèse chimique , Souris , Protéines proto-oncogènes c-myc/génétique , Protéines proto-oncogènes c-myc/métabolisme , Inhibiteurs de la topoisomérase-I/pharmacologie , Inhibiteurs de la topoisomérase-I/synthèse chimique , Inhibiteurs de la topoisomérase-I/pharmacocinétique , Inhibiteurs de la topoisomérase-I/composition chimique , Inhibiteurs de la topoisomérase-I/usage thérapeutique , Relation structure-activité , ADN topoisomérases de type I/métabolisme , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
The nuclear receptors hepatocyte nuclear factor 4α (HNF4α) and retinoic acid receptor-related orphan receptor-ß (RORß) are ligand-regulated transcription factors and potential drug targets for metabolic disorders. However, there is a lack of small molecular, selective ligands to explore the therapeutic potential in further detail. Here, we report the discovery of greater celandine (Chelidonium majus) isoquinoline alkaloids as nuclear receptor modulators: Berberine is a selective RORß inverse agonist and modulated target genes involved in the circadian clock, photoreceptor cell development, and neuronal function. The structurally related chelidonine was identified as a ligand for the constitutively active HNF4α receptor, with nanomolar potency in a cellular reporter gene assay. In human liver cancer cells naturally expressing high levels of HNF4α, chelidonine acted as an inverse agonist and downregulated genes associated with gluconeogenesis and drug metabolism. Both berberine and chelidonine are promising tool compounds to further investigate their target nuclear receptors and for drug discovery.
Sujet(s)
Berbérine , Chelidonium , Facteur nucléaire hépatocytaire HNF-4 , Isoquinoléines , Humains , Berbérine/pharmacologie , Berbérine/composition chimique , Berbérine/synthèse chimique , Ligands , Facteur nucléaire hépatocytaire HNF-4/métabolisme , Facteur nucléaire hépatocytaire HNF-4/génétique , Chelidonium/composition chimique , Isoquinoléines/pharmacologie , Isoquinoléines/composition chimique , Isoquinoléines/synthèse chimique , Benzophénanthridines/pharmacologie , Benzophénanthridines/composition chimique , Membre-3 du groupe F de la sous-famille-1 de récepteurs nucléaires/antagonistes et inhibiteurs , Membre-3 du groupe F de la sous-famille-1 de récepteurs nucléaires/agonistes , Relation structure-activité , Cellules HepG2 , Relation dose-effet des médicaments , Structure moléculaire , Lignée cellulaire tumorale , Chelidonium majusRÉSUMÉ
The development and optimization of metal-based anticancer drugs with novel cytotoxic mechanisms have emerged as key strategies to overcome chemotherapeutic resistance and side effects. Agents that simultaneously induce ferroptosis and autophagic death have received extensive attention as potential modalities for cancer therapy. However, only a limited set of drugs or treatment modalities can synergistically induce ferroptosis and autophagic tumor cell death. In this work, we designed and synthesized four new cycloplatinated (II) complexes harboring an isoquinoline alkaloid Câ§N ligand. On screening the in vitro activity of these agents, we found that Pt-3 exhibited greater selectivity of cytotoxicity, decreased resistance factors, and improved anticancer activity compared to cisplatin. Furthermore, Pt-3, which we demonstrate can initiate potent ferritinophagy-dependent ferroptosis, exhibits less toxic and better therapeutic activity than cisplatin in vivo. Our results identify Pt-3 as a promising candidate or paradigm for further drug development in cancer treatment.
