4,4',6-Trimethylangelicin, a new very photoreactive and non skin-phototoxic monofunctional furocoumarin.
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Animals↗
Biomedical subjects
D Vedaldi
Publications and source records attributed to D Vedaldi.
Photophysical, photochemical and photobiological studies of 4'-methylangelicins, potential agents for photochemotherapy.
In order to study the relationship between certain photophysical and photochemical properties of furocoumarins and their photobiological activities, the quantum yields of the formation of excited triplet states, the capacity to generate singlet oxygen in vitro and the effect of oxygen on photoinduced cell killing and on the induction of cytoplasmic "petite" mutations in Saccharomyces cerevisiae were determined for a series of 4'-methylangelicins and 3-carbethoxypsoralen (3-CPs). The capacity to generate singlet oxygen, in good agreement with the photophysical data, correlates well with the oxygen effect observed on the lethality of Saccharomyces cerevisiae shown by the various compounds and followed the ranking order 3-CPs greater than 4',4-dimethylangelicin greater than 4'-methylangelicin greater than 4',5-dimethylangelicin. On the other hand the oxygen effect on the induction of cytoplasmic "petite" mutations on yeast appears much less pronounced than that shown on survival. Concerning other photobiological properties previously studied no correlation was observed between the capacity to generate singlet oxygen in vitro and the skin photosensitizing activity of the compounds. Moreover, the generation of singlet oxygen by furocoumarins does not appear as the main cause for the photoinduction of skin tumors in mice.
Chemical Phenomena↗
Bis-pyridoquinolines as new bifunctional intercalators for DNA.
With the aim of obtaining new bifunctional intercalators for DNA, a new series of bis-pyridoquinolines were synthesized by joining two tricyclic planar moieties through a flexible chain. For preparing the corresponding potential monofunctional intercalators also a series of mono-pyridoquinolines were prepared by chemical synthesis by joining the same chromophore with a flexible side-chain. The melting profiles of the complexes between two bis-pyridoquinolines and DNA showed two different thermal transitions supporting the bis-intercalation of the ligand with the macromolecule. On the other hand, two mono-pyridoquinolines showed only one transition in the melting profile indicating a behaviour consistent with a mono-intercalation. The antiproliferative activity was tested in terms of DNA synthesis inhibition in Ehrlich ascite tumor cells; the examined bis-intercalating agent showed to be much more active than the tested mono-intercalating compound.
Aminoquinolines↗
Molecular conformation of N,N-dimethyl-4-amino-3-chloroangelicin C13H10O3NCl.
The title compound was characterized by X-ray diffraction analysis. The crystals belong to the triclinic system, space group P1, with four molecules in the unit cell having a = 16.344(5), b = 10.343(3), c = 7.283(2) A, alpha = 109.1(1), beta = 90.2(1), gamma = 94.2(1), dc = 1.51 Mgm-3. The structure was determined from 1945 intensity data with I greater than or equal to 3 sigma (I) collected on a Philips PW 1100 diffractometer and refined by full matrix least-squares to the final R values R = 0.046 and Rw = 0.046. The molecular conformation is close to that of angelicin, the additional methyl groups being sandwiched with respect to the molecular plane, in order to minimize their steric hindrance. The possible intercalation of the title compound inside DNA has been considered.
Chemical Phenomena↗
Chemical basis of the photosensitizing activity of angelicins.
Angelicins are a group of compounds that show marked photobiologic activity on various substrates; some of them have been proposed as potential agents for the photochemotherapy of skin diseases. A good correlation exists between the photosensitizing activity of these compounds and their capacity to induce monofunctional lesions to DNA; therefore, we believe the chemical nature of these photolesions, we isolated from the products of hydrolysis of the photocombinations between 5 angelicins (angelicin, 4-methyl, 5-methyl, 5'-methyl, and 5,5'-dimethylangelicin) and DNA, the corresponding new fluorescent monoadducts between the 4',5'-double bond of the furocoumarins and the 5,6-double bond of thymine.
Animals↗
4'-Methylangelicins: new potential agents for the photochemotherapy of psoriasis.
Three derivatives of angelicin (1) [4'-methyl-, 4,4'-dimethyl-, and 4',5-dimethylangelicin (2a-c)] have been prepared with the aim of obtaining new agents for the photochemotherapy of psoriasis. These compounds form a complex in the dark with DNA that shows an affinity for the macromolecule higher than that of the parent angelicin (1). A correlation between their octanol/water partition coefficients and the association constants of the complexes has been observed. Compounds 2a-c photobind to DNA to a much higher extent than 1 and also more effectively than 8-methoxypsoralen (8-MOP), taken as reference compound. When activated with UV-A, the three compounds strongly inactivate T2 phage and inhibit epidermal DNA synthesis in mice. Moreover, they show a mutagenic activity markedly lower than that of 8-methoxypsoralen on Escherichia coli wild-type strain. Due to its lack of skin phototoxicity, its low mutagenic activity, and its antiproliferative activity, 2c was chosen for clinical evaluation. It proved to be effective in clearing psoriasis in two patients.
