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1.
Ticks Tick Borne Dis ; 7(6): 1082-1088, 2016 10.
Article in English | MEDLINE | ID: mdl-27641952

ABSTRACT

In the framework of cooperation for development projects in Burkina Faso and Ethiopia, we collected ixodid ticks from cattle, small ruminants and camels. We optimized new TaqMan Probe real-time PCR assays to detect Rickettsia aeschlimannii and Rickettsia africae OmpA gene in the collected samples. Rickettsia africae was identified in 75.0% Amblyomma variegatum (95%CI: 56.6-88.5), while R. aeschlimannii in 24.0% Hyalomma truncatum (95%CI: 9.4-45.1) and 50.0% H. rufipes (95%CI: 29.9-70.0) collected from cattle in different provinces throughout Burkina Faso. Ticks from the Libaan zone, Somali Region of Ethiopia, were also infected by R. africae (28.5% prevalence in Amblyomma gemma, 95%CI: 14.7-46.0) and R. aeschlimannii (27.0% H. truncatum, 95%CI: 5.0-62.9; 88.3% H. rufipes, 95%CI: 60.5-99.3). All tested ticks were adults. The developed diagnostic tools were highly sensitive and enabled us to rapidly classify R. aeschlimannii and R. africae, which were identified in Burkina Faso and in the Somali Region of Ethiopia for the first time. Further studies are needed to assess the zoonotic risk and prevalence of infection in local human populations, who have high contact rates with ticks and their animal hosts.


Subject(s)
Ixodidae/microbiology , Real-Time Polymerase Chain Reaction/methods , Rickettsia/classification , Rickettsia/isolation & purification , Animals , Burkina Faso , Ethiopia , Phylogeny , Rickettsia/genetics
2.
Exp Appl Acarol ; 56(4): 391-401, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22349943

ABSTRACT

Between May 2006 and January 2007, blood samples and ticks were randomly collected from 220 nomadic animals from Filtu and Dollo Odo districts, Libaan zone, in the Somali Region of Ethiopia. Overall, 81.5% cattle, 98.2% camels, 53.4% goats and 61.1% sheep were infested by ixodid ticks. Collected ticks (n = 1,036) were identified as Rhipicephalus pulchellus (40.1%), R. pravus (25.8%), Amblyomma gemma (9.4%), Hyalomma rufipes (13.3%), H. truncatum (2.8%), H. impeltatum (1.2%) and H. dromedarii (0.5%); immature stages (6.1%) belonged to the genera Rhipicephalus and Amblyomma. Tick infestation burden was evaluated by the Tick Abundance Score method on 57 animals from Dollo Odo in August 2006, and it was significantly higher in cattle and camels than in small ruminants (p < 0.001). Reverse Line Blot Hybridisation was applied to detect Theileria, Babesia, Ehrlichia and Anaplasma spp. Five out of 50 blood samples from Filtu, four from cattle and, surprisingly, one from a camel, were positive for Theileria mutans and two from cattle for T. velifera. Adult ticks (n = 104) from both districts were tested and A. gemma from cattle were positive to T. velifera (1) and Ehrlichia ruminantium (5 samples). Positive E. ruminantium samples were also tested by PCR targeting pCS20 and 16S rRNA genes and submitted to DNA sequencing. The phylogenetic reconstruction of pCS20 fragment showed the presence of the Somali region sequences in the East-South African group. Our results are the first available on ticks and selected tick-borne diseases from the Somali region of Ethiopia and could be used as preliminary information for planning sustainable control strategies for tick and tick-borne pathogens in the study area and in neighbouring areas with similar socio-ecological features.


Subject(s)
Apicomplexa/isolation & purification , Ixodidae/parasitology , Livestock/parasitology , Tick Infestations/veterinary , Tick-Borne Diseases/veterinary , Animals , Apicomplexa/genetics , Base Sequence , DNA, Protozoan/chemistry , DNA, Protozoan/genetics , Ethiopia/epidemiology , Molecular Sequence Data , Phylogeny , Polymerase Chain Reaction/veterinary , RNA, Ribosomal, 16S/chemistry , RNA, Ribosomal, 16S/genetics , Rural Population , Sequence Alignment , Sequence Analysis, DNA , Tick Infestations/epidemiology , Tick Infestations/parasitology , Tick-Borne Diseases/epidemiology , Tick-Borne Diseases/parasitology
3.
J Photochem Photobiol B ; 56(2-3): 132-8, 2000 Jul.
Article in English | MEDLINE | ID: mdl-11079473