Sujet(s)
Antinéoplasiques , Ferroptose , Isoquinoléines , Tumeurs du sein triple-négatives , Ferroptose/effets des médicaments et des substances chimiques , Humains , Isoquinoléines/pharmacologie , Isoquinoléines/composition chimique , Isoquinoléines/synthèse chimique , Antinéoplasiques/pharmacologie , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Tumeurs du sein triple-négatives/traitement médicamenteux , Tumeurs du sein triple-négatives/anatomopathologie , Tumeurs du sein triple-négatives/métabolisme , Animaux , Femelle , Lignée cellulaire tumorale , Ferritines/métabolisme , Autophagie/effets des médicaments et des substances chimiques , Souris , Complexes de coordination/pharmacologie , Complexes de coordination/composition chimique , Complexes de coordination/synthèse chimique , Alcaloïdes/pharmacologie , Alcaloïdes/composition chimique , Alcaloïdes/synthèse chimique , Relation structure-activité , Tests de criblage d'agents antitumoraux , Prolifération cellulaire/effets des médicaments et des substances chimiques , Souris nudeRÉSUMÉ
A novel series of benzo[6,7]indolo[3,4-c]isoquinolines 3a-3f was designed by scaffold hopping of topoisomerase I inhibitor benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-ones (BBPIs), which were developed by structural modification of the natural marine product lamellarin. The unconventional pentacycle was constructed by Bischler-Napieralski-type condensation of amide 11 and subsequent intramolecular Heck reaction. In vitro anticancer activity of the synthesized benzo[6,7]indolo[3,4-c]isoquinolines was evaluated on a panel of 39 human cancer cell lines (JFCR39). Among the compounds tested, N-(3-morpholinopropyl) derivative 3e showed the most potent antiproliferative activity, with a mean GI50 value of 39 nM. This compound inhibited topoisomerase I activity by stabilizing the enzyme-DNA complex.
Sujet(s)
Antinéoplasiques , Coumarines , Composés hétérocycliques avec 4 noyaux ou plus , Isoquinoléines , Inhibiteurs de la topoisomérase-I , Humains , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Antinéoplasiques/pharmacologie , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , ADN topoisomérases de type I/métabolisme , Tests de criblage d'agents antitumoraux , Isoquinoléines/synthèse chimique , Isoquinoléines/composition chimique , Isoquinoléines/pharmacologie , Relation structure-activité , Inhibiteurs de la topoisomérase-I/synthèse chimique , Inhibiteurs de la topoisomérase-I/composition chimique , Inhibiteurs de la topoisomérase-I/pharmacologie , Conception de médicament , Coumarines/synthèse chimique , Coumarines/composition chimique , Coumarines/pharmacologie , Composés hétérocycliques avec 4 noyaux ou plus/synthèse chimique , Composés hétérocycliques avec 4 noyaux ou plus/composition chimique , Composés hétérocycliques avec 4 noyaux ou plus/pharmacologieRÉSUMÉ
Efforts have been devoted for the discovery and development of positive allosteric modulators (PAMs) of 5-HT2CR because of their potential advantages over the orthosteric agonist like Lorcaserin that was withdrawn from the market. On the other hand, pursuing a positive ago-allosteric modulator (PAAM) is considered as beneficial particularly when an agonist is not capable of affecting the potency of the endogenous agonist sufficiently. In search of a suitable PAAM of 5-HT2CR we adopted an in silico based approach that indicated the potential of the 3-(1-hydroxycycloalkyl) substituted isoquinolin-1-one derivatives against the 5-HT2CR as majority of these molecules interacted with the site other than that of Lorcaserin with superior docking scores. These compounds along with the regioisomeric 3-methyleneisoindolin-1-one derivatives were prepared via the Cu(OAc)2 catalyzed coupling of 2-iodobenzamide with 1-ethynylcycloalkanol under ultrasound irradiation. According to the in vitro studies, most of these compounds were not only found to be potent and selective agonists but also emerged as PAAM of 5-HT2CR whereas Lorcaserin did not show PAAM activities. According to the SAR study the isoquinolin-1(2H)-ones appeared as better PAAM than isoindolin-1-ones whereas the presence of hydroxyl group appeared to be crucial for the activity. With the potent PAAM activity for 5-HT2CR (EC50 = 1 nM) and 107 and 86-fold selectivity towards 5-HT2C over 5-HT2A and 5-HT2B the compound 4i was identified as a hit molecule. The compound showed good stability in male BALB/c mice brain homogenate (â¼85 % remaining after 2 h), moderate stability in the presence of rat liver microsomes (42 % remaining after 1 h) and acceptable PK properties with fast reaching in the brain maintaining â¼ 1:1 brain/plasma concentration ratio. The compound at a dose of 50 mg/kg exhibited decreased trend in the food intake starting from day 3 in S.D. rats, which reached significant by 5th day, and the effect was comparable to Lorcaserin (10 mg/kg) on day 5. Thus, being the first example of PAAM of 5-HT2CR the compound 4i is of further medicinal interest.
