ABSTRACT
The molecular structure of 1,4,6,8-tetramethylfuro[2,3-h]quinolin-2(1H)-one (FQ), a recent furocoumarin-like photosensitizer, has been modified with the aim of reducing its strong genotoxicity, by replacing the methyl group at 4 position with a hydroxymethyl one, and so obtaining 4-hydroxymethyl-1,6,8-trimethylfuro[2,3-h]quinolin-2(1H)-one (HOFQ). This modification gave rise to a strong reduction of lipophilicity and dark interaction with DNA. The formation of monoadducts (MA) was deeply affected, whereas the induction of bifunctional adducts between DNA and proteins (DPC(L>0)) was replaced by an efficient production of DNA-protein cross-links at zero length (DPC(L=0)), probably via guanine damage. Because of its angular molecular structure, HOFQ does not form interstrand cross-links (ISC): therefore, DPC(L=0) and MA represent the main lesions induced by HOFQ in DNA. In comparison with FQ (which induces MA and DPC(L>0)) and 8-methoxypsoralen (8-MOP) (MA, ISC, DPC(L>0)), HOFQ seems to be a more selective agent. In fact, contrary to FQ and 8-MOP, HOFQ, together with a noticeable antiproliferative activity, shows low levels of point mutations in bacteria and of clastogenic effects in mammalian cells. HOFQ is also an efficient apoptosis inducer, especially in comparison with 8-MOP, when tested at equitoxic experimental conditions; this property might be correlated with the complete HOFQ inability of inducing skin erythemas, a well-known side effect of classic furocoumarin photosensitization.
Subject(s)
Furans/chemistry , Furocoumarins/chemistry , Photosensitizing Agents/chemistry , Quinolones/chemistry , Ultraviolet Rays , Animals , Cell Line , Cell Proliferation , DNA/metabolism , DNA-Binding Proteins/metabolism , Furans/pharmacology , Furocoumarins/metabolism , Furocoumarins/pharmacology , Humans , Light , Molecular Structure , Photosensitizing Agents/metabolism , Photosensitizing Agents/pharmacology , Quinolones/pharmacology , Reactive Oxygen Species/metabolismABSTRACT
1,4,8-Trimethylfuro[2,3-h]quinolin-2(1H)-one (compound 5a) is the most interesting derivative among some new furoquinolinones prepared with the aim of moderating the strong toxic effects of 1,4,6,8-tetramethyl derivative (FQ), a powerful potential drug for photomedicine. Compound 5a showed a photobiological activity lower than FQ, but considerable higher than 8-MOP, the furocoumarin used in clinical photomedicine; contrary to classic furocoumarins, 5a induced a strong inhibition of protein synthesis in mammalian cells. Genotoxicity and skin erythema induction, the main side effects of both FQ and 8-MOP photosensitization, are virtually absent with 5a. This behavior seems to be connected to its particular reaction mechanism: differently from furocoumarin derivatives, 5a induced low levels of DNA-protein and no inter-strands cross-links, but formed covalent RNA-protein linkages, lesions not observed with known furocoumarins. Moreover, compound 5a generated reactive oxygen species to a considerable extent. For these features, compound 5a appears to be a new photosensitizing agent whose special activity deserves to be deeply investigated.