ABSTRACT

This paper reports the photobiological properties of two new thienocoumarins, 4,6,9-trimethyl-2H-thieno[3,2-g]-1-benzopyran-2-one (compound I) and the 6,9-dimethyl-4-methoxymethyl-2H-thieno[3,2-g]-1-benzopyran-2-one (compound II). Cell growth inhibition studies have revealed significant antiproliferative potency on human tumor cell lines. The photoaddition process of these tritium-labeled derivatives was investigated using various nucleic acid structures (calf thymus DNA, bacterial DNA, and synthetic polydeoxyribonucleotides). The results obtained show that both compounds photobind to DNA to a higher extent than 8-MOP, taken as the reference drug. The capacity to form interstrand crosslinks into DNA helix was also evaluated. Interestingly, notwithstanding the lack of cutaneous phototoxicity, II revealed a good ability to induce diadduct formation.


Subject(s)
Coumarins/chemistry , Coumarins/toxicity , DNA/chemistry , Photosensitizing Agents/chemistry , Photosensitizing Agents/toxicity , Polydeoxyribonucleotides/chemistry , Skin/drug effects , Thiophenes/chemistry , Thiophenes/toxicity , Animals , Cattle , Cell Division/drug effects , Cell Division/radiation effects , DNA/drug effects , DNA, Bacterial/chemistry , HL-60 Cells , Humans , Kinetics , Methoxsalen/toxicity , Skin/pathology , Skin/radiation effects , Tumor Cells, Cultured , Ultraviolet Rays
4.
Farmaco ; 54(3): 134-44, 1999 Mar 31.
Article in English | MEDLINE | ID: mdl-10371025

ABSTRACT

4,4',5'-Trimethyl-1'-thioangelicin (1) and 4,6,4',5'-tetramethyl-1'-thioangelicin (2), two newly synthesised isosters of furocoumarins having a sulfur atom in their five-membered ring, were studied in terms of interactions with DNA, both in the ground state and after UVA light absorption. The compounds were able to intercalate the macromolecule and to photobind efficiently, forming C4-cycloadducts with thymine. The antiproliferative effect of this binding was shown in Ehrlich and HeLa cells and by T2 phage inactivation. Tests on Salmonella typhimurium indicated low mutagenic activity. In particular, compound 1 has photobiological activity comparable with that of 4,6,4'-trimethylangelicin, but is less mutagenic.


Subject(s)
Coumarins/pharmacology , Furocoumarins/pharmacology , Mutagens/pharmacology , Photosensitizing Agents/pharmacology , Thiophenes/pharmacology , Cell Division/drug effects , Cell Division/radiation effects , Coumarins/chemical synthesis , Coumarins/radiation effects , Cross-Linking Reagents , DNA/drug effects , DNA Adducts , Furocoumarins/chemical synthesis , Furocoumarins/radiation effects , HeLa Cells , Humans , Mass Spectrometry , Molecular Structure , Mutagenesis/drug effects , Mutagenesis/radiation effects , Mutagens/chemical synthesis , Mutagens/radiation effects , Myoviridae/drug effects , Myoviridae/genetics , Myoviridae/radiation effects , Photobiology , Photochemistry , Photolysis , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/radiation effects , Reactive Oxygen Species , Salmonella typhimurium/drug effects , Salmonella typhimurium/genetics , Salmonella typhimurium/radiation effects , Thiophenes/chemical synthesis , Thiophenes/radiation effects
5.
Photochem Photobiol ; 68(2): 157-63, 1998 Aug.
Article in English | MEDLINE | ID: mdl-9723209

ABSTRACT

Some photobiological properties of 1'-thieno-4,6,4'-trimethylangelicin (TTMA), a new isoster of 4,6,4'-trimethylangelicin (TMA) were studied in comparison with the parent compound. The TTMA absorbs UVA light and photobinds in vitro to DNA more efficiently than TMA; however, in Ehrlich cells in vivo TTMA linked to DNA to a lesser extent than the parent compound. In general, the formation of damage into DNA is in line with this last result: In fact, TTMA and TMA form equivalent amounts of interstrand cross-links (ISC) both in vitro in linearized PM2 DNA and in vivo in HeLa cells. In this system TTMA induces DNA-protein cross-links (DPC) more efficiently than TMA; on the contrary, no significant amounts of single-strand breaks were detected with both compounds. The antiproliferative activity of TTMA is consistent with these results, being only slightly more pronounced than that of TMA. Experiments carried out using double irradiation demonstrated that these drugs are capable of inducing antiproliferative effects by biphotonic reactions, including the formation of both ISC and DPC. Thus, replacement of the oxygen atom by a sulfur increases the UV absorption of the drug and its capacity to photobind to DNA in vitro but does not yield a comparable enhancement of its photosensitizing properties in vivo; this might be due to various reasons, for instance to an increase in the lipophilic character that could modify the behavior in vivo.