Animals↗
7-Methyl and 4,7-dimethylallopsoralen: monofunctional photoreagents toward DNA as potential photochemotherapeutic agents in hyperproliferative conditions.
7-Methyl- (1 a) and 4,7-dimethylallopsoralen (1 b), prepared about ten years ago and till now considered non-photosensitizing agents, have been re-investigated for studying their photochemical and photobiological properties. They form a molecular complex with DNA in the ground state, undergoing intercalation between two base pairs of the macromolecule. By successive irradiation with U.V.-A they covalently photobind to DNA inducing only the formation of mono-adducts. They are not able to induce erythema on guinea pig skin, but show evident antiproliferative activity on various biological substrates. Compound (1 b) shows both photochemical and photobiological properties at a degree higher than that of compound (1 a).
Animals↗
Sequence specificity in DNA for the interaction with adriamycin or daunomycin.
The interactions of adriamycin and daunomycin with various polydeoxyribonucleotides and some natural DNAs having different base pairs composition were studied by means of fluorimetric titrations. The quenching of the fluorescence occurring in the drugs complexed with polynucleotides and DNA is more efficiently induced by the C-G rich regions than by the A-T rich ones. By contrast, the affinity of the drugs for polynucleotides and DNAs in forming the molecular intercalated complexes is correlated mainly with the sequence of purines and pyrimidines in each strand of the duplex polymers, fairly independently of their nature. The regions having an alternate sequence of purines and pyrimidines in each strand are much more preferred than the regions having a continuous sequence; among the various alternate sequences, those having the structure of poly d(A-T) X poly d(A-T) appear to be a little more preferred than the others.
Base Sequence↗
Receptor sites in DNA for the dark and photochemical interactions with 4,5'-dimethylangelicin, a potential agent for the photochemotherapy.
The study of the interactions in the ground state between 4,5'-dimethylangelicin, an angular furocoumarin, and various synthetic and natural DNA samples have evidenced the presence in the macromolecule of preferred sequences suitable for binding the small ligand. They are represented by an alternate sequence of purine and pyrimidine bases in each strand of the macromolecule, without difference between the two base pairs A-T and C-G. The study of the photochemical interactions between the same DNA samples and the 4,5'-dimethylangelicin shows that preferred sites are present in the macromolecule for the covalent addition of the furocoumarin to the macromolecule too. These sites however have more strict requirements than those useful for dark binding; they are in fact represented by alternate sequences of A-T in each strand such as those present in poly [d(A-T)] . poly-[d(A-T)]. Moreover fluorescence studies made on the same DNA samples irradiated in the presence of the furocoumarin suggest that the alternate C-G regions favour formation of 4'-5'-fluorescent adducts.
Base Composition↗
New monofunctional reagents for DNA as possible agents for the photochemotherapy of psoriasis: derivatives of 4,5'-dimethylangelicin.
With the aim of obtaining new agents for the photochemotherapy of psoriasis, we have prepared monofunctional reagents for DNA by starting from 4,5'-dimethylangelicin (2), an angular furocoumarin, and introducing in a 4'-(hydroxymethyl) (3), 4'-(methoxymethyl) (4), or 4'-(aminomethyl) group (5), in way analogous to what other authors have done previously on trioxsalen, a DNA bifunctional reagent. These new compounds form complexes with DNA in the ground state and by successive irradiation (UV-A) undergo monofunctional photoaddition to the macromolecule. Photobinding to DNA was highest for 3 and gradually lower for 4 and 5, respectively. These compounds do not form interstrand photocross-linkages in DNA and do not show any skin phototoxicity. Fluorimetric studies show that their 4',5' double bond is involved in the photoaddition to DNA. Their photobiological activity evaluated on Ehrlich ascites tumor cells and on T2 phages was strictly connected with their photobinding to DNA. The effect of the introduction of hydroxymethyl and methoxymethyl groups in angular 2 is somewhat similar to that previously described for trioxsalen: the introduction of an aminomethyl group in 2 markedly increases the affinity in the dark for DNA but under UV-A irradiation strongly inhibits photobinding to the macromolecule. By contrast, in the analogous derivative of trioxsalen both the affinity for DNA in the dark and the photobinding to DNA increased.
