RESUMEN
Among phosphorylated derivatives, phosphinates occupy a prominent place due to their ability to be bioisosteres of phosphates and carboxylates. These properties imply the necessity to develop efficient methodologies leading to phosphinate scaffolds. In recent years, our team has explored the nucleophilic potential of silylated phosphonite towards various electrophiles. In this paper, we propose to extend our study to other electrophiles. We describe here the implementation of a cascade reaction between (trimethylsilyl)imidates and hypophosphorous acid mediated by a Lewis acid allowing the synthesis of aminomethylenebisphosphinate derivatives. The present study focuses on methodological development including a careful NMR monitoring of the cascade reaction. The optimized conditions were successfully applied to various aliphatic and aromatic substituted (trimethylsilyl)imidates, leading to the corresponding AMBPi in moderate to good yields.
RESUMEN
This paper reports on the synthesis of new hydroxymethylene-(phosphinyl)phosphonates (HMPPs). A methodology has been developed to propose an optimized one-pot procedure without any intermediate purifications. Various aliphatic and (hetero)aromatic HMPPs were synthesized in good to excellent yields (53-98%) and the influence of electron withdrawing/donating group substitution on aromatic substrates was studied. In addition, the one-pot synthesis of HMPP was monitored by 31P NMR spectroscopy, allowing effective control of the end of the reaction and identification of all phosphorylated intermediate species, which enabled us to propose a reaction mechanism. Optimized experimental conditions were applied to the preparation of biological relevant aminoalkyl-HMPPs. A preliminary study of the complexation to hydroxyapatite (bone matrix) was carried out in order to verify its lower affinity towards bone compared to bisphosphonate molecules. Moreover, in vitro anti-tumor activity study revealed encouraging antiproliferative activities on three human cancer cell lines (breast, pancreas and lung).
Asunto(s)
Antineoplásicos , Neoplasias/tratamiento farmacológico , Organofosfonatos , Células A549 , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Neoplasias/metabolismo , Organofosfonatos/síntesis química , Organofosfonatos/química , Organofosfonatos/farmacologíaRESUMEN
An easily handled one-pot synthetic procedure was previously developed for the synthesis of bisphosphinates starting from acyl chlorides. Herein, other trivalent derivatives as acid anhydrides and activated esters were tested to form various bisphosphinates. This modulation of the reactivity can be controlled according to the nature of the acid derivative for the use of sensitive and functionalized substrates.
RESUMEN
A practical generalisable procedure to synthesize hydroxymethylene H-bisphosphinates has been optimised. Unlike previous reports, numerous alkyl (including an alendronate bisphosphinate analogue) or (hetero)aryl compounds were rapidly obtained in satisfactory to excellent yields. A side product could have been identified as a phosphino-phosphonate isomer and plausible mechanistic pathways are proposed here. Moreover to check the literature data, a pKa value study was also performed.
RESUMEN
A set of multivalent polyhydroxylated acetamidoazepanes based on ethylene glycol, glucoside, or cyclodextrin scaffolds was prepared. The compounds were assessed against plant, mammalian, and therapeutically relevant hexosaminidases. Multimerization was shown to improve the inhibitory potency with synergy, and to fine tune the selectivity profile between related hexosaminidases.
Asunto(s)
Antibacterianos/química , Azepinas/química , Hexosaminidasas/antagonistas & inhibidores , Iminoazúcares/química , Animales , Antibacterianos/farmacología , Azepinas/farmacología , Ciclodextrinas/química , Inhibidores Enzimáticos/metabolismo , Glicol de Etileno/química , Glucósidos/química , Iminoazúcares/farmacología , Plantas/metabolismoRESUMEN
The efficient synthesis and very easy isolation of dibenzo[24]crown-8-based [2]pseudorotaxane building blocks that contain an active ester motif at the extremity of the encircled molecular axle and an ammonium moiety as a template for the dibenzo[24]crown-8 is reported. The active ester acts both as a semistopper for the [2]pseudorotaxane species and as an extensible extremity. Among the various investigated active ester moieties, those that allow for the slippage process are given particular focus because this strategy produces fewer side products. Extension of the selected N-hydroxysuccinimide ester based pseudorotaxane building block by using either a mono- or a diamino compound, both containing a triazolium moiety, is also described. These provide a pH-dependent two-station [2]rotaxane molecular machine and a palindromic [3]rotaxane molecular machine, respectively. Molecular machinery on both interlocked compounds through variation of pH was studied and characterized by means of NMR spectroscopy.