Subject(s)
Furocoumarins/pharmacology , Photosensitizing Agents/pharmacology , Animals , Carcinoma, Ehrlich Tumor/drug therapy , Cell Division/drug effects , DNA Damage , HeLa Cells , Humans , Mice , Photochemotherapy , Tumor Cells, Cultured
6.
Farmaco ; 53(5): 313-9, 1998 May 30.
Article in English | MEDLINE | ID: mdl-9679280

ABSTRACT

This paper reports the synthesis of 4-methoxymethyl and 4-acetoxymethyl-6,9-dimethyl-2H-thieno[3,2-g]-1-benzopyran-2-one as well as 4-methoxymethyl- and 4-acetoxymethyl-6,9-dimethyl-2H-thieno[2,3-h]-1- benzopyran-2-one. The synthesized derivatives were tested on human cells in UVA irradiation conditions. Skin phototoxicity and cross-link formation in DNA were also studied. Results indicate that the new thienocoumarins have good antiproliferative activity, greater than that of the well-known photochemotherapeutic drug 8-methoxypsoralen, but they are practically devoid of skin photosensitization effects.


Subject(s)
Antineoplastic Agents/chemical synthesis , Coumarins/chemical synthesis , Photochemotherapy , Animals , Coumarins/pharmacology , Coumarins/toxicity , Dermatitis, Phototoxic/etiology , Guinea Pigs , HeLa Cells , Humans , Structure-Activity Relationship
7.
Farmaco ; 52(1): 7-12, 1997 Jan.
Article in English | MEDLINE | ID: mdl-9181674

ABSTRACT

The synthesis of 2H-benzopyrano[7,8-b][1,4]tetrahydrobenzodioxin-2-ones and 2H-benzopyrano [7,8-b][1,4]benzodioxin-2-ones is reported. This class of compounds, prepared with the aim of obtaining new monofunctional photosensitizing drug, appears to be ineffective upon UVA irradiation but shows a moderate but significant activity in the dark.


Subject(s)
Antineoplastic Agents/chemical synthesis , Benzopyrans/chemical synthesis , Dioxins/chemical synthesis , Photosensitizing Agents/chemical synthesis , Animals , Antineoplastic Agents/pharmacology , Benzopyrans/pharmacology , Carcinoma, Ehrlich Tumor/drug therapy , DNA, Neoplasm/biosynthesis , Dioxins/pharmacology , HeLa Cells , Humans , Photosensitizing Agents/pharmacology , T-Phages/drug effects , Tumor Cells, Cultured , Ultraviolet Rays
8.
J Photochem Photobiol B ; 34(2-3): 159-68, 1996 Jul.
Article in English | MEDLINE | ID: mdl-8810533

ABSTRACT

1,4,6,8-tetramethyl-2H-furo[2,3-h]quinolin-2-one (FQ) is a new isoster of angelicin characterised by an extremely strong photosensitizing activity, which is several times higher than that of 8-MOP and 4,6,4'-trimethylangelicin (TMA). Following treatment with 1.2 microM FQ and a dose as low as 0.05 kJ m(-2) of UVA irradiation, survival (colony forming ability) of HeLa cells was abolished, while TMA and 8-MOP (even at five times the concentration for the latter) were practically ineffective. Upon UVA irradiation FQ induces various types of lesions in mammalian cells in DNA: single-strand breaks (SSBs), many monoadducts and covalent DNA-protein cross-links (DPC), but not interstrand cross-links (ISC). Using the two step irradiation procedure, DPC induced by FQ appeared to be severe lesions, having a high antiproliferative activity; their formation requires the successive absorption of two photons, thus, in this respect, resembling ISC formation. In spite of its higher capacity for damaging DNA, FQ showed a skin-phototoxicity potency very similar to 8-MOP. As some benzopsoralens, FQ induced a certain antiproliferative activity also in the dark, which was accompanied by the formation of double-strand breaks into DNA associated with DPC. This lesion is generally induced by topoisomerase inhibitors. On the basis of these features, FQ can be expected to show useful activities in photochemotherapy and photopheresis. However, before medical use careful studies on its genotoxicity are required.


