RESUMEN
In the frame of our diversity-oriented research on multitarget small molecule anticancer agents, utilizing convergent synthetic sequences terminated by Sonogashira coupling reactions, a preliminary selection of representative alkyne-tethered vindoline hybrids was synthesized. The novel hybrids with additional pharmacophoric fragments of well-documented anticancer agents, including FDA-approved tyrosine-kinase inhibitors (imatinib and erlotinib) or ferrocene or chalcone units, were evaluated for their antiproliferative activity on malignant cell lines MDA-MB-231 (triple negative breast cancer), A2780 (ovarian cancer), HeLa (human cervical cancer), and SH-SY5Y (neuroblastoma) as well as on human embryonal lung fibroblast cell line MRC-5, which served as a reference non-malignant cell line for the assessment of the therapeutic window of the tested hybrids. The biological assays identified a trimethoxyphenyl-containing chalcone-vindoline hybrid (36) as a promising lead compound exhibiting submicromolar activity on A2780 cells with a marked therapeutic window.
Asunto(s)
Alquinos , Antineoplásicos , Proliferación Celular , Vinblastina , Humanos , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Alquinos/química , Alquinos/farmacología , Línea Celular Tumoral , Vinblastina/farmacología , Vinblastina/análogos & derivados , Vinblastina/química , Vinblastina/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Relación Estructura-ActividadRESUMEN
A series of novel vindoline-piperazine conjugates were synthesized by coupling 6 N-substituted piperazine pharmacophores at positions 10 and 17 of Vinca alkaloid monomer vindoline through different types of linkers. The in vitro antiproliferative activity of the 17 new conjugates was investigated on 60 human tumor cell lines (NCI60). Nine compounds presented significant antiproliferative effects. The most potent derivatives showed low micromolar growth inhibition (GI50) values against most of the cell lines. Among them, conjugates containing [4-(trifluoromethyl)benzyl]piperazine (23) and 1-bis(4-fluorophenyl)methyl piperazine (25) in position 17 of vindoline were outstanding. The first one was the most effective on the breast cancer MDA-MB-468 cell line (GI50 = 1.00 µM), while the second one was the most effective on the non-small cell lung cancer cell line HOP-92 (GI50 = 1.35 µM). The CellTiter-Glo Luminescent Cell Viability Assay was performed with conjugates 20, 23, and 25 on non-tumor Chinese hamster ovary (CHO) cells to determine the selectivity of the conjugates for cancer cells. These compounds exhibited promising selectivity with estimated half-maximal inhibitory concentration (IC50) values of 2.54 µM, 10.8 µM, and 6.64 µM, respectively. The obtained results may have an impact on the design of novel vindoline-based anticancer compounds.
Asunto(s)
Antineoplásicos , Proliferación Celular , Cricetulus , Piperazina , Piperazinas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Células CHO , Animales , Piperazinas/farmacología , Piperazinas/química , Piperazinas/síntesis química , Proliferación Celular/efectos de los fármacos , Piperazina/química , Piperazina/farmacología , Vinblastina/análogos & derivados , Vinblastina/farmacología , Vinblastina/química , Vinblastina/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Relación Estructura-Actividad , Supervivencia Celular/efectos de los fármacosRESUMEN
Hybrid compounds of flavones, namely chrysin and kaempferol, and substituted 1,2,3-triazole derivatives, were synthesized by click reaction of the intermediate O-propargyl derivatives. 4-Fluoro- and 4-nitrobenzyl-1,2,3-triazole-containing hybrid molecules were prepared. The mono- and bis-coupled hybrids were investigated on 60 cell lines of 9 common cancer types (NCI60) in vitro as antitumor agents. Some of them proved to have a significant antiproliferative effect.
Asunto(s)
Antineoplásicos , Flavonas , Relación Estructura-Actividad , Proliferación Celular , Triazoles/farmacología , Antineoplásicos/farmacología , Flavonas/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Línea Celular TumoralRESUMEN
Vinca alkaloids are well-known microtubule targeting agents, which are used against some types of cancer. Vindoline is one of the monomeric Vinca alkaloids which does not have anti-tumor effect, although its derivatives have serious impact on the field of these indole alkaloids. Chrysin is a secondary plant metabolite, which has broad-spectrum biological activity, among others anticancer activity. Chrysin had shown synergic effect with several antiproliferative compounds (e. g., doxorubicin, cisplatin and ciglitazone), therefore, we attempted the synthesis of a novel vindoline-chrysin hybrid molecule. However, in the first case a diphenylamine structure was isolated. The mechanism of the unexpected reaction was studied, and then the originally targeted hybrid was synthesized by a reverse route coupling. A further hybrid was produced using a different site of the molecule. The antitumor activities were determined against 60 human tumor cell lines (NCI60), where the aimed hybrid showed low micromolar GI50 values on most of the cell lines.
