RESUMEN
The development of therapies which are selective for tumor tissues is one of the most important goals in anticancer research. Within this framework photochemotherapy can be considered a very promising approach. Its therapeutic effectiveness depends on two connected factors: drug and light. The drug (photosensitizer) is able to exert an antiproliferative effect only after interaction with suitable light. Both the photosensitizing drug and light alone are ineffective at doses used for these treatments. Nowadays, photochemotherapy is used in the treatment of cutaneous T-cell lymphoma and cavitary tumors. In the first case the photosensitizer is a psoralen derivative (P) and long-wavelength ultraviolet radiation (UVA) is used (PUVA therapy). In the second case, the treatment with porphyrins, porphyrin-based and non porphyrin-based photosensitizers is followed by irradiation with 600-1000 nm light (photodynamic therapy, PDT). This review is concerned with PUVA and PDT treatments of cancer. The molecular mechanisms considered accountable for the photochemotherapeutic effects are discussed, the development of new chemical structures aimed at improving the effectiveness and/or overcoming some undesired side effects will also be reported. Moreover, some clinical applications will be described.
Asunto(s)
Neoplasias/tratamiento farmacológico , Fotoquimioterapia , Fármacos Fotosensibilizantes/uso terapéutico , HumanosRESUMEN
The synthesis of new tetrahydrobenzo- and benzopsoralen derivatives carrying at position 5 or 8 of the furocoumarin moiety a methoxy, hydroxy, or dimethylaminopropoxy side chain is reported. The study of their photoantiproliferative activity and ability to induce erythema on guinea pig skin allows us to state that the derivatives carrying the dimethylaminopropoxy side chain exhibit a very interesting photobiological pattern. Indeed, if compared with the lead compounds 5-MOP and 8-MOP, they exert a higher cytotoxic activity devoid of significant skin phototoxicity. Between them, the more interesting appears to be 16, a nonphototoxic compound whose antiproliferative activity on HeLa cells is 2 orders of magnitude higher than that of the reference drug 8-MOP. Photoreaction experiments have revealed that, like classic furocoumarins, A-T is the preferred nucleic base pair in its photobinding. Moreover, the extent of covalent photoaddition to DNA correlates well with the photobiological activity. For this compound a certain effect was also observed in the dark. Evaluation of the ability to induce DNA cleavage in the presence of human topoisomerase II has suggested that this enzyme is probably the target accountable for this effect.
Asunto(s)
Antineoplásicos/síntesis química , Cumarinas/síntesis química , ADN/química , Metoxaleno/análogos & derivados , Metoxaleno/síntesis química , 5-Metoxipsoraleno , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Cumarinas/química , Cumarinas/farmacología , ADN/efectos de la radiación , ADN-Topoisomerasas de Tipo II/química , Ensayos de Selección de Medicamentos Antitumorales , Cobayas , Humanos , Metoxaleno/química , Metoxaleno/farmacología , Fotoquimioterapia , Piel/efectos de los fármacos , Piel/efectos de la radiación , Células Tumorales Cultivadas , Rayos UltravioletaRESUMEN
Two isomeric psoralen derivatives (I and II in Fig. 1) bearing charged side chains, have been tested for activity against Herpes Simplex Virus type 1 (HSV-1) in the absence of u.v. irradiation. Striking differences have been observed both in antiviral and cytotoxic activity for the examined compounds, I being appreciably more effective. Metabolic and biochemical studies, as well as physico-chemical measurements indicate DNA as the major target. The different biological behaviour can be fully explained in terms of a modified affinity of the drugs toward DNA. The molecular basis for these findings probably stems from slightly different intercalation geometries, as shown by chiroptical studies. Comparable binding affinities for viral and cellular DNA fully account for lack of selective toxicity found in vivo. The present approach is proposed as a tool for the investigation of structure-function relationships in drug models.