Subject(s)
Photosensitizing Agents/pharmacology , Quinolones/pharmacology , Animals , Carcinoma, Ehrlich Tumor , Cell Division , Cross-Linking Reagents , DNA/biosynthesis , DNA/drug effects , DNA/radiation effects , DNA Damage , Furocoumarins/chemistry , Furocoumarins/pharmacology , Guinea Pigs , HL-60 Cells , HeLa Cells , Humans , Methoxsalen/chemistry , Methoxsalen/pharmacology , Photochemistry , Photosensitizing Agents/chemistry , Quinolones/chemistry , Spectrophotometry , Ultraviolet Rays
9.
J Med Chem ; 39(6): 1293-302, 1996 Mar 15.
Article in English | MEDLINE | ID: mdl-8632436

ABSTRACT

With the aim of obtaining new potential photochemotherapeutic agents, having increased antiproliferative activity and decreased undesired effects, we have prepared some new furoquinolinones. Two of them have been studied in detail: 1,4,6,8-tetramethyl-2H-furo[2,3-h]-quinolin-2-one (8), and 4,6,8,9-tetramethyl-2H-furo[2,3-h]quinolin-2-one (10). These compounds form a molecular complex with DNA, undergoing intercalation inside the duplex macromolecule, as shown by linear flow dichroism. The complexed ligands, by subsequent irradiation with UV-A light, photobind with the macromolecule forming only monocycloadducts with thymine with cis-syn configuration. In order to evaluate the electronic effects induced by the nitrogen atom in position 1 of 8, semiempirical calculations have been performed on both 4,6,4'-trimethylangelicin (TMA) and 8. The results obtained do not clearly differentiate between the two molecules which, at this level of approximation, show the possibility of photoreaction with both the 3,4- and 8,9-olefinic bonds for 8 and the 3,4- and 4',5'-bonds for TMA. In the lower energy conformation of intercalated 8, the furan ring is turned toward the minor groove of the polynucleotide, in such a way that photoreaction of this ring with thymine is favored. These compounds unexpectedly inhibit DNA and RNA synthesis in Ehrlich cells, in the dark. They also show a strong photoantiproliferative activity, 2 orders of magnitude higher than 8-methoxypsoralen (8-MOP), the most used drug for photochemotherapy. Their mutagenic activity on Escherichia coli is similar to that of TMA and 8-MOP. On the basis of these results, the compounds should deserve evaluation of their activity in the treatment of hyperproliferative skin diseases.


Subject(s)
Furocoumarins/chemical synthesis , Photochemotherapy , Skin Diseases/drug therapy , DNA/metabolism , Furocoumarins/pharmacology , Furocoumarins/toxicity , Mutagens/toxicity , Myoviridae/drug effects , RNA/biosynthesis
10.
Farmaco ; 50(6): 479-88, 1995 Jun.
Article in English | MEDLINE | ID: mdl-7669186

ABSTRACT

Furocoumarins are a group of natural and synthetic compounds, some of which are used for the photochemotherapeutic treatment of certain skin diseases. With the aim of decreasing the side-effects of furocoumarin photochemotherapy and possibly increasing the therapeutic effects of these drugs, some new furocoumarin isosters were synthesized. The chemical synthesis of furocoumarin isosters at the furan ring, such as pyrrolo-, thieno-, oxazolo- and triazolocoumarins are reported. For all these compounds the key intermediate is a properly functionalized coumarin, to which the third heterocyclic ring is condensed by successive steps. Linear and angular pyrrolo-, tetrahydrobenzo- and benzopyrrolocoumarins show reduced photobiological activity, but have a strong antiproliferative effect in the dark, probably through an interaction with topoisomerases. Oxazolocoumarins are too unstable to be studied; triazolocoumarins show very poor activity. Tienocoumarins have not yet been studied. Furocoumarin isosters at the benzene ring are represented by 8-azapsoralens. Chemical synthesis involves the key 8-azacoumarin in the place of coumarin. These compounds have photochemical and photobiological properties which are very similar to those of psoralens. In particular, 4,4',5'- is effective in the photochemotherapeutic treatment of psoriasis. Furoquinolinones and 4-azapsoralens are reported among the isosters at the pyrone ring. While the synthesis of pyrroloquinolinones involves properly functionalized 7-aminoquinolinones as key intermediate, that of 4-azapsoralen requires a quite different synthetic pathway, involving a properly functionalized benzofuran derivative as key intermediate. Furoquinolinones have dramatically high activity both in the dark and under light activation; 4-azapsoralens have not yet been investigated.