Asunto(s)
Antineoplásicos/síntesis química , Flavonoides/química , Vinblastina/análogos & derivados , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Alcaloides Indólicos/química , Relación Estructura-Actividad , Vinblastina/químicaRESUMEN
Chrysin is a naturally occurring flavonoid with mild anticancer activity. In this paper we report the synthesis of new chrysin derivatives alkylated with N-phenylchloroacetamides in position 7. A novel method was developed for the preparation of 7-aminochrysin derivatives via the Smiles rearrangement, resulting in diphenylamine-type compounds. In silico studies of the Smiles rearrangement were performed. We also present the in vitro antiproliferative activity of the synthesized compounds against 60 human tumor cell lines (NCI60). The most potent derivative exhibited nanomolar antitumor activity on the MCF7 cell line of breast cancer (GI50 = 30 nM) and on the HCT-15 cell line of colon cancer (GI50 = 60 nM).
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Flavonoides/síntesis química , Flavonoides/farmacología , Alquilación , Antineoplásicos/química , Espectroscopía de Resonancia Magnética con Carbono-13 , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Flavonoides/química , Humanos , Cinética , Espectroscopía de Protones por Resonancia Magnética , TemperaturaRESUMEN
New Vinca alkaloid derivatives were synthesized to improve the biological activity of the natural alkaloid vindoline. To this end, experiments were performed to link vindoline with various structural units, such as amino acids, a 1,2,3-triazole derivative, morpholine, piperazine and N-methylpiperazine. The structure of the new compounds was characterized by NMR spectroscopy and mass spectrometry (MS). Several compounds exhibited in vitro antiproliferative activity against human gynecological cancer cell lines with IC50 values in the low micromolar concentration range.
Asunto(s)
Aminoácidos/química , Antineoplásicos Fitogénicos/síntesis química , Citotoxinas/síntesis química , Morfolinas/química , Piperazinas/química , Triazoles/química , Vinblastina/análogos & derivados , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Técnicas de Química Sintética , Citotoxinas/farmacología , Relación Dosis-Respuesta a Droga , Células HeLa , Humanos , Concentración 50 Inhibidora , Células MCF-7 , Estructura Molecular , Relación Estructura-Actividad , Vinblastina/químicaRESUMEN
Some Vinca alkaloids (eg, vinblastine, vincristine) have been widely used as antitumor drugs for a long time. Unfortunately, vindoline, a main alkaloid component of Catharanthus roseus (L.) G. Don, itself, has no antitumor activity. In our novel research program, we have prepared and identified new vindoline derivatives with moderate cytostatic activity. Here, we describe the effect of conjugation of vindoline derivative with oligoarginine (tetra-, hexa-, or octapeptides) cell-penetrating peptides on the cytostatic activity in vitro and in vivo. Br-Vindoline-(l)-Trp-OH attached to the N-terminus of octaarginine was the most effective compound in vitro on HL-60 cell line. Analysis of the in vitro activity of two isomer conjugates (Br-vindoline-(l)-Trp-Arg8 and Br-vindoline-(d)-Trp-Arg8 suggests the covalent attachment of the vindoline derivatives to octaarginine increased the antitumor activity significantly against P388 and C26 tumour cells in vitro. The cytostatic effect was dependent on the presence and configuration of Trp in the conjugate as well as on the cell line studied. The configuration of Trp notably influenced the activity on C26 and P388 cells: conjugate with (l)-Trp was more active than conjugate with the (d)-isomer. In contrast, conjugates had very similar effect on both the HL-60 and MDA-MB-231 cells. In preliminary experiments, conjugate Br-vindoline-(l)-Trp-Arg8 exhibited some inhibitory effect on the tumor growth in P388 mouse leukemia tumor-bearing mice. Our results indicate that the conjugation of modified vindoline could result in an effective compound even with in vivo antitumor activity.
