Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Photobiological properties of a new tetramethylfuroquinolinone. 881 May 33

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.
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PMID:New tetracyclic analogues of photochemotherapeutic drugs 5-MOP and 8-MOP: synthesis, DNA interaction, and antiproliferative activity. 1054 84

4-Hydroxymethyl-1,6,8-trimethylfuro[2,3-h]quinolin-2(1H)-one (HOFQ) was prepared by a new profitable way, which allowed to synthesize also 4-methoxymethyl-1,6,8-trimethylfuro[2,3-h]quinolin-2(1H)-one (MOFQ), and 4-hydroxymethyl-6,8-dimethylfuro[2,3-h]quinolin-2(1H)-one (HOHFQ). Some biological activities of the three compounds were studied in comparison with 8-MOP. In the dark, they inhibited topoisomerase II, leading to a moderate antiproliferative activity in mammalian cells. The antiproliferative activity was also tested upon UVA irradiation in mammalian cells: all compounds showed higher activity than 8-MOP, without mutagenicity and skin phototoxicity, with the best results for HOFQ. Photobinding to DNA was investigated, demonstrating a different sequence specificity for these furoquinolinones in comparison with furocoumarins. For all these features, HOFQ and the other analogues appeared very promising photochemotherapeutic agents, whose mechanism of action will be further investigated.
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PMID:4-Hydroxymethyl- and 4-methoxymethylfuro[2,3-h]quinolin-2(1H)-ones: synthesis and biological properties. 1262 58