Sujet(s)
Indoles , Isoquinoléines , Agonistes des récepteurs 5-HT2 de la sérotonine , Animaux , Mâle , Souris , Rats , Encéphale , Agonistes des récepteurs 5-HT2 de la sérotonine/synthèse chimique , Agonistes des récepteurs 5-HT2 de la sérotonine/composition chimique , Agonistes des récepteurs 5-HT2 de la sérotonine/pharmacologie , Souris de lignée BALB C , Isoquinoléines/synthèse chimique , Isoquinoléines/composition chimique , Isoquinoléines/pharmacologie , Indoles/synthèse chimique , Indoles/composition chimique , Indoles/pharmacologieRÉSUMÉ
Recent reports of antiepileptic activity of the fungal alkaloid TMC-120B have renewed the interest in this natural product. Previous total syntheses of TMC-120B comprise many steps and have low overall yields (11-17 steps, 1.5-2.9% yield). Thus, to access this compound more efficiently, we herein present a concise and significantly improved total synthesis of the natural product. Our short synthesis relies on two key cyclization steps to assemble the central scaffold: isoquinoline formation via an ethynyl-imino cyclization and an intramolecular Friedel-Crafts reaction to form the furanone.
Sujet(s)
Alcaloïdes/composition chimique , Aspergillus/composition chimique , Benzofuranes/synthèse chimique , Isoquinoléines/composition chimique , Benzofuranes/composition chimique , Cyclisation , Isoquinoléines/synthèse chimique , Structure moléculaire , StéréoisomérieRÉSUMÉ
Synthesis of novel C3-substituted 5,6-dihydropyrrolo[2,1-a]isoquinolines via a three-component domino reaction of 1-aroyl-3,4-dihydroisoquinolines, terminal alkynes and CH-acids under microwave irradiation in dry acetonitrile is described. The method developed enables the obtainment of highly functionalized compounds with pharmacophore groups, which are potentially biologically active.
Sujet(s)
Isoquinoléines/composition chimique , Pyrroles/composition chimique , Alcynes/composition chimique , Réaction de cycloaddition , Isoquinoléines/synthèse chimique , Spectroscopie par résonance magnétique , Micro-ondes , Conformation moléculaire , Pyrroles/synthèse chimiqueRÉSUMÉ
This article describes the syntheses and biological activity of five 3-arylisoquinoline natural products corydamine (1), N-formyl Corydamine (2), hypecumine (3), Decumbenine B (XW) and 2-(1,3-dioxolo [4,5-h]isoquinolin-7-yl)-4,5-dimethoxy-N-methyl-Benzeneethanamine (A), and twelve analogues. Among them, 1, 2, and A were synthesized for the first time. In vitro screening for anti-proliferative activity showed that derivative 1a could significantly inhibit the proliferation of HCC cells (IC50 = 9.82 µM on Huh7 cells and 6.83 µM on LM9 cells), and arrest cell cycle at G2/M phase. The mechanistic studies further suggested compound 1a was a dual inhibitor of Topo I and Topo II, and Topo II inhibitory activity was superior to etoposide. In addition, 1a could significantly inhibit the invasion and migration of cancer cells by inhibiting the expression of MMP-9, and induce apoptosis through inhibiting the activation of the PI3K/Akt/mTOR signaling pathway. Moreover, in vivo studies demonstrated 1a could obviously reduce the growth of xenograft tumor and possessed good pharmacokinetic parameters, which indicated the potential value of 1a in treating liver cancer.
