RESUMEN
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.
Asunto(s)
Alcaloides de Amaryllidaceae , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/farmacología , Alcaloides de Amaryllidaceae/síntesis química , Humanos , Estereoisomerismo , Línea Celular Tumoral , Isoquinolinas/química , Isoquinolinas/farmacología , Isoquinolinas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Supervivencia Celular/efectos de los fármacosRESUMEN
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.
Asunto(s)
Diseño de Fármacos , Isoquinolinas , Bloqueantes Neuromusculares , Bloqueantes Neuromusculares/farmacología , Bloqueantes Neuromusculares/síntesis química , Bloqueantes Neuromusculares/química , Relación Estructura-Actividad , Animales , Isoquinolinas/química , Isoquinolinas/farmacología , Isoquinolinas/síntesis química , Conejos , Receptores Nicotínicos/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Dosis-Respuesta a Droga , Mivacurio , Atracurio/análogos & derivados , Atracurio/farmacología , Atracurio/síntesis química , Atracurio/químicaRESUMEN
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.
Asunto(s)
Antineoplásicos , Diseño de Fármacos , G-Cuádruplex , Isoquinolinas , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-myc , Inhibidores de Topoisomerasa I , G-Cuádruplex/efectos de los fármacos , Humanos , Animales , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Isoquinolinas/farmacología , Isoquinolinas/química , Isoquinolinas/farmacocinética , Isoquinolinas/síntesis química , Ratones , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Inhibidores de Topoisomerasa I/farmacología , Inhibidores de Topoisomerasa I/síntesis química , Inhibidores de Topoisomerasa I/farmacocinética , Inhibidores de Topoisomerasa I/química , Inhibidores de Topoisomerasa I/uso terapéutico , Relación Estructura-Actividad , ADN-Topoisomerasas de Tipo I/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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.
Asunto(s)
Artritis Reumatoide , Isoquinolinas , Transducción de Señal , Animales , Humanos , Masculino , Ratas , Antirreumáticos/farmacología , Antirreumáticos/química , Antirreumáticos/síntesis química , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Artritis Experimental/metabolismo , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Isoquinolinas/química , Isoquinolinas/farmacología , Isoquinolinas/síntesis química , Estructura Molecular , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Quinolonas/síntesis química , Quinolonas/química , Quinolonas/farmacologíaRESUMEN
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.
Asunto(s)
ADN , Rodio , Rodio/química , Catálisis , Estructura Molecular , ADN/química , Isoquinolinas/química , Isoquinolinas/síntesis químicaRESUMEN
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.
Asunto(s)
Antineoplásicos , Cumarinas , Compuestos Heterocíclicos de 4 o más Anillos , Isoquinolinas , Inhibidores de Topoisomerasa I , Humanos , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN-Topoisomerasas de Tipo I/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Isoquinolinas/síntesis química , Isoquinolinas/química , Isoquinolinas/farmacología , Relación Estructura-Actividad , Inhibidores de Topoisomerasa I/síntesis química , Inhibidores de Topoisomerasa I/química , Inhibidores de Topoisomerasa I/farmacología , Diseño de Fármacos , Cumarinas/síntesis química , Cumarinas/química , Cumarinas/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacologíaRESUMEN
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.
Asunto(s)
Berberina , Chelidonium , Factor Nuclear 4 del Hepatocito , Isoquinolinas , Humanos , Berberina/farmacología , Berberina/química , Berberina/síntesis química , Ligandos , Factor Nuclear 4 del Hepatocito/metabolismo , Factor Nuclear 4 del Hepatocito/genética , Chelidonium/química , Isoquinolinas/farmacología , Isoquinolinas/química , Isoquinolinas/síntesis química , Benzofenantridinas/farmacología , Benzofenantridinas/química , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Relación Estructura-Actividad , Células Hep G2 , Relación Dosis-Respuesta a Droga , Estructura Molecular , Línea Celular Tumoral , Chelidonium majusRESUMEN
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.
Asunto(s)
Antineoplásicos , Ferroptosis , Isoquinolinas , Neoplasias de la Mama Triple Negativas , Ferroptosis/efectos de los fármacos , Humanos , Isoquinolinas/farmacología , Isoquinolinas/química , Isoquinolinas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Animales , Femenino , Línea Celular Tumoral , Ferritinas/metabolismo , Autofagia/efectos de los fármacos , Ratones , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Alcaloides/farmacología , Alcaloides/química , Alcaloides/síntesis química , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular/efectos de los fármacos , Ratones DesnudosRESUMEN
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.
