RESUMEN
Our laboratories have been investigating synthetic analogues of marine alkaloid rigidins that possess promising anticancer activities. These analogues, based on the 7-deazahypoxanthine skeleton, are available in one- or two-step synthetic sequences and exert cytotoxicity by disrupting microtubule dynamics in cancer cells. In the present work we extended the available structure-activity relationship (SAR) data to N3- and N9-substituted derivatives. Although N3 substitution results in loss of activity, the N9-substituted compounds retain nanomolar antiproliferative activities and the anti-tubulin mode of action of the original unsubstituted compounds. Furthermore, our results also demonstrate that multidrug-resistance (MDR) proteins do not confer resistance to both N9-unsubstituted and -substituted compounds. It was found that sublines overexpressing ABCG2, ABCC1, and ABCB1 proteins are as responsive to the rigidin analogues as their parental cell lines. Thus, the study reported herein provides further impetus to investigate the rigidin-inspired 7-deazahypoxanthines as promising anticancer agents.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Alcaloides/farmacología , Antineoplásicos/farmacología , Hipoxantina/farmacología , Microtúbulos/efectos de los fármacos , Pirimidinas/farmacología , Pirroles/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Alcaloides/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Perros , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Hipoxantina/síntesis química , Hipoxantina/química , Células MCF-7 , Células de Riñón Canino Madin Darby/efectos de los fármacos , Microtúbulos/metabolismo , Estructura Molecular , Pirimidinas/química , Pirroles/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Docking studies of tubulin-targeting C2-substituted 7-deazahypoxanthine analogues of marine alkaloid rigidins led to the design and synthesis of compounds containing linear C2-substituents. The C2-alkynyl analogue was found to have double- to single-digit nanomolar antiproliferative IC50 values and showed statistically significant tumor size reduction in a colon cancer mouse model at nontoxic concentrations. These results provide impetus and further guidance for the development of these rigidin analogues as anticancer agents.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Toxinas Marinas/química , Toxinas Marinas/farmacología , Xantinas/síntesis química , Xantinas/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Colchicina/metabolismo , Neoplasias del Colon/tratamiento farmacológico , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Ratones , Ratones Desnudos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Tubulina (Proteína)/efectos de los fármacos , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacologíaRESUMEN
Polygodial, a terpenoid dialdehyde isolated from Polygonum hydropiperâ L., is a known agonist of the transient receptor potential vanilloidâ 1 (TRPV1). In this investigation a series of polygodial analogues were prepared and investigated for TRPV1-agonist and anticancer activities. These experiments led to the identification of 9-epipolygodial, which has antiproliferative potency significantly exceeding that of polygodial. 9-Epipolygodial was found to maintain potency against apoptosis-resistant cancer cells as well as those displaying the multidrug-resistant (MDR) phenotype. In addition, the chemical feasibility for the previously proposed mechanism of action of polygodial, involving the formation of a Paal-Knorr pyrrole with a lysine residue on the target protein, was demonstrated by the synthesis of a stable polygodial pyrrole derivative. These studies reveal rich chemical and biological properties associated with polygodial and its direct derivatives. These compounds should inspire further work in this area aimed at the development of new pharmacological agents, or the exploration of novel mechanisms of covalent modification of biological molecules with natural products.
Asunto(s)
Antineoplásicos/síntesis química , Sesquiterpenos/química , Antineoplásicos/farmacología , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/toxicidad , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Técnicas de Placa-Clamp , Estructura Terciaria de Proteína , Sesquiterpenos/síntesis química , Sesquiterpenos/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/metabolismoRESUMEN
Many types of cancer, including glioma, melanoma, non-small cell lung cancer (NSCLC), among others, are resistant to proapoptotic stimuli and thus poorly responsive to current therapies based on the induction of apoptosis in cancer cells. The current investigation describes the synthesis and anticancer evaluation of unique C12-Wittig derivatives of polygodial, a sesquiterpenoid dialdehyde isolated from Persicaria hydropiper (L.) Delabre. These compounds were found to undergo an unprecedented pyrrole formation with primary amines in a chemical model system, a reaction that could be relevant in the biological environment and lead to the pyrrolation of lysine residues in the target proteins. The anticancer evaluation of these compounds revealed their promising activity against cancer cells displaying various forms of drug resistance, including resistance to proapoptotic agents. Mechanistic studies indicated that compared to the parent polygodial, which displays fixative general cytotoxic action against human cells, the C12-Wittig derivatives exerted their antiproliferative action mainly through cytostatic effects explaining their activity against apoptosis-resistant cancer cells. The possibility for an intriguing covalent modification of proteins through a novel pyrrole formation reaction, as well as useful activities against drug resistant cancer cells, make the described polygodial-derived chemical scaffold an interesting new chemotype warranting thorough investigation.
Asunto(s)
Aminas/química , Antineoplásicos/farmacología , Citostáticos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Pirroles/síntesis química , Sesquiterpenos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citostáticos/síntesis química , Citostáticos/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Conformación Molecular , Polygonum/química , Pirroles/química , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificación , Relación Estructura-ActividadRESUMEN
Two protocols for oxygenation of aromatic C-H bonds ortho-positioned to the phthalazine ring were developed. The transannulation of the phthalazine ring to a naphthalene moiety by an Inverse Electron Demand Diels-Alder (IEDDA) reaction led to the synthesis of naphtho[2,1-c]chromenes, 1-(ortho-hydroxyaryl)naphthalenes and 6,7-dihydrobenzo[b]naphtho[1,2-d]oxepine. This new strategy based on the utilization of transformable nitrogen heterocycles in C-H functionalization chemistry can be potentially applicable to the synthesis of a broad range of biaryl compounds.