Asunto(s)
Antivirales/farmacología , Furocumarinas/farmacología , Animales , Línea Celular , ADN/biosíntesis , ADN/metabolismo , Furocumarinas/metabolismo , Humanos , Conformación Molecular , Simplexvirus/efectos de los fármacos , Relación Estructura-Actividad , Tritio , Proteínas Virales/biosíntesisRESUMEN
The synthesis and the photobiological activity of two new derivatives of psoralen (3,4'-dimethylpsoralen and 3,4',8-trimethylpsoralen) has been described. They are congeners of the monofunctional linear furocoumarin 3,4'-dimethyl-8-methoxypsoralen. Both compounds bind very efficiently to DNA, the extent of this process being modulated by the nature of substituents at position 8. The number of photolesions is linearly related to adenine-thymine content of the nucleic acid which indicates lack of specificity for particular sequences of the nucleic acid. The structural arrangement of DNA (single stranded, double stranded, nucleosomes and chromatin) plays an additional role in affecting the photobinding process. Unlike their 8-methoxy congener the new derivatives cross-link DNA to a substantial extent. Their photobiological properties, including erythema formation, reflect very closely those of 8-methoxypsoralen (8-MOP). The conclusion can be drawn that 3,4'-dimethyl-8-MOP represents a unique derivative in its family.
Asunto(s)
Carcinoma de Ehrlich/metabolismo , Replicación del ADN/efectos de los fármacos , ADN/metabolismo , Furocumarinas/síntesis química , Fármacos Sensibilizantes a Radiaciones/síntesis química , Piel/efectos de los fármacos , Rayos Ultravioleta , Animales , Relación Dosis-Respuesta en la Radiación , Furocumarinas/metabolismo , Furocumarinas/farmacología , Cobayas , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Metoxaleno/farmacología , Ratones , Ratones Endogámicos , Conformación Molecular , Fármacos Sensibilizantes a Radiaciones/metabolismo , Fármacos Sensibilizantes a Radiaciones/farmacología , Piel/efectos de la radiaciónAsunto(s)
ADN , Furocumarinas/efectos de la radiación , Rayos Ultravioleta , Animales , Bovinos , Relación Estructura-Actividad , TimoRESUMEN
The interaction of two water-soluble furocoumarins, 8-(omega-diethyl aminopropyloxy)psoralen hydrochloride (I) and its 5-isomer (II), with DNA has been investigated by spectroscopic, equilibrium dialysis, hydrodynamic and chiroptical techniques. Both compounds intercalate into the polynucleotide double helix. From the dependence of the binding on ionic strength, ion release and binding free energy corrected for counterion release have been quantitatively estimated. It is shown that the differences in DNA-affinity observed for compounds I and II arise primarily from non electrostatic contributions. The binding process is exothermic, with slightly different van't Hoff enthalpies for the examined furocoumarins. Helix lengthening and dichroic effects indicate different intercalation geometries for the isomeric compounds. These studies allow a possible explanation for the finding that isomer I exhibits largely better DNA-photobinding properties, while isomer II is by far more effective as an antiviral agent.
Asunto(s)
ADN , Furocumarinas , Animales , Bovinos , Cinética , Conformación de Ácido Nucleico , Solubilidad , Termodinámica , TimoRESUMEN
Photobinding to DNA and cross-linking formation in vitro, as well as the skin photosensitizing activity on guinea pigs of two water-soluble derivatives of psoralen (5 and 8-diethylaminopropyloxypsoralen hydrochloride) have been studied. For purposes of comparison, the results have been correlated with those obtained, in the same experimental conditions, with 5- and 8-methoxypsoralen. The water-soluble 8-derivative showed an increased photoaddition to DNA and cross-linking formation, when compared with 8-methoxy-derivative; on the contrary, the water-soluble 5-derivative was less photoreactive than the corresponding 5-methoxy-derivative. The skin photosensitizing potency of 8-diethylaminopropyloxypsoralen (the more interesting of the two compounds) appears weaker than that of 8-methoxypsoralen after topical application, but higher after oral ingestion or subcutaneous injection.
Asunto(s)
Furocumarinas/farmacología , Animales , ADN/metabolismo , Furocumarinas/metabolismo , Furocumarinas/toxicidad , Cobayas , Trastornos por Fotosensibilidad/inducido químicamente , Piel/efectos de los fármacosRESUMEN
3-Amino- and 3-oxy-derivatives of psoralen, thus having electron-donating groups at the 3-position of the alpha-pyronic ring, were prepared and studied as regards their capacities of interaction and photoreaction with native DNA in vitro. Very interesting properties were shown especially by the 3-amino-derivatives, namely 3-amino-4'-methylpsoralen and 3-diethylaminoacetylamido-4'-methylpsoralen, having a very high photobinding capacity with DNA and behaving as pure, or fairly pure, monofunctional reagents. These properties appear to be quite suitable for the therapeutic treatment of psoriasis and other skin diseases characterized by an increased reproducing activity of epidermal cells.