Sujet(s)
Alcaloïdes/pharmacologie , Antinéoplasiques/pharmacologie , Carcinome hépatocellulaire/traitement médicamenteux , Conception de médicament , Isoquinoléines/pharmacologie , Tumeurs du foie/traitement médicamenteux , Alcaloïdes/synthèse chimique , Alcaloïdes/composition chimique , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Carcinome hépatocellulaire/anatomopathologie , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Relation dose-effet des médicaments , Tests de criblage d'agents antitumoraux , Humains , Isoquinoléines/synthèse chimique , Isoquinoléines/composition chimique , Tumeurs du foie/anatomopathologie , Structure moléculaire , Relation structure-activitéRÉSUMÉ
The discovery that certain indenoisoquinolines inhibit the religation reaction of DNA in the topoisomerase I-DNA-indenoisoquinoline ternary complex led to a structure-based drug design research program which resulted in three representatives that entered Phase I clinical trials in cancer patients at the National Cancer Institute. This has stimulated a great deal of interest in the design and execution of new synthetic pathways for indenoisoquinoline production. More recently, modulation of the substitution pattern and chemical nature of substituents on the indenoisoquinoline scaffold has resulted in a widening scope of additional biological targets, including RXR, PARP-1, MYC promoter G-quadruplex, topoisomerase II, estrogen receptor, VEGFR-2, HIF-1α, and tyrosyl DNA phosphodiesterases 1 and 2. Furthermore, convincing evidence has been advanced supporting the potential use of indenoisoquinolines for the treatment of diseases other than cancer. The rapidly expanding indenoisoquinoline knowledge base has provided a firm foundation for further advancements in indenoisoquinoline chemistry, pharmacology, and therapeutics.
Sujet(s)
Antinéoplasiques/pharmacologie , ADN topoisomérases de type I/effets des médicaments et des substances chimiques , Conception de médicament , Isoquinoléines/composition chimique , Isoquinoléines/pharmacologie , Tests de criblage d'agents antitumoraux , Humains , Isoquinoléines/synthèse chimiqueRÉSUMÉ
The scaffold of TIQ-A, a previously known inhibitor of human poly-ADP-ribosyltransferase PARP1, was utilized to develop inhibitors against human mono-ADP-ribosyltransferases through structure-guided design and activity profiling. By supplementing the TIQ-A scaffold with small structural changes, based on a PARP10 inhibitor OUL35, selectivity changed from poly-ADP-ribosyltransferases towards mono-ADP-ribosyltransferases. Binding modes of analogs were experimentally verified by determining complex crystal structures with mono-ADP-ribosyltransferase PARP15 and with poly-ADP-ribosyltransferase TNKS2. The best analogs of the study achieved 10-20-fold selectivity towards mono-ADP-ribosyltransferases PARP10 and PARP15 while maintaining micromolar potencies. The work demonstrates a route to differentiate compound selectivity between mono- and poly-ribosyltransferases of the human ARTD family.
Sujet(s)
ADP ribose transferases/antagonistes et inhibiteurs , Isoquinoléines/pharmacologie , Inhibiteurs de poly(ADP-ribose) polymérases/pharmacologie , Protéines proto-oncogènes/antagonistes et inhibiteurs , Thiophènes/pharmacologie , ADP ribose transferases/métabolisme , Cristallographie aux rayons X , Relation dose-effet des médicaments , Humains , Isoquinoléines/synthèse chimique , Isoquinoléines/composition chimique , Modèles moléculaires , Structure moléculaire , Inhibiteurs de poly(ADP-ribose) polymérases/synthèse chimique , Inhibiteurs de poly(ADP-ribose) polymérases/composition chimique , Poly(ADP-ribose) polymerases/métabolisme , Protéines proto-oncogènes/métabolisme , Relation structure-activité , Thiophènes/synthèse chimique , Thiophènes/composition chimiqueRÉSUMÉ
Alzheimers disease (AD) is the most common neurodegenerative disorder, characterized by neuronal loss and cognitive impairment. Currently, very few drugs are available for AD treatment, and a search for new therapeutics is urgently needed. Thus, in the current study, twenty-eight new derivatives of montanine-type Amaryllidaceae alkaloids were synthesized and evaluated for their ability to inhibit human recombinant acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE). Three derivatives (1n, 1o, and 1p) with different substitution patterns demonstrated significant selective inhibitory potency for hAChE (IC50 < 5 µM), and one analog, 1v, showed selective hBuChE inhibition activity (IC50 = 1.73 ± 0.05 µM). The prediction of CNS availability, as disclosed by the BBB score, suggests that the active compounds in this survey should be able pass through the blood-brain barrier (BBB). Cytotoxicity screening and docking studies were carried out for the two most pronounced cholinesterase inhibitors, 1n and 1v.