Subject(s)
Cell Division/drug effects , Furocoumarins/chemical synthesis , Animals , DNA/biosynthesis , Depression, Chemical , Furocoumarins/chemistry , Furocoumarins/pharmacology , Humans , Skin/drug effects , Skin/metabolism
11.
Farmaco ; 50(2): 125-30, 1995 Feb.
Article in English | MEDLINE | ID: mdl-7766277

ABSTRACT

The synthesis and some biological properties of 4-hydroxymethyltetrahydro- and 4-hydroxymethylbenzopsoralen are reported. The two compounds exhibited activity in the dark and by UVA irradiation. The tetrahydrobenzo derivative was more effective than the corresponding aromatic compound. Benzopsoralens were more cytotoxic in malignant (HL60 and HeLa) cell lines than in normal ones (NCTC 2544). Their toxicity decreased in confluent cultures of NCTC 2544 cells.


Subject(s)
Furocoumarins/chemical synthesis , Furocoumarins/pharmacology , HeLa Cells , Humans , Structure-Activity Relationship , Tumor Cells, Cultured
12.
Mutat Res ; 311(2): 277-85, 1994 Dec 01.
Article in English | MEDLINE | ID: mdl-7526193

ABSTRACT

The ability of 4-hydroxymethyl-4',5'-benzopsoralen (HMBP) to damage DNA of Chinese hamster ovary cells (CHO) and to inhibit the activity of topoisomerase II in vitro has been studied. This compound is characterized by a fourth ring condensed at the furan-side in the psoralen molecule. Contrary to other known furocoumarin derivatives, HMBP induces chromosomal aberrations in mammalian cells without UVA activation. The lesions induced in the dark by HMBP in DNA were studied by alkaline and neutral elution in CHO cells; comparable amounts of single-strand breaks and DNA-protein cross-links as well as the formation of double-strand breaks were detected. Moreover, HMBP appeared to inhibit the activity of mammalian topoisomerase II in vitro, in both the catenation and the decatenation assay. In these experiments the drug was effective only when it was pre-incubated with DNA substrate. These results are also consistent with the cytotoxic and mutagenic activity of HMBP in the dark, as tested on V79 Chinese hamster cells (V79/HGPRT system).


Subject(s)
DNA Adducts , DNA Damage , Furocoumarins , Furocoumarins/toxicity , Mutagens/toxicity , Topoisomerase II Inhibitors , Animals , CHO Cells/drug effects , CHO Cells/enzymology , Cricetinae , Cricetulus , Cross-Linking Reagents , Darkness , Furocoumarins/chemistry , Mutagenicity Tests , Regression Analysis
13.
J Photochem Photobiol B ; 26(2): 197-201, 1994 Nov.
Article in English | MEDLINE | ID: mdl-7815193

ABSTRACT

4,6,4'-Trimethylangelicin, a well-known effective photosensitizer described as a pure monofunctional reactant with DNA, can induce interstrand cross-links in mammalian cell DNA in vivo (about 15% relative to 8-methoxypsoralen), as observed using alkaline elution and Chinese hamster ovary cells. Experiments performed using the two-step irradiation method and HeLa cells support these data. In contrast with 4,6,4'-trimethylangelicin, 4'-methylangelicin and 4,4'-dimethylangelicin do not form interstrand cross-links. These results are consistent with those recently reported by Chen et al. (X. Chen, J. Kagan, F. Dall'Acqua, D. Averbeck and E. Bisagni, J. Photochem. Photobiol. B: Biol, 22 (1994) 51-57) using pBR322 and M13 DNA. The cross-linking ability of 4,6,4'-trimethylangelicin does not seem to be related to a particular feature of these DNAs but to the compound itself.


