RESUMEN
Efficient synthetic routes have been developed for the preparation of two new polyazamacrocycles tagged with structural motifs recognised by the Trypanosoma brucei P2 aminopurine transporter. Biological testing of these compounds showed highly selective anti-protozoal activity against trypanosomes.
Asunto(s)
Antiprotozoarios/farmacología , Benzamidinas/química , Química Farmacéutica/métodos , Guanidina/química , Tripanosomiasis Africana/tratamiento farmacológico , Tripanosomiasis Africana/metabolismo , Secuencias de Aminoácidos , Animales , Transporte Biológico , Línea Celular , Diseño de Fármacos , Humanos , Modelos Químicos , Plasmodium falciparum/metabolismo , Purinas/químicaRESUMEN
A focused library of C2-substituted-1,4,7,10-tetraazacyclododecanes was synthesised and the compounds were tested for their ability to kill trypanosome and malaria parasites. Several compounds showed significant in vitro activity and were selectively active against the parasites over human embryonic kidney cells used as a counter screen.
Asunto(s)
Antiprotozoarios/uso terapéutico , Compuestos Aza/uso terapéutico , Riñón/efectos de los fármacos , Compuestos Macrocíclicos/uso terapéutico , Malaria/tratamiento farmacológico , Trypanosoma/efectos de los fármacos , Animales , Antiprotozoarios/síntesis química , Antiprotozoarios/farmacología , Compuestos Aza/síntesis química , Compuestos Aza/farmacología , Humanos , Riñón/citología , Riñón/embriología , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacología , Malaria/parasitología , Modelos Químicos , Pruebas de Sensibilidad Parasitaria , Relación Estructura-ActividadRESUMEN
A short, highly efficient approach for the synthesis of a novel class of polyazamacrocycles containing N-functionalised carbamate side-chains has been developed. The key steps involved a phase-transfer mediated macrocyclisation to form the ring system as well as a tin-catalysed reaction with isocyanates to introduce the carbamate side-chains. X-Ray crystallography confirmed successful formation of the 1,4,7,10-tetraazacyclododecane ring and N-functionalisation of all the amine centres. Preliminary testing of the biological activity of the compounds revealed significant anti-parasitic activity against bloodstream form African trypanosomes.
Asunto(s)
Antiprotozoarios/síntesis química , Antiprotozoarios/farmacología , Carbamatos/química , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacología , Animales , Antiprotozoarios/química , Carbamatos/síntesis química , Carbamatos/farmacología , Línea Celular , Humanos , Compuestos Macrocíclicos/química , Pruebas de Sensibilidad Parasitaria , Trypanosoma brucei brucei/efectos de los fármacosRESUMEN
A family of 5-deazaflavin derivatives has been synthesised using a two-step convergent strategy. The biological activity of these compounds was evaluated in cells, by assessing their ability to stabilize and activate p53. These compounds may act as low molecular weight inhibitors of the E3 activity of HMD2 in tumours that retain wild-type p53. Importantly, we have demonstrated that the nitro group present in all three of the original lead compounds [1-3 (HL198C-E)] is not essential for observation of this biological activity.
Asunto(s)
Células Epiteliales/efectos de los fármacos , Flavinas/síntesis química , Flavinas/farmacología , Proteína p53 Supresora de Tumor/efectos de los fármacos , Apoptosis/efectos de los fármacos , Western Blotting , Ciclo Celular/efectos de los fármacos , Daño del ADN , Relación Dosis-Respuesta a Droga , Doxorrubicina/farmacología , Evaluación Preclínica de Medicamentos , Células Epiteliales/química , Células Epiteliales/metabolismo , Flavinas/química , Citometría de Flujo , Humanos , Estructura Molecular , Peso Molecular , Proteínas Proto-Oncogénicas c-mdm2/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/fisiología , Sensibilidad y Especificidad , Estereoisomerismo , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The melanin biosynthetic pathway from tyrosine is a potential target for combating malignant melanoma. N-Acetyl-4-S-cysteaminylphenol 1 is a previously synthesized analogue of tyrosine that probably acts by this pathway. It interferes with cell growth and proliferation via selective oxidation in melanocytes to an oquinone that can alkylate cellular nucleophiles. We previously synthesized a range of analogues of the original lead compound 1 most of which displayed greater cytotoxicity than 1. Eighteen new analogues with the amide group reversed have now been synthesized and tested for antimelanoma activity. Most of these reverse amides showed greater cytotoxicity than N-acetyl-4-S-cysteaminylphenol towards five representative melanoma cell lines. The highest cytotoxicity was observed for the piperidine and hexamethyleneimine derivatives 7, 8, 12, 13, and 17 and the catechol 18. The most active compound, 7, had cytotoxicity comparable to cisplatin against the five melanoma cell lines. The moderate activity of 7 and 18 against SK-Mel-24 (non-tyrosinase containing) and an ovarian cell line suggests that interference with the melanin pathway may not be the only mode of action of these compounds. Assays of some of the compounds as substrates for tyrosinase showed that the catechol 18 was the best substrate and that the piperidine derivative 7 was the best substrate of the phenolic compounds synthesized.