Sujet(s)
Alcaloïdes/pharmacologie , Maladie d'Alzheimer/traitement médicamenteux , Anticholinestérasiques/pharmacologie , Isoquinoléines/pharmacologie , Simulation de docking moléculaire , Acetylcholinesterase/métabolisme , Alcaloïdes/synthèse chimique , Alcaloïdes/composition chimique , Maladie d'Alzheimer/métabolisme , Barrière hémato-encéphalique/effets des médicaments et des substances chimiques , Barrière hémato-encéphalique/métabolisme , Butyrylcholine esterase/métabolisme , Anticholinestérasiques/synthèse chimique , Anticholinestérasiques/composition chimique , Relation dose-effet des médicaments , Humains , Isoquinoléines/synthèse chimique , Isoquinoléines/composition chimique , Structure moléculaire , Relation structure-activitéRÉSUMÉ
In spite of possessing a wide range of pharmacological properties the anti-inflammatory activities of isoquinolin-1(2H)-ones were rarely known or explored earlier. PDE4 inhibitors on the other hand in addition to their usefulness in treating inflammatory diseases have been suggested to attenuate the cytokine storm in COVID-19 especially TNF-α. In our effort, a new class of isoquinolin-1(2H)-ones derivatives containing an aminosulfonyl moiety were designed and explored as potential inhibitors of PDE4. Accordingly, for the first time a CuCl2-catalyzed inexpensive, faster and ligand/additive free approach has been developed for the synthesis of these predesigned isoquinolin-1(2H)-one derivatives via the coupling-cyclization strategy. Thus, the CuCl2-catalyzed reaction of 2-iodobenzamides with appropriate terminal alkynes proceeded with high chemo and regioselectivity affording the desired compounds in 77-84% yield within 1-1.5 h. The methodology also afforded simpler isoquinolin-1(2H)-ones devoid of aminosulfonyl moiety showing a broader generality and scope of this approach. Several of the synthesized compounds especially 3c, 3k and 3s showed impressive inhibition (83-90%) of PDE4B when tested at 10 µM in vitro whereas compounds devoid of aminosulfonyl moiety was found to be less active. In spite of high inhibition showed at 10 µM these compounds did not show proper concertation dependent inhibition below 1 µM that was reflected in their IC50 values e.g. 2.43 ± 0.32, 3.26 ± 0.24 and 3.63 ± 0.80 µM for 3k, 3o and 3s respectively. The anti-inflammatory potential of these compounds was indicated by their TNF-α inhibition (60-50% at 10 µM). The in silico docking studies of these molecules suggested good interactions with PDE4B and selective inhibition of PDE4B by 3k over PDE4D that was supported by in vitro assay results. These observations together with the favorable ADME and safety predicted for 3kin silico not only suggested 3k as an interesting hit molecule for further studies but also reveal the first example of isoquinolin-1(2H)-one based inhibitor of PDE4B.
Sujet(s)
Anti-inflammatoires/composition chimique , Cuivre/composition chimique , Cyclic Nucleotide Phosphodiesterases, Type 4/composition chimique , Isoquinoléines/composition chimique , Inhibiteurs de la phosphodiestérase-4/composition chimique , Animaux , Anti-inflammatoires/synthèse chimique , Catalyse , Cyclisation , Dosages enzymatiques , Humains , Isoquinoléines/synthèse chimique , Souris , Structure moléculaire , Inhibiteurs de la phosphodiestérase-4/synthèse chimique , Cellules RAW 264.7 , Relation structure-activité , Facteur de nécrose tumorale alpha/antagonistes et inhibiteursRÉSUMÉ
Covering: up to April 2021During the past decades, a plethora of natural products with restricted rotation about a biaryl axis have been discovered, among them the naphthylisoquinoline (NIQ) alkaloids, mostly C,C-coupled and having remarkable bioactivities. Within this fascinating class of naturally occurring biaryl compounds, NIQ alkaloids bearing an N,C-heterobiaryl axis have attracted particular attention. They are structurally and biosynthetically unprecedented, with interesting stereochemical implications and biological activities. In contrast to existing articles and reviews about axially chiral - yet C,C-coupled - natural products, this is the first, comprehensive review on the new subclass of N,C-coupled NIQs, their isolation and structural elucidation, their N,C-axial chirality, their biosynthetic origin, their promising antiparasitic and antileukemic activities, and their total synthesis.