Subject(s)
DNA/drug effects , Furocoumarins/pharmacology , Photosensitizing Agents/pharmacology , Ultraviolet Rays , Animals , CHO Cells , Cricetinae , DNA/radiation effects , Dose-Response Relationship, Radiation , HeLa Cells , Humans , Photochemotherapy
14.
Farmaco ; 49(10): 615-23, 1994 Oct.
Article in English | MEDLINE | ID: mdl-7826467

ABSTRACT

Pyrroloquinolinones, furocoumarin analogues, contain a divinilbenzene moiety, suggesting possible photoreactivity. Quantum mechanics calculations indicate that the pyrrole-side double bond exhibits strong photoreactivity, while the pyridone-side double bond is only poorly photoreactive. Intercalation models obtained by molecular mechanics calculations suggest that, in the cis-syn intercalation arrangement, the pyridone-side double bond is well aligned with the nearby thymine, supporting possible C4-cycloaddition with the 5,6 double bond of thymine, while the pyrrole-side double bond assumes an unfavourable position for photobinding. These data suggest that photoreaction between the pyridone-side and thymine double bonds may takes place, although with very low yield. Experimental evidence concerning DNA-photobinding exhibited by 2,6-dimethyl-9-methoxy-4H-pyrroloquinolinone (Compound I) confirms theoretical predictions. The formation of C4-cycloadducts between the pyridone side double bond and thymine also takes place with very low yield. Compound I shows marked BSA photobinding, suggesting that pyrroloquinolinones may photoreact with proteins. The three pyrroloquinolinones examined show high yields of singlet oxygen generation, suggesting that photobiological effects may be obtained through this photodynamic pathway, rather than through DNA photobinding.


Subject(s)
DNA/metabolism , Furocoumarins/metabolism , Photochemotherapy , Photosensitizing Agents/metabolism , Quinolones/metabolism , Base Sequence , Computers , Models, Molecular , Molecular Sequence Data , Serum Albumin, Bovine/metabolism
15.
Farmaco ; 49(10): 607-14, 1994 Oct.
Article in English | MEDLINE | ID: mdl-7530010

ABSTRACT

Searching new photochemotherapeutic agents, a series of methylpirroloquinolinones were prepared by a new synthetic pathway, thus univocally obtaining the title compounds. The photobiological activity of some of these compounds was assayed; upon UVA activation, a marked capacity of inhibiting macromolecular synthesis in Ehrlich cells was observed, which appeared to be markedly high testing protein synthesis. Pyrroloquinolinones induced a strong inhibition of the clonal growing capacity of HeLa cells cultivated in vitro. Studying DNA photodamage in HL60 cells high amounts of single strand breaks and DNA-protein cross-links were detected. Pyrroloquinolines inhibited T2 bacteriophage infectivity, but induced no significant amounts of revertants in E. coli WP2 TM9, a strain very sensitive to DNA damage. On the contrary, 8-MOP, tested in the same experimental conditions exhibited an evident photomutagenecity. These data suggest that pyrroloquinolines induced antiproliferative effects by a mechanism in which DNA-photobinding practically does not takes place, and therefore different from that shown by known furocoumarins. Pyrroloquinolinones showed also a moderate antiproliferative activity in the dark.


Subject(s)
Furocoumarins/chemical synthesis , Photochemotherapy , Photosensitizing Agents/chemical synthesis , Quinolones/chemical synthesis , Cell Division/drug effects , DNA/biosynthesis , DNA Damage , Furocoumarins/pharmacology , HeLa Cells , Humans , Photosensitizing Agents/pharmacology , Quinolones/pharmacology , RNA/biosynthesis
16.
J Photochem Photobiol B ; 24(2): 101-8, 1994 Jul.
Article in English | MEDLINE | ID: mdl-7931848