Subject(s)
Furans/pharmacology , Furans/toxicity , Furocoumarins/pharmacology , Furocoumarins/toxicity , Photosensitizing Agents/pharmacology , Photosensitizing Agents/toxicity , Quinolones/pharmacology , Quinolones/toxicity , Animals , Cell Division/drug effects , Cell Line, Tumor , Cricetinae , DNA/drug effects , DNA/metabolism , DNA Replication/drug effects , Dose-Response Relationship, Radiation , Drug Evaluation, Preclinical , Furans/chemical synthesis , Furocoumarins/chemical synthesis , HeLa Cells/drug effects , Humans , Mice , Molecular Structure , Photobiology , Photosensitizing Agents/chemical synthesis , Proteins/drug effects , Proteins/metabolism , Quinolones/chemical synthesis , RNA/drug effects , RNA/metabolism , Reactive Oxygen Species/metabolism , Skin/drug effects , Skin/radiation effects , Ultraviolet Rays/adverse effectsABSTRACT
The N-substituted tricyclic 2-aminochromone derivatives 1a, 2a, and 2b were obtained by treating the corresponding (methylthio) or (methylsulfinyl) derivatives 10, 11, or 12, respectively, with an excess of the proper amines. Compound 2c was synthesized through the reaction of 2-naphthol with the ethyl N,N-diphenylmalonamate/POCl(3) reagent 14. The N-substituted 4-aminocoumarin bicyclic and tricyclic derivatives 5-8 were prepared by treating the corresponding chloro derivatives with the excess suitable amines. Compounds 1, 2, 5-8 were tested in vitro for their antiproliferative activity (DNA synthesis inhibition in Ehrlich cells) and cytotoxicity (MTT test in HeLa cells). The inhibitory properties of three selected compounds (5c, 5e, 7c) on protein and RNA syntheses in Ehrlich cells were also evaluated. Among the 27 compounds tested, 10 4-aminocoumarin derivatives (5-8) and two 2-aminochromone derivatives (1a and 2a) showed an appreciable antiproliferative activity (IC(50) range: 1.74-13.8 microM), whereas only four compounds 5-8 exhibited a comparable cytotoxic activity (IC(50) range: 4.95-12.9 microM).
Subject(s)
Chromones/toxicity , Coumarins/toxicity , Growth Inhibitors/toxicity , Pyrans/toxicity , Animals , Carcinoma, Ehrlich Tumor/drug therapy , Chromones/chemistry , Chromones/pharmacology , Coumarins/chemistry , Coumarins/pharmacology , Dose-Response Relationship, Drug , Growth Inhibitors/chemistry , Growth Inhibitors/pharmacology , HeLa Cells , Humans , Mice , Pyrans/chemistry , Pyrans/pharmacology , Xenograft Model Antitumor Assays/methodsABSTRACT
A new platinum(II) complex containing a pyridine nucleus and a dithiocarbamate moiety as ligands ([Pt(ESDT)(Py)Cl]) was evaluated for in vitro cytotoxicity in the cisplatin-sensitive human ovarian 2008 and in the isogenic-resistant C13* cell lines. In both cell types, a tumor cell growth inhibition greater than cisplatin and a complete lack of cross-resistance in C13* cells were found. Despite its molecular size, [Pt(ESDT)(Py)Cl] accumulation was much higher than cisplatin both in parent and resistant cells. Studying the mechanism of action in cell-free media, we established that [Pt(ESDT)(Py)Cl] more efficiently interacts with DNA in vitro compared to cisplatin maintaining a binding preference for GG rich sequences of DNA. On the contrary, DNA platination in vivo by [Pt(ESDT)(Py)Cl] was found lower than cisplatin. An analysis of the type of DNA lesions induced by [Pt(ESDT)(Py)Cl] suggests that the cytotoxic efficacy and the ability to overcome cisplatin resistance seem to be related to a different mechanism of interaction with DNA and/or with other key cellular components.
Subject(s)
Antineoplastic Agents/pharmacology , Cisplatin/analogs & derivatives , DNA Adducts/metabolism , DNA Damage , Organoplatinum Compounds/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Cattle , Cisplatin/pharmacokinetics , Cisplatin/pharmacology , DNA/drug effects , DNA/metabolism , Female , Humans , Organoplatinum Compounds/pharmacokinetics , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Plasmids/metabolism , Pyridines/pharmacokinetics , Pyridines/pharmacology , Thiocarbamates/pharmacokinetics , Thiocarbamates/pharmacology , Tumor Cells, CulturedABSTRACT
New furoquinolinones unsubstituted at the N(1) position were prepared and their photobiological activities were studied in comparison with 4,6,8,9-tetramethylfuro[2,3-h]quinolin-2(1H)-one (HFQ) and 8-MOP. The anti-proliferative activity of furoquinolinones 3a-f was tested upon UVA irradiation in mammalian cells, studying DNA synthesis and clonal growth capacity, and in micro-organisms, evaluating T2 infectivity. Almost all compounds appeared to be more active than 8-MOP, and free of any mutagenic activity and skin phototoxicity. Among them, compound 3b was the most effective one. Similarly to HFQ, compound 3b appeared to be very active also in DNA damaging, forming monoadducts and DPC(L=0), but no ISC and DPC(L>0), both responsible for furocoumarin genotoxicity and phototoxicity. Moreover, Ehrlich ascites cells, photoinactivated by the new furoquinolinone 3b and injected into recipient mice, proved to be capable of inducing protection against a successive challenge performed with the same tumor cells. For all these features, 3b seemed to be a new promising potential drug for PUVA therapy and photopheresis.