Asunto(s)
Indoles , Isoquinolinas , Agonistas del Receptor de Serotonina 5-HT2 , Animales , Masculino , Ratones , Ratas , Encéfalo , Agonistas del Receptor de Serotonina 5-HT2/síntesis química , Agonistas del Receptor de Serotonina 5-HT2/química , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Ratones Endogámicos BALB C , Isoquinolinas/síntesis química , Isoquinolinas/química , Isoquinolinas/farmacología , Indoles/síntesis química , Indoles/química , Indoles/farmacologíaRESUMEN
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.
Asunto(s)
Alcaloides/química , Aspergillus/química , Benzofuranos/síntesis química , Isoquinolinas/química , Benzofuranos/química , Ciclización , Isoquinolinas/síntesis química , Estructura Molecular , EstereoisomerismoRESUMEN
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.
Asunto(s)
Isoquinolinas/química , Pirroles/química , Alquinos/química , Reacción de Cicloadición , Isoquinolinas/síntesis química , Espectroscopía de Resonancia Magnética , Microondas , Conformación Molecular , Pirroles/síntesis químicaRESUMEN
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.
Asunto(s)
Alcaloides/farmacología , Antineoplásicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Diseño de Fármacos , Isoquinolinas/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Alcaloides/síntesis química , Alcaloides/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/química , Neoplasias Hepáticas/patología , Estructura Molecular , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , ADN-Topoisomerasas de Tipo I/efectos de los fármacos , Diseño de Fármacos , Isoquinolinas/química , Isoquinolinas/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Isoquinolinas/síntesis químicaRESUMEN
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.
Asunto(s)
ADP Ribosa Transferasas/antagonistas & inhibidores , Isoquinolinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Tiofenos/farmacología , ADP Ribosa Transferasas/metabolismo , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/química , Modelos Moleculares , Estructura Molecular , Inhibidores de Poli(ADP-Ribosa) Polimerasas/síntesis química , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/químicaRESUMEN
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.
Asunto(s)
Alcaloides/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Isoquinolinas/farmacología , Simulación del Acoplamiento Molecular , Acetilcolinesterasa/metabolismo , Alcaloides/síntesis química , Alcaloides/química , Enfermedad de Alzheimer/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antiinflamatorios/química , Cobre/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Isoquinolinas/química , Inhibidores de Fosfodiesterasa 4/química , Animales , Antiinflamatorios/síntesis química , Catálisis , Ciclización , Pruebas de Enzimas , Humanos , Isoquinolinas/síntesis química , Ratones , Estructura Molecular , Inhibidores de Fosfodiesterasa 4/síntesis química , Células RAW 264.7 , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
P-Glycoprotein (P-gp) is an efflux pump located at the blood-brain barrier (BBB) that contributes to the protection of the central nervous system by transporting neurotoxic compounds out of the brain. A decline in P-gp function has been related to the pathogenesis of neurodegenerative diseases. P-gp inducers can increase the P-gp function and are considered as potential candidates for the treatment of such disorders. The P-gp inducer MC111 increased P-gp expression and function in SW480 human colon adenocarcinoma and colo-320 cells, respectively. Our study aims to evaluate the P-gp inducing effect of MC111 in the whole brain in vivo, using the P-gp tracer [18F]MC225 and positron emission tomography (PET). Eighteen Wistar rats were treated with either vehicle solution, 4.5 mg/kg of MC111 (low-dose group), or 6 mg/kg of MC111 (high-dose group). Animals underwent a 60 min dynamic PET scan with arterial-blood sampling, 24 h after treatment with the inducer. Data were analyzed using the 1-tissue-compartment model and metabolite-corrected plasma as the input function. Model parameters such as the influx constant (K1) and volume of distribution (VT) were calculated, which reflect the in vivo P-gp function. P-gp and pregnane xenobiotic receptor (PXR) expression levels of the whole brain were assessed using western blot. The administration of MC111 decreased K1 and VT of [18F]MC225 in the whole brain and all of the selected brain regions. In the high-dose group, whole-brain K1 was decreased by 34% (K1-high-dose = 0.20 ± 0.02 vs K1-control = 0.30 ± 0.02; p < 0.001) and in the low-dose group by 7% (K1-low-dose = 0.28 ± 0.02 vs K1-control = 0.30 ± 0.02; p = 0.42) compared to controls. Whole-brain VT was decreased by 25% in the high-dose group (VT-high-dose = 5.92 ± 0.41 vs VT-control = 7.82 ± 0.38; p < 0.001) and by 6% in the low-dose