RESUMEN
The synthesis of the first series of a new class of nucleoside phosphonate analogues is described. Addition of a carboxyl group at the α position of carbocyclic nucleoside phosphonate analogues leads to a novel class of potent HIV reverse transcriptase (RT) inhibitors, α-carboxy nucleoside phosphonates (α-CNPs). Key steps in the synthesis of the compounds are Rh-catalyzed O-H insertion and Pd-catalyzed allylation reactions. In cell-free assays, the final products are markedly inhibitory against HIV RT and do not require phosphorylation to exhibit anti-RT activity, which indicates that the α-carboxyphosphonate function is efficiently recognized by HIV RT as a triphosphate entity, an unprecedented property of nucleoside monophosph(on)ates.
Asunto(s)
Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Antivirales/síntesis química , Antivirales/farmacología , VIH-1/efectos de los fármacos , Nucleósidos/síntesis química , Organofosfonatos/síntesis química , Organofosfonatos/farmacología , Paladio/química , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Fármacos Anti-VIH/síntesis química , Antivirales/química , Catálisis , Diseño de Fármacos , Humanos , Modelos Moleculares , Nucleósidos/farmacología , Organofosfonatos/química , Fosforilación , Relación Estructura-ActividadRESUMEN
The antitumoral activity of hydroxymethylene bisphosphonates (HMBP) such as alendronate or zoledronate is hampered by their exceptional bone-binding properties and their short plasmatic half-life which preclude their accumulation in non-skeletal tumors. In this context, the use of lipophilic prodrugs represents a simple and straightforward strategy to enhance the biodistribution of bisphosphonates in these tissues. We describe in this article the synthesis of light-responsive prodrugs of HMBP alendronate. These prodrugs include lipophilic photo-removable nitroveratryl groups which partially mask the highly polar alendronate HMBP scaffold. Photo-responsive prodrugs of alendronate are stable in physiological conditions and display reduced toxicity compared to alendronate against MDA-MB-231 cancer cells. However, the antiproliferative effect of these prodrugs is efficiently restored after cleavage of their nitroveratryl groups upon exposure to UV light. In addition, substitution of alendronate with such photo-responsive substituents drastically reduces its bone-binding properties, thereby potentially improving its biodistribution in soft tissues after i.v. administration. The development of such lipophilic photo-responsive prodrugs is a promising approach to fully exploit the anticancer effect of HMBPs on non-skeletal tumors.
Asunto(s)
Neoplasias , Profármacos , Humanos , Alendronato/farmacología , Alendronato/química , Profármacos/farmacología , Distribución Tisular , Difosfonatos/farmacología , Difosfonatos/químicaRESUMEN
The rise of chemical biology has led to the development of sophisticated molecular devices designed to explore and manipulate biological processes. Within this framework, we developed the first chemical system programmed for the selective internalization and subsequent enzyme-catalyzed double release of bioactive compounds inside a targeted population of cells. This system is composed of five distinct units including a targeting ligand, an enzymatic trigger, a self-immolative linker and two active compounds articulated around a chemical amplifier. Designed as such, this molecular assembly is capable in an autonomous manner to recognize a selected population of cells, penetrate into the intracellular medium through endocytosis and transform a single enzymatic activation step into the release of two active units. Demonstrating that an enzyme-catalyzed amplification process can occur spontaneously under the conditions prevailing within the cells could be an important step toward the development of innovative molecular systems for a diverse range of applications spanning drug delivery, biological sensors and diagnostics.
