RESUMEN
Benzopyridothiadiazepine (2a) and benzopyridooxathiazepine (2b) were modified to produce tricyclic quinazolinone 15-18 or benzothiadiazine 26-27 derivatives. These compounds were evaluated in cytotoxicity and tubulin inhibition assays and led to potent inhibitors of tubulin polymerization. N-[2(4-Methoxyphenyl)ethyl]-1,2-dihydro-pyrimidino[2,1-b]quinazolin-6-one (16a) exhibited the best in vitro cytotoxic activity (GI50 10-66.9 nM) against the NCI 60 human tumor cell line and significant potency against tubulin assembly (IC50 0.812 µM). In mechanism studies, 16a was shown to block cell cycle in G2/M phase and to disrupt microtubule formation and displayed good antivascular properties as inhibition of cell migration, invasion, and endothelial tube formation. Compound 16a was evaluated in C57BL/6 mouse melanoma B16F10 xenograft model to validate its antitumor activity, in comparison with reference ABT-751 (1). Compound 16a displayed strong in vivo antitumor and antivascular activities at a dose of 5 mg/kg without obvious toxicity, whereas 1 needed a 10-fold higher concentration to reach similar effects.
Asunto(s)
Antimitóticos/química , Antimitóticos/uso terapéutico , Melanoma/tratamiento farmacológico , Sulfonamidas/química , Sulfonamidas/uso terapéutico , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Antimitóticos/síntesis química , Antimitóticos/farmacología , Benzotiadiazinas/síntesis química , Benzotiadiazinas/química , Benzotiadiazinas/farmacología , Benzotiadiazinas/uso terapéutico , Línea Celular Tumoral , Humanos , Masculino , Melanoma/irrigación sanguínea , Melanoma/metabolismo , Ratones , Ratones Endogámicos C57BL , Quinazolinonas/síntesis química , Quinazolinonas/química , Quinazolinonas/farmacología , Quinazolinonas/uso terapéutico , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacología , Moduladores de Tubulina/uso terapéutico , BencenosulfonamidasRESUMEN
A series of 1-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-ones designed as conformationally restricted CA-4 analogues, were tested for their tubulin polymerization and growth inhibitory activities. The 3-hydroxy-4-methoxy derivatives 11d and 12d are potent inhibitors of tubulin assembly but only the N-methylated amid counterpart 12d possesses potent anticancer activity in a large panel of cancer cell lines. Upon treatment with compound 12d, remarkable cell shape changes as cell migration and tube formation were elicited in HUVECs, consistent with vasculature damaging activity.
Asunto(s)
Vasos Sanguíneos/efectos de los fármacos , Quinazolinonas/farmacología , Moduladores de Tubulina/farmacología , Tubulina (Proteína)/química , Proliferación Celular/efectos de los fármacos , PolimerizacionRESUMEN
The synthesis of new acridinone and dioxophenothiazine derivatives along with their tubulin polymerization inhibitory and antiproliferative activities is reported. The analysis of correlation for cytotoxic and antitubulin potential of tested compounds showed that 4-methoxyphenylethyl derivatives 18a and 19a were highly cytotoxic but were regarded to have no significant antitubulin activity. However, the introduction of a 3-hydroxy substituent leading to compounds 18e and 19e, strongly increased the antitubulin potential but was associated with a loss of the antiproliferative activity. Modeling studies, topoisomerase inhibition assays and cell cycle analysis have been performed to better investigate the mechanism of action of such compounds.
Asunto(s)
Acridonas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Sistemas de Liberación de Medicamentos , Tubulina (Proteína)/metabolismo , Acridonas/síntesis química , Acridonas/química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Fenotiazinas/síntesis química , Fenotiazinas/química , Fenotiazinas/farmacología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
The synthesis of new 4-amino-tetrahydroquinazolino[3,2-e]purine derivatives along with their activity in cell-free enzymatic assays on Src is reported. Some compounds emerged as moderately active inhibitors of the enzyme and showed antiproliferative effects on the murine leukemia L1210 cell line. Docking studies have been also performed to analyze the binding mode of compounds under study and to identify the structural determinants of their interaction. Therefore, this study provides a new promising scaffold with moderate enzymatic inhibitory activities for further development of new anticancer drugs targeting Src tyrosine kinase.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Purinas/síntesis química , Purinas/farmacología , Quinazolinas/síntesis química , Quinazolinas/farmacología , Familia-src Quinasas/antagonistas & inhibidores , Animales , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Ratones , Modelos Moleculares , Estructura Molecular , Purinas/química , Quinazolinas/química , Estereoisomerismo , Relación Estructura-Actividad , Familia-src Quinasas/metabolismoRESUMEN
Herein, we describe the structure-activity relationship study of a new 1-(arylalkyl)-11H-benzo[f]-1,2-dihydropyrido[3,2,c][1,2,5]oxathiazepine 5,5-dioxide series of antimitotic agents. The pharmacological results obtained from previous works allowed us to identify compound 1 as a new cytotoxic agent inhibiting tubulin polymerization. We have undertaken the synthesis of its non-methylated analogue 7 and have extended our investigations to a novel, structurally related benzopyridooxathiazepine dioxide series. Among all analogues synthesized in this study, compound 10b was the most promising, being 12-fold more potent than compound 1. Its activity over a panel of five tumoral cell lines was in the nanomolar range for all of the histological types tested and flow cytometric studies performed on L1210 cells showed an accumulation of the cells in the G2/M phases of the cell cycle with a significant percentage of tetraploid cells (8N DNA content). This interesting pharmacological profile, resulting from inhibition of tubulin polymerization, encouraged us to perform preliminary in vivo studies.
Asunto(s)
Antimitóticos/química , Antineoplásicos/química , Tiazepinas/química , Tiazepinas/farmacología , Moduladores de Tubulina/química , Animales , Antimitóticos/síntesis química , Antimitóticos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Ciclo Celular , Línea Celular Tumoral , Humanos , Ratones , Relación Estructura-Actividad , Tiazepinas/síntesis química , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/farmacologíaRESUMEN
The synthesis of novel thiadiazepine derivatives, that could be considered as constraint analogues of E-7010, are reported. These molecules were evaluated for their antiproliferative activity toward the murine L1210 leukemia cell line. Flow cytometric studies performed on L1210 cells with the most cytotoxic compounds showed an accumulation of the cells in the G2/M phases of the cell cycle with a significant percentage of tetraploid cells (8N DNA content). Submicromolar cytotoxicities were observed with compounds 2b, 4b, 4e, 4g, and 4i. Two of them, compounds 2b and 4b, were found to be potent inhibitors of tubulin polymerization with IC50 of respectively 3.8 and 2.4 microM compared to 2.4 microM for desoxypodophyllotoxin. A 4-methoxyphenylethyl substitution on the pyridinyl nitrogen of the benzopyridothiadiazepine was found to be essential for the antiproliferative activity. The in vitro activities of compounds 2b and 4b make benzopyridothiadiazepine dioxides a promising new class of tubulin binders which warrant further in vivo evaluation.