Asunto(s)
ADN/metabolismo , Furocumarinas/síntesis química , Fenómenos Químicos , Química Física , ADN/efectos de la radiación , Diálisis , Furocumarinas/farmacología , Fotoquímica , Solubilidad , Espectrofotometría UltravioletaRESUMEN
The dark and photochemical interactions with DNA in vitro as well as the photobiological properties of two psoralen derivatives having a carbomethoxy-group inserted in 3 or 5' position of the furocoumarin nucleus were studied. 3-Carbomethoxy-4',8-dimethylpsoralen photoreacts with DNA in vitro to a very small extent and, as a consequence, it appears to be photobiologically ineffective. On the contrary, 5'-carbomethoxy-4,8-dimethylpsoralen appears very interesting, showing a photobinding and cross-linking capacity with DNA in vitro higher than that of 8-MOP. A similarly higher photobiological activity was also demonstrated, with respect to this reference compound, in experiments on inhibition of DNA and RNA synthesis in Ehrlich ascites tumor cells, and on the killing of bacteria and of T2 bacteriophage. Finally, this compound inhibited the tumor transmitting capacity of Ehrlich ascites tumor cells.
Asunto(s)
ADN/metabolismo , Furocumarinas/síntesis química , Animales , Antineoplásicos , Bacterias/efectos de los fármacos , Carcinoma de Ehrlich/tratamiento farmacológico , Fenómenos Químicos , Química , Furocumarinas/metabolismo , Furocumarinas/farmacología , Ratones , Fotoquímica , Fagos T/efectos de los fármacosRESUMEN
In an effort to establish a relationship between mechanism of binding and affinity to DNA, cytotoxic activity, and genotoxic activity, we have studied four new anthracenedione derivatives bearing charged side chain groups at various positions of the polycyclic aromatic system. Cytotoxicity, genotoxicity, and thermodynamic DNA binding parameters were shown to be directly related, indicating the polynucleotide as an important target for drug action, rather than a minor, subterminal interacting site. This finding was further supported by the observation of extensive anthraquinone accumulation occurring in the nuclear compartment. The relative binding affinities of the drugs are discussed in terms of nature and position of side-chain substituents. Different binding modes were found: three compounds intercalate into the nucleic acid double helix, and one interacts with the exterior of the macromolecule. The biological results suggest that the mode of complex formation plays a less relevant role than DNA binding efficiency.
Asunto(s)
Antraquinonas/farmacología , Antineoplásicos/farmacología , ADN/metabolismo , Animales , Antraquinonas/metabolismo , Línea Celular , Dicroismo Circular , Electroforesis , Fluorescencia , Humanos , Ratones , Espectrofotometría , Relación Estructura-Actividad , TermodinámicaRESUMEN
The activity of four tilorone analogous compounds against three different strains of E. coli bacteriophages T1, T2 and phiX-174, was studied. Among the compounds we tested, only a fluorene derivative (2,7-bis-2-[2-(diethylamino)acetyl]fluorene) yielded a high inhibition of phage growth, to a greater extent with respect to tilorone, used as a reference compound. This activity, not due to a toxic effect on the host bacteria, did not appear connected with a complex formation between the drug and DNA. In fact, among the studied compounds, this is not the one showing the highest binding parameters with DNA; in addition, when the mature virions were incubated in the presence of the drug and then diluted and assayed for their plaque-forming capacity, this drug turned out to be practically ineffective. Fluorene derivative appears to be an antiviral drug acting on an unidentified metabolic process of phage growth, and therefore it is a model for new antiviral drugs showing a selective activity.
Asunto(s)
Antivirales , Fluorenos/farmacología , Tilorona/farmacología , Bacteriófago phi X 174/efectos de los fármacos , Colifagos/efectos de los fármacos , Fagos T/efectos de los fármacos , Tilorona/análogos & derivadosRESUMEN
The in vitro formation and properties of the molecular complex between mitomycin C and native DNA were examined by means of various experimental methods; the data obtained indicate that the complex is extremely weak and that the chromophoric moiety of the antibiotic is not involved in its formation. The alkylating activity of mitomycin C was also studied using 3H-mitomycin C; while monofunctional alkylation increases almost in parallel with the concentration of the antibiotic, the difunctional alkylation, causing inter-strand cross-linkages in DNA, rapidly reaches a maximum and then remains constant even when increasing the concentration of the antibiotic and monofunctional alkylation. On the basis of these results, the currently accepted molecular model of the mitomycin--DNA interaction must be revised; a new model of this interaction is presented, which is in better agreement with the properties of mitomycin C and with the latest findings on the subject.