Animals↗
Methylangelicins: new potential agents for the photochemotherapy of psoriasis. Structure-activity study on the dark and photochemical interactions with DNA.
The interactions both in the ground and in the excited state between various methylangelicins, previously prepared with the aim to increase the low photobiological activity of the parent angelicin 1, and DNA have been studied. In general, the new methylangelicins show an increased capacity to photobind monofunctionally to DNA and a parallel increment of photobiological activity in comparison with the parent 1. This increase appears to be connected with various factors, such as the augmented affinity toward DNA for the dark complex formation and the electronic effect connected with the introduction into 1 of one or two methyl groups. The new compounds, on the basis of their photobiological activity and their lack of skin phototoxicity, appear as possible agents for the photochemistry of skin diseases characterized by cell hyperproliferation.
Chemical Phenomena↗
Pre-clinical evaluation of new antiproliferative agents for the photochemotherapy of psoriasis: angelicin derivatives.
To have, before the clinical evaluation, sufficiently predictive information about the antiproliferative and phototoxic effect of new potential agents for the photochemotherapy of psoriasis some simple tests have been worked out. The antiproliferative activity was evaluated studying the inhibition of DNA synthesis first in Ehrlich ascites tumor cells, and then in mouse skin in vivo, both by topical application and oral administration. The phototoxicity was studied by topical application on guinea-pig skin, and for the most interesting compounds also in man. A group of angelicin derivatives, which can photoreact with DNA forming only monofunctional adducts, was submitted to this evaluation; a number of such compounds proved to be very active, practically as active as psoralen and 8-methoxypsoralen (8-MOP), two bifunctional furocoumarins capable of inducing both monofunctional adducts and inter-strand cross-links in DNA. Methylangelicins having a marked lipophilic character were only a little more active in inhibiting the epidermal DNA synthesis of mouse when given orally in comparison with topical application, while angelicin derivatives carrying a polar group at the 4' position in the furanic ring were not very active by topical application, but much more effective after systemic administration. These results can be explained supposing a different ability of compounds to penetrate into mouse skin by topical application and the presence of some pharmacokinetic and metabolic factors. Contrary to bifunctional furocoumarins, the angelicin derivatives studied proved to be non-phototoxic on the skin of guinea-pig and also on that of man.
Animals↗
Photochemotherapy of skin-diseases: comparative studies on the photochemical and photobiological properties of various mono- and bifunctional agents.
The antiproliferative activity of the classic photochemotherapeutic agents, that is bifunctional psoralens (8-methoxypsoralen, 8-MOP; 5-methoxypsoralen, 5-MOP; 4,5',8-trimethylpsoralen, TMP) as well as of those more recently proposed, that is, monofunctional furocoumarins (methylangelicins and 3-carbethoxypsoralen, 3-CPs) is ascribed to their capacity to photo-induce lesions in DNA. In this connection while bifunctional agents photo-induce both mono- and bifunctional (inter-strand cross-linkages) damages in the macromolecule both in vitro and in vivo, monofunctional furocoumarins photodamage DNA only through monofunctional lesions. To have a direct and precise comparison between the classic agents (8-MOP, 5-MOP, TMP) and those recently proposed (4,5'-dimethylangelicin, 4,5'-DMA; 3-CPs), we have made a comparative study of the capacity of the various compounds to form the dark complex with DNA as well as of their capacity to induce mono- and bifunctional damages in the macromolecule. A comparative study on the antiproliferative activity in terms of capacity to inhibit DNA and RNA synthesis in Ehrlich ascites tumor cells as well as of the capacity to inhibit epidermal DNA synthesis in mice is also reported. The emerging picture can give a precise comparison in terms of both photobinding to DNA, as well as antiproliferative and skin-phototoxic activities between the classic agents 8-MOP, 5-MOP, TMP and the new monofunctional agents 4,5'-DMA and 3-CPs.
Chemical Phenomena↗
A new water soluble derivative of 4,5'-dimethylangelicin as a potential agent for photochemotherapy.