group (VT-low-dose = 7.35 ± 0.38 vs VT-control = 7.82 ± 0.37; p = 0.38) compared to controls. k2 values did not vary after treatment. The treatment did not affect the metabolism of [18F]MC225. Western blot studies using the whole-brain tissue did not detect changes in the P-gp expression, however, preliminary results using isolated brain capillaries found an increasing trend up to 37% in treated rats. The decrease in K1 and VT values after treatment with the inducer indicates an increase in the P-gp functionality at the BBB of treated rats. Moreover, preliminary results using brain endothelial cells also sustained the increase in the P-gp expression. In conclusion, the results verify that MC111 induces P-gp expression and function at the BBB in rats. An increasing trend regarding the P-gp expression levels is found using western blot and an increased P-gp function is confirmed with [18F]MC225 and PET.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Barrera Hematoencefálica/metabolismo , Isoquinolinas/administración & dosificación , Tomografía de Emisión de Positrones/métodos , Radiofármacos/administración & dosificación , Tetrahidronaftalenos/administración & dosificación , Animales , Transporte Biológico , Barrera Hematoencefálica/citología , Células Endoteliales/metabolismo , Isoquinolinas/sangre , Isoquinolinas/síntesis química , Cinética , Masculino , Radiofármacos/sangre , Radiofármacos/síntesis química , Ratas , Ratas Wistar , Tetrahidronaftalenos/sangre , Tetrahidronaftalenos/síntesis químicaRESUMEN
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.
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Alcaloides/aislamiento & purificación , Productos Biológicos/aislamiento & purificación , Isoquinolinas/aislamiento & purificación , Alcaloides/síntesis química , Alcaloides/farmacología , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Productos Biológicos/síntesis química , Productos Biológicos/farmacología , Caryophyllales/química , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/farmacología , Leucemia/tratamiento farmacológico , Estructura Molecular , EstereoisomerismoRESUMEN
Several new cyano-substituted derivatives with pyrrolo[1,2-a]quinoline and pyrrolo[2,1-a]isoquinoline scaffolds were synthesized by the [3 + 2] cycloaddition of (iso)quinolinium ylides to fumaronitrile. The cycloimmonium ylides reacted in situ as 1,3-dipoles with fumaronitrile to selectively form distinct final compounds, depending on the structure of the (iso)quinolinium salt. Eleven compounds were evaluated for their anticancer activity against a panel of 60 human cancer cell lines. The most potent compound 9a showed a broad spectrum of antiproliferative activity against cancer cell lines representing leukemia, melanoma and cancer of lung, colon, central nervous system, ovary, kidney, breast and prostate cancer. In vitro assays and molecular docking revealed tubulin interaction properties of compound 9a.
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Isoquinolinas/análisis , Isoquinolinas/síntesis química , Nitrilos/química , Pirroles/química , Benzofenonas/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Humanos , Isoquinolinas/farmacología , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Simulación del Acoplamiento Molecular , Paclitaxel/farmacología , ProtonesRESUMEN
The development of new molecules for the treatment of leishmaniasis is, a neglected parasitic disease, is urgent as current anti-leishmanial therapeutics are hampered by drug toxicity and resistance. The pyrrolo[1,2-b]isoquinoline core was selected as starting point, and palladium-catalyzed Heck-initiated cascade reactions were developed for the synthesis of a series of C-10 substituted derivatives. Their in vitro leishmanicidal activity against visceral (L. donovani) and cutaneous (L. amazonensis) leishmaniasis was evaluated. The best activity was found, in general, for the 10-arylmethyl substituted pyrroloisoquinolines. In particular, 2ad (IC50 = 3.30 µM, SI > 77.01) and 2bb (IC50 = 3.93 µM, SI > 58.77) were approximately 10-fold more potent and selective than the drug of reference (miltefosine), against L. amazonensis on in vitro promastigote assays, while 2ae was the more active compound in the in vitro amastigote assays (IC50 = 33.59 µM, SI > 8.93). Notably, almost all compounds showed low cytotoxicity, CC50 > 100 µg/mL in J774 cells, highest tested dose. In addition, we have developed the first Perturbation Theory Machine Learning (PTML) algorithm able to predict simultaneously multiple biological activity parameters (IC50, Ki, etc.) vs. any Leishmania species and target protein, with high values of specificity (>98%) and sensitivity (>90%) in both training and validation series. Therefore, this model may be useful to reduce time and assay costs (material and human resources) in the drug discovery process.