RESUMEN
Sophoridine, which is derived from the Leguminous plant Sophora alopecuroides L., has certain pharmacological activity as a new anticancer drug. Herein, a series of novel N-substituted sophoridine derivatives was designed, synthesized and evaluated with anticancer activity. Through QSAR prediction models, it was discovered that the introduction of a benzene ring as a main pharmacophore and reintroduced into a benzene in para position on the phenyl ring in the novel sophoridine derivatives improved the anticancer activity effectively. In vitro, 28 novel compounds were evaluated for anticancer activity against four human tumor cell lines (A549, CNE-2, HepG-2, and HEC-1-B). In particular, Compound 26 exhibited remarkable inhibitory effects, with an IC50 value of 15.6 µM against HepG-2 cells, surpassing cis-Dichlorodiamineplatinum (II). Molecular docking studies verified that the derivatives exhibit stronger binding affinity with DNA topoisomerase I compared to sophoridine. In addition, 26 demonstrated significant inhibition of DNA Topoisomerase I and could arrest cells in G0/G1 phase. This study provides valuable insights into the design and synthesis of N-substituted sophoridine derivatives with anticancer activity.
Asunto(s)
Alcaloides , Matrinas , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad Cuantitativa , Quinolizinas , Sophora , Inhibidores de Topoisomerasa I , Humanos , Inhibidores de Topoisomerasa I/farmacología , Inhibidores de Topoisomerasa I/síntesis química , Quinolizinas/farmacología , Quinolizinas/síntesis química , Quinolizinas/química , Estructura Molecular , Sophora/química , Alcaloides/farmacología , Alcaloides/síntesis química , Alcaloides/química , Línea Celular Tumoral , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/síntesis química , Indolizinas/farmacología , Indolizinas/química , Indolizinas/síntesis química , ADN-Topoisomerasas de Tipo I/metabolismo , Fitoquímicos/farmacología , Fitoquímicos/síntesis químicaRESUMEN
We report that compound 13, a novel phosphatidylserine-targeting zinc(II) dipicolylamine drug conjugate, readily triggers a positive feedback therapeutic loop through the in situ generation of phosphatidylserine in the tumor microenvironment. Linker modifications, pharmacokinetics profiling, in vivo antitumor studies, and micro-Western array of treated-tumor tissues were employed to show that this class of conjugates induced regeneration of apoptotic signals, which facilitated subsequent recruitment of the circulating conjugates through the zinc(II) dipicolylamine-phosphatidylserine association and resulted in compounding antitumor efficacy. Compared to the marketed compound 17, compound 13 not only induced regressions in colorectal and pancreatic tumor models, it also exhibited at least 5-fold enhancement in antitumor efficacy with only 40% of the drug employed during treatment, culminating in a >12.5-fold increase in therapeutic potential. Our study discloses a chemically distinct apoptosis-targeting theranostic, with built-in complementary functional moieties between the targeting module and the drug mechanism to expand the arsenal of antitumor therapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Complejos de Coordinación/uso terapéutico , Indolizinas/uso terapéutico , Neoplasias/tratamiento farmacológico , Fosfatidilserinas/metabolismo , Picolinas/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Diseño de Fármacos , Humanos , Indolizinas/síntesis química , Indolizinas/química , Masculino , Ratones Endogámicos ICR , Ratones Desnudos , Estructura Molecular , Picolinas/síntesis química , Picolinas/química , Relación Estructura-Actividad , Inhibidores de Topoisomerasa I/síntesis química , Inhibidores de Topoisomerasa I/química , Inhibidores de Topoisomerasa I/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Zinc/químicaRESUMEN
[reaction: see text] Polyhydroxylated indolizidines have potential for treatment of HIV, hepatitis C and HSV infection, multiple sclerosis, angiogenesis, cancer, and diabetes. A new synthetic approach to the title compounds from a 5-C-methoxypyranosyl azide has been developed. The route incorporates the aldol reaction and a novel catalytic reductive amination cascade to generate the indolizidine ring.
Asunto(s)
Indolizinas/síntesis química , Aminación , Castanospermum/química , Catálisis , Estructura Molecular , Plantas Medicinales/química , EstereoisomerismoRESUMEN
[structure: see text] Biomimetic intramolecular Chichibabin pyridine syntheses using two molecules of an aldehyde and 4-aminobutanal dimethyl acetal (6) proceed efficiently in AcOH at 95 degrees C to give 2,3-dihydro-1H-indolizinium salts. Reaction occurs at 25 degrees C if 1-pyrroline (5) is used instead of 6. This reaction has been used for a one-step synthesis of ficuseptine (1) and the first syntheses of juliprosine (2) and juliprosopine (17t), which is now assigned as the trans stereoisomer.