A water soluble derivative of 4,5'-dimethylangelicin (I) having a long chain linking an amino group to the planar furocoumarinic moiety, that is 4'-N,N-dimethylaminoethoxymethyl-4,5'-dimethylangelicin (III), has been prepared. This compound is able to form effectively the intercalated complex with DNA like the previously prepared 4'-aminomethyl-4,5'-dimethylangelicin (II), however while the compound (II) showed very poor photobinding to DNA, the new derivative (III) shows high photobinding to the macromolecule. It is proposed that these data illustrate the importance of the geometry of intercalation for the subsequent covalent photobinding to the macromolecule. Also some photophysical data of (II) and of (III) appear to confirm the critical role of the position assumed by the chromophore of the two compounds when intercalated in duplex DNA. The compound (III) displays high photobiological effects, also in terms of antiproliferative activity as shown by its capacity to inhibit DNA and RNA synthesis in Ehrlich cells, the growth of an E. coli culture and the infectivity of T2 phage. (III) on the basis of these properties seems to deserve a clinical evaluation of its potential photochemotherapeutic activity in the treatment of psoriasis.
Animals↗
Photoreaction between 4,7-dimethylallopsoralen and DNA: isolation of a fluorescent cycloadduct between the furocoumarin and thymine.
A new fluorescent adduct has been isolated from the products of hydrolysis of DNA irradiated in the presence of 4,7-dimethylallopsoralen. The close similarity of the U.V. absorption spectrum of this compound to that of a synthetic 4',5'-dihydroallopsoralen shows that the 4',5'- double bond initially present in the 4,7-dimethylallopsoralen was saturated in the photoreaction with DNA, and this is consistent with a C4 cycloaddition at this level. The irradiation of the photoadduct at 254 nm provoked its photodissociation into the parent compounds, that is, thymine and 4,7-dimethylallopsoralen. These data are consistent with a cycloadduct between the 4',5'- double bond of 4,7-dimethnylallopsoralen and the 5,6- double bond of thymine.
Chemical Phenomena↗
Photochemical and photobiological properties of 4,5'-dimethylpsoralen, a bifunctional contaminant of synthetic 4,5'-dimethylangelicin.
4,5'-Dimethylpsoralen, a bifunctional furocoumarin, can be formed as an impurity in the synthesis of its angular isomer, that is 4,5'-dimethylangelicin; the latter has recently been proposed as a potential monofunctional agent for photochemotherapy. To have precise information on the possible modifications of the photochemical and photobiological properties of synthetic 4,5'-dimethylangelicin caused by the presence of its linear isomer, we have studied the interactions of the latter with DNA in both the ground and the excited state and its photobiological activity. 4,5'-Dimethylpsoralen photobinds much more effectively to DNA than its angular isomer and is capable to form effectively inter-strand cross-linkages in DNA while dimethylangelicin is unable to form these bifunctional adducts in DNA. Dimethylpsoralen shows a strong skin-phototoxicity while angelicin lacks this activity. Moreover the antiproliferative activity of the psoralen derivative in terms of DNA synthesis inhibition in Ehrlich cells and of inhibition of infectivity of T2 phages, is about four times higher than that of the angular isomer. These data stress the necessity of the absence of the isomeric linear furocoumarin in the synthetic 4,5'-dimethylangelicin because its presence can markedly modify the photobiological and phototherapeutic properties of the angelicin derivative.
Animals↗
Studies on the interaction between steffimycins and DNA.
The complexes formed between steffimycins and DNA were studied using various physicochemical techniques. The binding process has been followed spectrophotometrically or fluorimetrically. The binding parameters n and K, evaluated according to McGhee and Von Hippel, show a good affinity of these antibiotics for the macromolecule. Flow dichroism measurements showed that in the complex with DNA, the antracycline moiety of the steffimycins is intercalated between two base pairs of the macromolecule. The binding experiments with various polydeoxyribonucleotides and with various DNA samples, having different base pair compositions, suggest that an alternate sequence of A-T, such as that of poly[d(A-T)] . poly[d(A-T)], represents a good receptor site for the binding of steffimycins to DNA. The lack of in vivo activity of these antibiotics is discussed.
Anthracyclines↗
New studies on the interaction between 8-methoxypsoralen and DNA in vitro.
Some aspects of the interactions between DNA and 8-methoxypsoralen (8-MOP) in its ground state (complex formation) or in its excited state (photobinding) have been investigated. 8-MOP shows a low affinity towards DNA in the complex formation; this fact minimizes the possible biological consequences deriving from this interaction, when it occurs in vivo. In covalent photobinding to DNA, 8-MOP forms mainly monofunctional adducts, and to a lesser extent bifunctional adducts, showing a behavior similar to that of other linearly condensed furocoumarins (psoralens); the ratio between mono- and bifunctional adducts was found to be 9:1. The covalent photobinding to DNA does not occur at random along the macromolecule, but preferentially at the level of specific receptor sites. The regions having an alternate sequence of A-T seem to be the best receptor sites for the formation of monoadducts while the regions containing an alternate sequence of A-T and C-G appeared to be the preferential sites for the cross-linkage formation.
Base Sequence↗