Subject(s)
DNA Damage/drug effects , Photosensitizing Agents/adverse effects , Quinolones/adverse effects , Animals , Bacteriophage T4/drug effects , Bacteriophage T4/growth & development , Bacteriophage T4/radiation effects , Cell Division/drug effects , Cell Division/radiation effects , Cell Survival/drug effects , Cell Survival/radiation effects , DNA/biosynthesis , DNA/chemistry , DNA/metabolism , DNA Damage/radiation effects , Escherichia coli , Guinea Pigs , Humans , Mice , Mutagenesis/drug effects , Mutagenesis/radiation effects , Neoplasms, Experimental/pathology , Photosensitivity Disorders/chemically induced , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/toxicity , Quinolones/chemical synthesis , Quinolones/toxicity , Structure-Activity Relationship , Tumor Cells, Cultured , Ultraviolet RaysABSTRACT
A new furoquinolinone derivative, namely 4-hydroxymethyl-1,6,8-trimethylfuro[2,3-h]quinolin-2(1H)-one (HOFQ), was synthesized and its biological activity studied. By UVA activation, HOFQ induced strong antiproliferative effects in Ehrlich ascite cells, which lost their ability to transmit the tumor by transplantation. HOFQ exhibited poor genotoxicity and absence of skin phototoxicity. Actually, HOFQ sensitization forms DNA-protein cross-linkages but not interstrands cross-links. Therefore, HOFQ appears to be a new promising drug for PUVA photochemotherapy and photopheresis.
Subject(s)
Antineoplastic Agents/chemical synthesis , Furans/chemical synthesis , Quinolones/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , CHO Cells , Carcinoma, Ehrlich Tumor/drug therapy , Cricetinae , Cross-Linking Reagents/chemical synthesis , Cross-Linking Reagents/chemistry , Cross-Linking Reagents/pharmacology , DNA/chemistry , DNA Damage , Drug Screening Assays, Antitumor , Escherichia coli/genetics , Furans/chemistry , Furans/pharmacology , Guinea Pigs , Methoxsalen/pharmacology , Mice , Mutagenicity Tests , Neoplasm Transplantation , Quinolones/chemistry , Quinolones/pharmacology , Skin/radiation effects , Structure-Activity Relationship , Tumor Cells, Cultured , Ultraviolet RaysABSTRACT
A number of new furo and thienoquinolinones carrying an electron-withdrawing function or unsubstituted at the position 3 were synthesized in order to obtain new potential photochemotherapeutic agents with increased antiproliferative activity and decreased toxic side effects. Our interest in studying the SAR of these derivatives also prompted us to investigate the influence of N-methylation on biological activity, by preparing N-methyl derivatives. The antiproliferative activity of all the newly synthesized compounds was evaluated and compared to 8-methoxypsoralen (8-MOP), the drug widely used in PUVA-therapy. The 3-unsubstituted thienoquinolinones were generally the most potent derivatives, followed by the furo-analogues. In particular, the unsubstituted thieno[2,3-h]quinoline-2(1H)one showed the highest activity in T2 bacteriophage, HeLa cells and Ehrlich cells tests. All the compounds, assayed on Escherichia coli WP2 TM9, showed a similar mutagenic activity, very close to that of 8-MOP. Except for 2-oxo-1,2-dihydrothieno[2,3-h]quinoline-3-carboxylic acid, which appeared to be very effective, all compounds generated singlet oxygen to slightly larger amounts when compared to 8-MOP. The N-methyl analogues only induced moderate skin erythemas on albino guinea pigs, while all other derivatives appeared to be entirely inactive. On the basis of these results, the unsubstituted thieno[2,3h]quinoline 2(1H)one seems to be the most interesting potential drug for PUVA photochemotherapy and photopheresis.