Asunto(s)
Alcaloides/síntesis química , Indolizinas/síntesis química , Fenantrenos/síntesis química , Piridinas/síntesis química , Estructura Molecular , Plantas Medicinales/química , Prosopis/química , EstereoisomerismoRESUMEN
An enantioselective and diastereoselective synthesis of six 5,7-dimethylindolizidine isomers is described via an intramolecular cyclization that involves an allylsilyl nucleophilic group and an acyliminium ion. The first total synthesis of naturally occurring (-)-dendroprimine has been achieved in five steps.
Asunto(s)
Alcaloides/síntesis química , Química Orgánica/métodos , Indolizinas/síntesis química , Alcaloides/química , Catálisis , Ciclización , Dendrobium/química , Hidrogenación , Indolizinas/química , Estructura Molecular , Plantas Medicinales/química , EstereoisomerismoRESUMEN
The title alkaloid 1 and its B-nor-congener 3, both of which display potent and unusual anti-mitotic properties, have been synthesized in racemic form and characterised by single-crystal X-ray analysis.
Asunto(s)
Aldehídos/síntesis química , Aldehídos/farmacología , Alcaloides/síntesis química , Alcaloides/farmacología , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/farmacología , Indolizinas/síntesis química , Indolizinas/farmacología , Plantas Medicinales/química , Alcaloides/química , Línea Celular Tumoral , Cristalografía por Rayos X , Fase G2/efectos de los fármacos , Humanos , Modelos Moleculares , Paclitaxel/farmacología , Estereoisomerismo , Tubulina (Proteína)/química , Tubulina (Proteína)/efectos de los fármacos , Vinblastina/farmacologíaRESUMEN
A series of 6,7-diphenyl-2,3,8,8a-tetrahydro-1H-indolizin-5-one analogues were synthesized and evaluated for cytotoxic activity against eight human cancer cell lines. Compounds 18, 21, 28, 29, 30 and 31 showed cytotoxic activity with GI(50) values in the range of 2.1-8.1 microM concentration. Among these, compounds 21 and 28 exhibited good pharmacokinetic properties. These compounds were further evaluated for their in vivo efficacy in modified hollow fibre assay (HFA).
Asunto(s)
Antineoplásicos/síntesis química , Indolizinas/síntesis química , Indolizinas/farmacología , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Indolizinas/farmacocinética , Ratones , Farmacocinética , Relación Estructura-ActividadRESUMEN
This review covers the isolation, structure determination, synthesis and biological activity of indolizidine and quinolizidine alkaloids from microbial, plant and animal sources. Included in the review are slaframine; hydroxylated indolizidines and their analogues; alkaloids from ants and amphibians; metabolites of the genera Prosopis, Streptomyces and Nuphar and the Lythraceae; phenanthroindolizidines and related alkaloids; lupin alkaloids; and alkaloids from sponges. tunicates and coccinellid beetles. The literature from July 2000 to June 2001 is reviewed, and 172 references are cited.
Asunto(s)
Alcaloides , Indolizinas , Quinolizinas , Alcaloides/síntesis química , Alcaloides/química , Alcaloides/farmacología , Anfibios , Animales , Hormigas/química , Catálisis , Escarabajos/química , Indolizinas/síntesis química , Indolizinas/química , Indolizinas/farmacología , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Plantas Medicinales/química , Poríferos/química , Quinolizinas/síntesis química , Quinolizinas/química , Quinolizinas/farmacología , Estereoisomerismo , Streptomyces/química , Streptomyces/metabolismo , Urocordados/químicaAsunto(s)
Alcaloides/química , Indolizinas/química , Quinolizinas/química , Alcaloides/síntesis química , Alcaloides/farmacología , Anfibios/fisiología , Animales , Bacterias/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Hongos/química , Humanos , Indolizinas/síntesis química , Indolizinas/farmacología , Insectos/química , Toxinas Marinas/química , Estructura Molecular , Extractos Vegetales/química , Extractos Vegetales/farmacología , Quinolizinas/síntesis química , Quinolizinas/farmacologíaRESUMEN
The total synthesis of piclavines A1, A2, A3, and A4 has been achieved starting from compound 10 with enantiomeric enhancement. Their biological activities (antibacterial, antimicrobacterial, and antiviral activities and inhibition of cell growth) were evaluated.