ABSTRACT

Some photobiological properties of 2,6-dimethyl-9-methoxy-4H-pyrrolo[3,2,1-ij]quinolin-4-one (PQ) have been studied in comparison with 8-methoxypsoralen (8-MOP). In Ehrlich cells, PQ induced a moderate inhibition in DNA and RNA syntheses in the dark, which appeared to be more pronounced upon UVA irradiation. In contrast to 8-MOP, in the presence of UVA, PQ also affected protein synthesis. Likewise marked antiproliferative effects were also observed in the study of the clonal growth of CHO cells cultivated in vitro. Using alkaline elution and CHO cells, a moderate formation of single-strand breaks (SSBs) and of DNA-protein cross-links (DPCs) was observed by incubation in the dark; upon UVA irradiation the amount of both lesions increased greatly, whereas no inter-strand cross-links (ISCs) were formed. As expected, 8-MOP did not damage DNA in the dark, but induced SSBs, ISCs and DPCs in the presence of UVA. The induction of SSBs by both compounds seems to be directly related to a photochemical event rather than to incisions during DNA repair. As the induction of ISCs, and also the formation of DPCs by 8-MOP and UVA, appears to be based on a two-step reaction involving photo-bound 8-MOP-DNA moieties. In contrast, the formation of DPCs by PQ and UVA seems to involve photosensitization by free PQ molecules connected with SSB and DPC formation rather than with a DNA photo-binding activity. The PQ activity observed in the dark could probably be ascribed to a moderate inhibition of topoisomerases.


Subject(s)
Photosensitizing Agents/toxicity , Pyrroles/toxicity , Quinolones/toxicity , Animals , CHO Cells , Carcinoma, Ehrlich Tumor/metabolism , Cell Division/drug effects , Cell Division/radiation effects , Cricetinae , DNA, Neoplasm/biosynthesis , Dose-Response Relationship, Radiation , Kinetics , Methoxsalen/chemistry , Methoxsalen/toxicity , Mice , Neoplasm Proteins/biosynthesis , Pyrroles/chemistry , Quinolones/chemistry , RNA, Neoplasm/biosynthesis , Spectrophotometry, Ultraviolet , Tumor Cells, Cultured , Ultraviolet Rays
17.
Photochem Photobiol ; 59(3): 277-83, 1994 Mar.
Article in English | MEDLINE | ID: mdl-8016205

ABSTRACT

The isolation and characterization of photocycloadducts with pyrimidine bases from DNA samples irradiated (365 nm) in the presence of four 4',5'-substituted methylangelicins was performed. All these furocoumarins yielded mainly the cis-syn furan-side cycloadduct with thymine. For 4',5'-dimethyl-, 5,4',5'-trimethyl- and 6,4',5'-trimethylangelicin this adduct was accompanied by two pyrone-side adducts (cis-syn and cis-anti), whereas the 4,4',5'-trimethyl derivative gave the furan-side adduct with cytosine. The characterization of the regio- and stereochemistry of the adducts was accomplished by 1H NOE (nuclear Overhauser effect) and 1H-13C HMBC (heteronuclear multiple-bond connectivity) spectroscopies. The formation of different cycloadducts in DNA by the various derivatives highlights the role of the methyl groups in determining the regio- and stereochemistry of the cycloaddition.


Subject(s)
DNA/radiation effects , Furocoumarins/chemistry , Animals , DNA/chemistry , Furocoumarins/pharmacology , Humans , In Vitro Techniques , Male , Models, Molecular , Photochemistry , Photochemotherapy , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Pyrimidines/chemistry , Pyrimidines/radiation effects , Stereoisomerism
18.
Farmaco ; 47(12): 1529-41, 1992 Dec.
Article in English | MEDLINE | ID: mdl-1294168

ABSTRACT

The photobiological activity of a series of psoralen isosters carrying a nitrogen atom at 8 position, new potential drugs for the photochemotherapy of hyperproliferative skin diseases, have been studied; the more active derivatives appeared to be 5,4'-dimethyl-8-azapsoralen and 3,4,4'-trimethyl-8-azapsoralen which induced a strong inhibition of DNA synthesis in Ehrlich ascites cells, very similar to that provoked by 8-methoxypsoralen, the furocoumarin at present used in photochemotherapy. Such compounds induced a small amount of inter-strand DNA cross-links and were non phototoxic when assayed on guinea-pig skin; however, both derivatives appeared to be highly mutagenic in E. coli WP2 TM6. This strain contains the plasmid R46 and it is proficient in DNA repair, and therefore monoadducts do not should be mutagenic in such a strain. Because the first steps of excision, which remove monoadducts, and of the main cross-link repair use the same enzymes (produced by the uvrABC complex), in the presence of a great number of monofunctional lesions, it is possible that there are not sufficient enzyme molecules for removing cross-links according this pathway, which could be repaired by a second one, uvrABC independent and based on glycosilase activity, which works at reduced levels and is much less accurate.