Asunto(s)
Amidas/química , Antineoplásicos/síntesis química , Antineoplásicos/toxicidad , Cisteamina/análogos & derivados , Melanoma/tratamiento farmacológico , Melanoma/patología , Fenoles/química , Fenoles/toxicidad , Antineoplásicos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cisteamina/síntesis química , Cisteamina/química , Cisteamina/toxicidad , Humanos , Estructura Molecular , Fenoles/síntesis química , Relación Estructura-ActividadRESUMEN
Interference with the biosynthetic pathway to melanin may be a useful means for developing new chemotherapeutic drugs to combat malignant melanoma. N-Acetyl-4-S-cysteaminylphenol (1) is an analogue of tyrosine that is involved in the pathway to melanin. It is probably oxidized selectively in melanocytes to an o-quinone that can alkylate thiol groups on important cellular enzymes, resulting in interference with cell growth and proliferation. We previously synthesized a range of more lipophilic analogues of 1 by independently varying the acyl portion and introducing substitution alpha to the nitrogen. Most of the new compounds displayed greater cytotoxicity than the original lead compound 1. We also made a series of tertiary amides that again showed higher cytotoxicity than 1. In this work three new acetamides and two new cyclohexanecarboxamides containing 4-S-cysteaminylphenol were prepared incorporating both substitution alpha to the nitrogen and different substituents on the nitrogen of the amide in each compound to increase lipophilicity and to reduce further the possibility of hydrolysis of the amides. Most of the new tertiary amides showed greater cytotoxicity towards five representative melanoma cell lines than the parent secondary amide. The highest cytotoxicity against these five cell lines with IC50 values of 1-15 nicroM, comparable to cisplatin, was observed for N-[2[(4-hydroxyphenyl)thio]-1,1-dimethylethyl]-N-methylcyclohexanecarboxamide (8c). The IC50 values of 14.5 and 5.4 microM for this compound against SK-Mel-24 (not containing tyrosinase) and an ovarian cell line, respectively, suggest that interference with the melanin pathway may not be the only mode of action of this new compound. The cyclohexanecarboxamides were better substrates for mushroom tyrosinase (EC 1.14.18.1) than the acetamides.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Cisteamina/análogos & derivados , Ensayos de Selección de Medicamentos Antitumorales , Melanoma/tratamiento farmacológico , Fenoles/síntesis química , Fenoles/farmacología , Agaricales/enzimología , Amidas/química , Línea Celular Tumoral , Proliferación Celular , Cisteamina/síntesis química , Cisteamina/farmacología , Humanos , Concentración 50 Inhibidora , Melaninas/química , Modelos Químicos , Monofenol Monooxigenasa/química , Monofenol Monooxigenasa/metabolismo , Nitrógeno/química , Oxígeno/metabolismo , Estereoisomerismo , Sulfuros/química , Factores de Tiempo , Rayos UltravioletaRESUMEN
We are seeking to develop more effective alkylating agents as antitumour agents. In previous work conformationally restricted nitrogen mustards were synthesised containing piperidine or pyrrolidine rings. The free bases were designed to be bifunctional alkylating agents via aziridinium ion formation and the effects of varying the distances between the two alkylating sites were studied. Some efficient cross-linkers of naked DNA were prepared but few of these compounds exhibited significant cytotoxicity in human tumour cells in vitro. We have extended this work by making tri- and tetra-azamacrocyclic compounds containing two to four potential alkylating sites. Most of these compounds were powerful DNA alkylating agents and showed cytotoxicity (IC(50) values 6-100microM) comparable with chlorambucil (45microM) and melphalan (8.5microM). In particular the cyclen derivative 2a was more than 10(4) times more effective at cross-linking DNA (2a XL(50)<<10nM) than chlorambucil (XL(50) 100microM), and showed significant cytotoxicity in human tumour cells in vitro.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos Aza/síntesis química , Reactivos de Enlaces Cruzados/síntesis química , ADN/efectos de los fármacos , Compuestos Macrocíclicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Compuestos Aza/química , Compuestos Aza/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Reactivos de Enlaces Cruzados/química , Reactivos de Enlaces Cruzados/farmacología , ADN/química , Electroforesis en Gel de Agar/métodos , Humanos , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacología , Estructura MolecularRESUMEN
Tumor hypoxia provides a key difference between healthy and cancerous cells. It can be exploited to produce drug selectivity, offering a reductase-rich environment for prodrug activation. Nitrogen mustard drugs are cytotoxic, but usually unselective. Polyamine mustards are candidates for conversion into hypoxia-selective prodrugs via complexation with metals. Reduction to a less stable complex can free the active drug. The novel Cu(II) complexes of N-mustard derivatives of 1,4,7-triazacyclononane (tacn), 1,4,7,10-tetraazacyclododecane (cyclen), and 1,4,8,11-tetraazacyclotetradecane (cyclam) were assessed in vitro as hypoxia-selective cytotoxins. The cyclen mustard complex showed 24-fold selectivity as a hypoxia-selective bioreductive prodrug, with an IC50 value of 2 microM against the lung tumor cell line A549. Reversible redox behavior and stability of the cyclen-Cu(II) complex in aqueous solution correlated with good hypoxia selectivity. The two other related complexes showed irreversible redox behavior and low aqueous stability and were not hypoxia-selective. The use of macrocyclic nitrogen mustard complexes represents a promising new strategy in the design of hypoxia-selective cytotoxins.