Asunto(s)
Antineoplásicos/farmacología , Galactósidos/farmacología , beta-Galactosidasa/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Biocatálisis , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Galactósidos/biosíntesis , Galactósidos/química , Humanos , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales Cultivadas , beta-Galactosidasa/químicaRESUMEN
Massive attack: Galactoside prodrugs have been designed that can be selectively activated by lysosomal ß-galactosidase located inside cancer cells expressing a specific tumor-associated receptor. This efficient enzymatic process triggers a potent cytotoxic effect, releasing the potent antimitotic agent MMAE and allowing the destruction of both receptor-positive and surrounding receptor-negative tumor cells.
Asunto(s)
Aminobenzoatos/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Oligopéptidos/uso terapéutico , Profármacos/uso terapéutico , beta-Galactosidasa/metabolismo , Aminobenzoatos/administración & dosificación , Aminobenzoatos/química , Aminobenzoatos/metabolismo , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Humanos , Ratones , Neoplasias/enzimología , Neoplasias/patología , Oligopéptidos/administración & dosificación , Oligopéptidos/química , Oligopéptidos/metabolismo , Profármacos/administración & dosificación , Profármacos/química , Profármacos/metabolismoRESUMEN
We prepared a new glucuronide prodrug of cyclopamine designed to target selectively the Hedgehog signalling pathway of cancer cells. This prodrug includes a novel self-immolative linker bearing a hydrophilic side chain that can be easily introduced via"click chemistry". With this design, the prodrug exhibits reduced toxicity compared to the free drug on U87 glioblastoma cells. However, in the presence of ß-glucuronidase, the prodrug conducts to the quick release of cyclopamine thereby restoring its antiproliferative activity.
Asunto(s)
Antineoplásicos/farmacología , Glucurónidos/farmacología , Profármacos/farmacología , Alcaloides de Veratrum/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Química Clic , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Glucurónidos/síntesis química , Glucurónidos/química , Humanos , Cinética , Estructura Molecular , Profármacos/síntesis química , Profármacos/química , Transducción de Señal , Relación Estructura-Actividad , Células Tumorales Cultivadas , Alcaloides de Veratrum/síntesis química , Alcaloides de Veratrum/químicaRESUMEN
The synthesis of a new set of triazole bisphosphonates 8a-d and 9a-d presenting an alkyl or phenyl substituent at the C-4 or C-5 position of the triazole ring is described. These compounds have been evaluated for their antiproliferative activity against MIA PaCa-2 (pancreas), MDA-MB-231 (breast) and A549 (lung) human tumor cell lines. 4-hexyl- and 4-octyltriazole bisphosphonates 8b-c both displayed remarkable antiproliferative activities with IC50 values in the micromolar range (0.75-2.4 µM) and were approximately 4 to 12-fold more potent than zoledronate. Moreover, compound 8b inhibits geranylgeranyl pyrophosphate biosynthesis in MIA PaCa-2 cells which ultimately led to tumor cells death.
Asunto(s)
Antineoplásicos/farmacología , Difosfonatos/farmacología , Terpenos/antagonistas & inhibidores , Triazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Difosfonatos/síntesis química , Difosfonatos/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Terpenos/metabolismo , Triazoles/síntesis química , Triazoles/química , Células Tumorales CultivadasRESUMEN
The development of novel therapeutic strategies allowing the destruction of tumour cells while sparing healthy tissues is one of the main challenges of cancer chemotherapy. Here, we report on the design and antitumour activity of a low-molecular-weight drug delivery system programmed for the selective release of the potent monomethylauristatin E in the tumour microenvironment of solid tumours. After intravenous administration, this compound binds covalently to plasmatic albumin through Michael addition, thereby enabling its passive accumulation in tumours where extracellular ß-glucuronidase initiates the selective release of the drug. This targeting device produces outstanding therapeutic efficacy on orthotopic triple-negative mammary and pancreatic tumours in mice (50% and 33% of mice with the respective tumours cured), leading to impressive reduction or even disappearance of tumours without inducing side effects.