Asunto(s)
Antineoplásicos/administración & dosificación , Péptidos de Penetración Celular/química , Leucemia/tratamiento farmacológico , Oligopéptidos/química , Vinblastina/análogos & derivados , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células HL-60 , Humanos , Ratones , Estructura Molecular , Vinblastina/administración & dosificación , Vinblastina/química , Vinblastina/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Our successful work for the synthesis of cyclopropanated vinblastine and its derivatives by the Simmonsâ»Smith reaction was followed to build up further three-membered rings into the 14,15-position of the vindoline part of the dimer alkaloid. Halogenated 14,15-cyclopropanovindoline was prepared by reactions with iodoform and bromoform, respectively, in the presence of diethylzinc. Reactions of dichlorocarbene with vindoline resulted in the 10-formyl derivative. Unexpectedly, in the case of the dimer alkaloids vinblastine and vincristine, the rearranged products containing an oxirane ring in the catharanthine part were isolated from the reactions. The attempted epoxidation of vindoline and catharanthine also led to anomalous rearranged products. In the epoxidation reaction of vindoline, an o-quinonoid derivative was obtained, in the course of the epoxidation of catharanthine, a hydroxyindolenine type product and a spiro derivative formed by ring contraction reaction, were isolated. The coupling reaction of vindoline and the spiro derivative obtained in the epoxidation of catharanthine did not result in a bisindole alkaloid. Instead, two surprising vindoline trimers were discovered and characterized by NMR spectroscopy and mass spectrometry.
Asunto(s)
Alcaloides de la Vinca/síntesis química , Catharanthus/química , Técnicas de Química Sintética , Halogenación , Hidrocarburos Clorados/química , Estructura Molecular , Vinblastina/análogos & derivados , Vinblastina/química , Alcaloides de la Vinca/químicaRESUMEN
The synthetic investigation of biologically active natural compounds serves two main purposes: (i) the total synthesis of alkaloids and their analogues; (ii) modification of the structures for producing more selective, more effective, or less toxic derivatives. In the chemistry of dimeric Vinca alkaloids enormous efforts have been directed towards synthesizing new derivatives of the antitumor agents vinblastine and vincristine so as to obtain novel compounds with improved therapeutic properties.
Asunto(s)
Antineoplásicos/química , Vinblastina/química , Vincristina/química , Acoplamiento Oxidativo , Vinblastina/análogos & derivados , Vincristina/análogos & derivadosRESUMEN
Galanthamine as an Amaryllidaceae alkaloid has an important role in the treatment of Alzheimer's disease. Some efforts were made to elaborate the total synthesis, and hundreds of its derivatives were prepared to find a more effective molecule with advantageous properties. Moreover, almost every part of the tetracycle was changed; in members of the rings, in the nature and position of the heteroatoms, and ring-opened analogues were also synthesized. In this review the basic synthetic works and the most important derivatives and analogues are overviewed.
Asunto(s)
Galantamina/análogos & derivados , Galantamina/síntesis química , Alcaloides/química , Amaryllidaceae/química , Galantamina/química , HumanosRESUMEN
We report for the first time on neuronal signaling for the evaluation of interactions between native plasmamembrane and polyamidoamine (PAMAM) dendrimers. Generation 5 polycationic (G5-NH(2)), novel ß-D-glucopyranose-conjugated G5-NH(2) and generation 4.5 polyanionic (G4.5-COONa) polyamidoamine (PAMAM) dendrimers (1-0.0001 mg/ml) were applied in acute brain slices. Functional toxicity assessments-validated by fluorescence imaging of dead cells-were performed by employing electrophysiological indicators of plasma membrane breakdown and synaptic transmission relapse. Irreversible membrane depolarization and decrease of membrane resistance predicted substantial functional neurotoxicity of unmodified G5-NH(2), but not of the G4.5-COONa PAMAM dendrimers. Model calculations suggested that freely moving protonated NH(2) groups of terminal monomeric units of PAMAM dendrimers may be able directly destroy the membrane or inhibit important K(+) channel function via contacting the positively charged NH(2). In accordance, conjugation of surface amino groups by ß-D-glucopyranose units reduced functional neurotoxicity that may hold great potential for biomedical applications.