Asunto(s)
Antineoplásicos Alquilantes/síntesis química , Cobre , Compuestos de Mostaza Nitrogenada/síntesis química , Compuestos Organometálicos/síntesis química , Profármacos/síntesis química , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacología , Hipoxia de la Célula , Línea Celular Tumoral , Cristalografía por Rayos X , Diseño de Fármacos , Estabilidad de Medicamentos , Humanos , Cinética , Ligandos , Estructura Molecular , Compuestos de Mostaza Nitrogenada/química , Compuestos de Mostaza Nitrogenada/farmacología , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Oxidación-Reducción , Profármacos/química , Profármacos/farmacología , Solubilidad , TermodinámicaRESUMEN
Examples of five classes of diamines were synthesized and tested for antifungal activity. Two classes, the bis(cyclohexylmethyl)diamines and the bis(benzyl)diamines, were most effective in reducing mycelial growth of the oat leaf stripe pathogen Pyrenophora avenae Ito & Kuribay when used at a concentration of 250microM. The bis(benzyl)diamine BBD5 and the hydroxypyridylethylamine HPE2 both reduced powdery mildew infection of barley seedlings by greater than 70% when applied as a post-inoculation spray at 250 microM. Several of the compounds examined, and especially BBD5 and HPE2, reduced the formation of spermidine but greatly increased spermine levels. These changes in P avenae treated with BBD5 and HPE2 were also accompanied by greatly elevated activity of polyamine oxidase. It is suggested that the antifungal activity of these compounds may be related to the accumulation of spermine and specifically to its toxicity.
Asunto(s)
Bencilaminas/síntesis química , Diaminas/síntesis química , Etanolaminas/síntesis química , Hongos/efectos de los fármacos , Fungicidas Industriales/síntesis química , Piridinas/síntesis química , Bencilaminas/farmacología , Diaminas/química , Diaminas/farmacología , Etanolaminas/farmacología , Hongos/crecimiento & desarrollo , Fungicidas Industriales/farmacología , Estructura Molecular , Micelio/efectos de los fármacos , Micelio/crecimiento & desarrollo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/efectos de los fármacos , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/metabolismo , Piridinas/farmacología , Espermidina/metabolismo , Espermina/metabolismo , Poliamino OxidasaRESUMEN
The synthesis of several thiazolo[4, 5-d]pyrimidines containing a fluorophenyl moiety substituted at different positions and through different bridges is described. Twenty new compounds were prepared and evaluated for their anticancer activity using the USA-NCI in-vitro screening program. Three compounds were found active and their anticancer activity against 60 human tumor cell lines are described in detail.
Asunto(s)
Antineoplásicos/síntesis química , Pirimidinas/síntesis química , Tiazoles/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 Inhibidora , Pirimidinas/farmacología , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacología , Células Tumorales CultivadasRESUMEN
The biosynthetic pathway to melanin is a realistic target for therapeutic intervention in the development of new drugs to combat malignant melanoma. N-Acetyl-4-S-cysteaminylphenol (1) is an analogue of a biosynthetic intermediate in the pathway to melanin. It probably acts as a prodrug and is oxidized selectively in melanocytes to an o-quinone, which can alkylate cellular nucleophiles resulting in interference with cell growth and proliferation. We previously synthesized a range of more lipophilic analogues of 1 by varying the acyl portion and introducing substitution alpha to the nitrogen. Most of the new compounds displayed greater cytotoxicity than the original lead compound 1. We have now prepared 12 new compounds with varying acyl portions and three different substituents on the nitrogen of the amide in order to increase lipophilicity and to reduce the possibility of hydrolysis of the amides. Most of the tertiary amides showed greater cytotoxicity towards five representative melanoma cell lines than the parent secondary amide. The highest cytotoxicity, comparable to cisplatin, was observed for the benzyl substituted compounds 4, 8, 12, and 16 and the cyclohexylacetamide derivatives 13-15 against these five cell lines. The moderate activity of 13-16 against SK-Mel-24 (non-tyrosinase containing) and an ovarian cell line suggests that interference with the melanin pathway may not be the only mode of action of these new compounds.