RESUMEN
Carvacrol, an aromatic terpenic compound, known to be antimicrobial was grafted onto gold surfaces via two strategies based on newly-synthesized cross-linkers involving either an ester bond which can be cleaved by microbial esterases, or a covalent ether link. Surface functionalizations were characterized at each step by reflection absorption infrared spectroscopy (RAIRS). The two functionalized gold samples both led to a loss of culturability of the yeast Candida albicans, higher than 65%, indicating that the activity of the freshly-designed surfaces was probably due to still covalently immobilized carvacrol. On the contrary, when a phenyl group replaced the terpenic moiety, the yeast culturability increased by about 30%, highlighting the specific activity of carvacrol grafted on the surfaces. Confocal microscopy analyses showed that the mode of action of the functionalized surfaces with the ester or the ether of carvacrol was, in both cases, fungicidal and not anti-adhesive. Finally, this study shows that covalently immobilization of terpenic compounds can be used to design promising antimicrobial surfaces.
RESUMEN
The development of mechanically interlocked molecular systems programmed to operate autonomously in biological environments is an emerging field of research with potential medicinal applications. Within this framework, functional rotaxane- and pseudorotaxane-based architectures are starting to attract interest for the delivery of anticancer drugs, with the ultimate goal to improve the efficiency of cancer chemotherapy. Here, we report an enzyme-sensitive [2]-rotaxane designed to release a potent anticancer drug within tumor cells. The molecular device includes a protective ring that prevents the premature liberation of the drug in plasma. However, once located inside cancer cells the [2]-rotaxane leads to the release of the drug through the controlled disassembly of the mechanically interlocked components, in response to a determined sequence of two distinct enzymatic activations. Furthermore, in vitro biological evaluations reveal that this biocompatible functional system exhibits a noticeable level of selectivity for cancer cells overexpressing ß-galactosidase.
RESUMEN
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Activation of the developmental hedgehog (Hh) pathway is observed in GBM, particularly in the so-called glioma stem cells (GSCs). An inhibitor of this pathway is the steroidal alkaloid cyclopamine, an antagonist of the Hh coreceptor Smoothened (SMO). To limit the toxicity of cyclopamine toward Hh-dependent non-tumor cells, our group previously reported the synthesis of a prodrug (called 1b), designed to deliver cyclopamine in the presence of ß-glucuronidase, an enzyme found in the necrotic area of GBM. Here, we aimed to analyze the in vitro, ex vivo, and in vivo cytotoxic properties of this prodrug in the C6 rat GBM cells. In the presence of ß-glucuronidase, the activated prodrug 1b was toxic and downregulated expression of Gli1, a Hh target gene, in C6 cells and C6-GSCs, but not in normal rat astrocytes in which the Hh pathway is weakly activated. In the absence of ß-glucuronidase, prodrug 1b displayed no obvious toxicity toward rat brain tissue explants while cyclopamine clearly affected brain tissue viability. When administered to rats bearing fluorescent C6-derived GBM, the prodrug 1b reduced the tumor density more efficiently than cyclopamine. Prodrug 1b thus appears as a promising concept to optimize confinement of cyclopamine cytotoxicity within the tumors, with more limited effects in the surrounding normal brain tissue.
Asunto(s)
Antineoplásicos/farmacología , Glioblastoma/metabolismo , Alcaloides de Veratrum/farmacología , Animales , Antineoplásicos/uso terapéutico , Antineoplásicos/toxicidad , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Línea Celular Tumoral , Células Cultivadas , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Glucuronidasa/metabolismo , Proteínas Hedgehog/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratas , Ratas Wistar , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/metabolismo , Receptor Smoothened , Alcaloides de Veratrum/uso terapéutico , Alcaloides de Veratrum/toxicidad , Proteína con Dedos de Zinc GLI1RESUMEN
The design of novel antitumor agents allowing the destruction of malignant cells while sparing healthy tissues is one of the major challenges in medicinal chemistry. In this context, the use of non-toxic prodrugs programmed to be selectively activated by beta-glucuronidase present at high concentration in the microenvironment of most solid tumors has attracted considerable attention. This review summarizes the major progresses that have been realized in this field over the past ten years. This includes the new prodrugs that have been designed to target a wide variety of anticancer drugs, the prodrugs employed in the course of a combined therapy, the dendritic glucuronide prodrugs and the concept of ß-glucuronidase-responsive albumin binding prodrugs.