Asunto(s)
ADN/metabolismo , Mitomicinas/metabolismo , Alquilación , Fenómenos Químicos , Química Física , Cromatografía en Gel , Dicroismo Circular , Diálisis , Espectrofotometría UltravioletaRESUMEN
Four series of diethylaminoalkoxyderivatives of coumarin (at the positions 4 and 7) and furocoumarin (at the positions 5 and 8) have been prepared, in order to study their complexing capacity with DNA, these compounds having a double possibility of interaction, that is intercalation of the aromatic moiety between two base pairs and formation of an electrostatic bond between their terminal amino group and a phosphoric group of DNA. Some biological effects connected with the interaction with DNA have also been studied. The results obtained showed that coumarin derivatives have a low complexing capacity and lack any biological activity. The furocoumarin derivatives showed a markedly increased complexing capacity both in respect to the coumarin derivatives and to the parent furocoumarin (psoralen, as well as its 5- and 8-methoxy derivatives) and proved able to inhibit DNA and RNA synthesis in Ehrlich ascites tumor cells, as well as the growth of Staphylococcus aureus and of various strains of Escherichia coli. This activity was generally low but was constantly higher in 5-than in 8-derivatives, the same behavior being found with regard to the complexing capacity with DNA. A good correlation between the ability to form complexes with DNA and the capacity to inhibit cells growth was clearly evidenced.
Asunto(s)
Cumarinas/metabolismo , ADN/metabolismo , Furocumarinas/metabolismo , Animales , Carcinoma de Ehrlich/metabolismo , Bovinos , Diálisis , Escherichia coli/efectos de los fármacos , Sustancias Macromoleculares , Ratones , Espectrofotometría Ultravioleta , Análisis Espectral , Staphylococcus aureus/efectos de los fármacosRESUMEN
Four compounds having a molecular structure analogous to that of tilorone and tilorone itself, taken as a reference compound, were examined for complex formation ability with DNA. While the association constants of the various complexes were almost the same, the r values in saturation conditions (that is the highest number of molecules bound per nucleotide of DNA) increased with the size of the planar moiety or with the length of the two basic side chains of the molecules. Concerning the structure of the complexes, it was evidenced by means of flow dichroism measurements that the non-covalent binding to DNA occurs via an intercalative mode. Moreover, it was observed that by decreasing the ionic strength, the affinity of the drugs for the macromolecule increases, indicating that in complex formation, electrostatic forces exerted between the DNA phosphate residues and the positively charged nitrogen of the side chains of the drugs are involved. It seems also possible that, in this condition, and in the presence of high concentrations of the drug, a secondary binding consisting only of electrostatic interactions outside of the helix takes place. In connection with the complexing ability with DNA, the examined compounds proved able to inhibit DNA and RNA synthesis in Ehrlich ascites tumor cells. A correlation was found between complexing ability and inhibitory activity on nucleic acid synthesis.
Asunto(s)
ADN , Fluorenos , Tilorona , Animales , Bovinos , Fenómenos Químicos , Química , Tilorona/análogos & derivadosRESUMEN
Four compounds derived from the furocoumarin, benzodipyrone and benzodifuran nucleus respectively, have been synthesized. They have molecular structures analogous to that of tilorone, namely an aromatic tricyclic moiety and two basic chains linked to the nucleus through ester or amido groups. Like tilorone, the new compounds efficiently from complexes with DNA, consisting in an intercalation of the planar aromatic moiety between two base pairs and an electrostatic interaction of the positively charged nitrogen atoms of the side chains with the phosphate groups of the macromolecule. When tested for their capacity to stimulate interferon production in mice, the compounds showed different activities; in particular the diethylamino ethyl ester of bis-benzodifuranic acid (III) proved to be twice as active as tilorone, assayed in the same experimental conditions for comparison purposes.