Subject(s)
Furocoumarins/chemical synthesis , Photochemotherapy , Animals , Carcinoma, Ehrlich Tumor/metabolism , Cross-Linking Reagents/pharmacology , DNA Repair/drug effects , DNA, Neoplasm/biosynthesis , Darkness , Dermatitis, Phototoxic/physiopathology , Escherichia coli/drug effects , Escherichia coli/genetics , Furocoumarins/pharmacology , Furocoumarins/toxicity , Guinea Pigs , Mutagenicity Tests , Mutagens/chemical synthesis , Mutagens/pharmacology
19.
Farmaco ; 46(11): 1381-406, 1991 Nov.
Article in English | MEDLINE | ID: mdl-1811623

ABSTRACT

The effect of the introduction of one, two or three methyl groups at the level of 3,4 or 4',5' photoreactive site of angelicin, in terms of extent of intercalation and DNA-photobinding, was studied. The introduction of one methyl group both in the 3 or 4 and in 4' or 5' position increases the affinity of angelicin toward DNA for the molecular complex formation and enhances the DNA-photobinding, even if to a different extent. The increase is more pronounced for occupancy of 5' or 4' position; much less pronounced is the enhancement in the case of 3 or 4 positions. The introduction of two methyl groups in 3,4 or in 4',5' positions leads to an increased capacity to form the intercalated complex with DNA; the photoreactivity is also enhanced, but to a larger extent for 4',5'-dimethylangelicin. No steric hindrance, therefore, seems to be exerted by the introduction of one or two methyl groups at the level of the photoreactive sites of angelicin. The introduction of a third methyl group in 4',5'-dimethyl or in 3,4-dimethylangelicin exhibits a strong enhancement of the DNA photobinding; in particular 4,4',5'-trimethylangelicin appears the most photoreactive towards DNA. Angelicins carrying methyl groups in 3,4 positions exhibit lower antiproliferative activity than derivatives carrying methyl groups in 4',5' positions. No correlation was observed between antiproliferative activity and DNA-photobinding; may be that the presence of methyl groups in 3,4 or in 4',5' positions affects the type of cycloadducts formed. The different ratio of adducts may affect the antiproliferative effect.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
DNA/chemistry , Furocoumarins/chemical synthesis , Animals , Carcinoma, Ehrlich Tumor/metabolism , Cell Division/drug effects , Chemical Phenomena , Chemistry, Physical , Circular Dichroism , DNA/drug effects , DNA, Neoplasm/biosynthesis , Dialysis , Furocoumarins/pharmacology , Furocoumarins/toxicity , Guinea Pigs , Humans , Intercalating Agents/chemistry , Mutagens/chemistry , Photochemistry , Photosensitivity Disorders/chemically induced , Photosensitivity Disorders/physiopathology , Structure-Activity Relationship , T-Phages/drug effects , Water
20.
J Photochem Photobiol B ; 5(1): 25-39, 1990 Apr 01.
Article in English | MEDLINE | ID: mdl-2111390

ABSTRACT

In an investigation to find monofunctional reactants for DNA which can act as new agents in the photochemotherapy of psoriasis, we have synthesized and studied some methylpsoralen derivatives which contain an acetyl group at one of the two reactive sites of the furocoumarin skeleton (at the 3 or 5' positions). The compounds do not react easily with DNA; their photobiological properties (e.g. the lack of an ability to inhibit DNA synthesis in Ehrlich ascites tumour cells, to induce T2 phage sensitization and to induce erythema in guinea-pig skin) are exactly in line with this behaviour. Some interesting features are shown by 4,8-dimethyl-5'-acetylpsoralen: it is capable of producing a very large amount of singlet oxygen--an order of magnitude higher than the other compounds and 8-methoxypsoralen (used as reference). In spite of this property, 4,8-dimethyl-5'-acetylpsoralen is non-phototoxic to the skin, and its other photobiological properties appear to be in line with its lack of interaction with DNA rather than its enhanced singlet oxygen production.


Subject(s)
Furocoumarins/chemical synthesis , Acetylation , Animals , Carcinoma, Ehrlich Tumor/metabolism , DNA/drug effects , DNA/metabolism , DNA/radiation effects , DNA Replication/drug effects , Dose-Response Relationship, Radiation , Furocoumarins/pharmacology , Guinea Pigs , Indicators and Reagents , Magnetic Resonance Spectroscopy , Methoxsalen/pharmacology , Mice , Photochemistry , Skin/drug effects , Skin/radiation effects , Structure-Activity Relationship , Ultraviolet Rays
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