Asunto(s)
Antineoplásicos/farmacología , Glucuronidasa/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Profármacos/farmacología , Antineoplásicos/uso terapéutico , Humanos , Profármacos/uso terapéuticoRESUMEN
Recent data suggest that inhibition of the Hedgehog pathway could be a therapeutic target for glioblastoma. Alkaloid cyclopamine inhibits Hedgehog signaling, depleting stem-like cancer cells derived from glioblastoma. However, this compound is toxic for somatic stem cells, preventing its use for clinical applications. In this study, we tested a derivatization product of cyclopamine in the form of cyclopamine glucuronide prodrug (CGP-2). This compound was used in vitro and in vivo toward glioblastoma-initiating cells (GIC). Results obtained in vitro indicate that CGP-2 is active only in the presence of ß-glucuronidase, an enzyme detected in high levels in necrotic areas of glioblastomas. CGP-2 decreased proliferation and inhibited the self-renewal of all GIC lines tested. Hedgehog pathway blockade by 10 µmol/L of CGP-2 induced a 99% inhibition of clonogenicity on GICs, similar to cyclopamine treatment. Combination of CGP-2 with radiation decreased clonogenic survival in all GIC lines compared with CGP-2 alone. In a subcutaneous glioblastoma xenograft model, a two-week CGP-2 treatment prevented tumor growth with 75% inhibition at 8 weeks, and this inhibition was still significant after 14 weeks. Unlike cyclopamine, CGP-2 had no detectable toxic effects in intestinal crypts. Our study suggests that inhibition of the Hedgehog pathway with CGP-2 is more effective than conventional temozolomide adjuvant, with much lower concentrations, and seems to be an effective therapeutic strategy for targeting GICs.
Asunto(s)
Glioblastoma/tratamiento farmacológico , Glucurónidos/química , Células Madre Neoplásicas/citología , Profármacos/química , Alcaloides de Veratrum/química , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Proteínas Hedgehog/antagonistas & inhibidores , Humanos , Concentración 50 Inhibidora , Metilcelulosa/química , Ratones , Ratones Desnudos , Trasplante de NeoplasiasRESUMEN
We developed a glucuronide prodrug of the potent monomethylauristatin E (MMAE). This prodrug is significantly less toxic than the parent drug. However, in the presence of ß-glucuronidase the prodrug leads to the efficient release of MMAE thereby triggering a subnanomolar cytotoxic activity against several cancer cell lines. Preliminary in vivo experiments conducted in C57BL/6 mice bearing a subcutaneous murine Lewis Lung Carcinoma (LLC) demonstrated the potential of this targeting system for the selective treatment of solid tumors.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Glucurónidos/farmacología , Oligopéptidos/farmacología , Profármacos/síntesis química , Profármacos/farmacología , Animales , Antineoplásicos/química , Carcinoma Pulmonar de Lewis/patología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Glucurónidos/síntesis química , Glucurónidos/química , Humanos , Células KB , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Oligopéptidos/síntesis química , Oligopéptidos/química , Profármacos/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
In this paper we describe the synthesis and biological evaluation of the first ß-glucuronidase-responsive albumin-binding prodrug designed for the selective delivery of doxorubicin at the tumor site. This prodrug leads to superior antitumor efficacy in mice compared to HMR 1826, a well-known glucuronide prodrug of doxorubicin that cannot bind covalently to circulating albumin. Furthermore, this compound inhibits tumor growth in a manner similar to that of doxorubicin while avoiding side effects induced by the free drug.