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Synthesis, characterization and cytotoxic activity of substituted benzyl iminoether Pt(II) complexes of the type cis- and trans-[PtCl2{E-N(H)=C(OMe)CH2-C6H4-p-R}2] (R=Me, OMe, F). X-ray structure of trans-[PtCl2{E-N(H)=C(OMe)CH2-C6H4-p-F}2].

New substituted benzyl iminoether derivatives of the type cis- and trans-[PtCl(2){E-N(H)C(OMe)CH(2)-C(6)H(4)-p-R}(2)] (R=Me (1a, 2a), OMe (3a, 4a), F (5a, 6a)) have been synthesized and characterized by elemental analyses, FT-IR spectroscopy and NMR techniques. The iminoether ligands are in the E configuration, which is stable in solution and in the solid state, as confirmed by the (1)H NMR data. Complex trans-[PtCl(2){E-N(H)C(OMe)CH(2)-C(6)H(4)-p-F}(2)] (6a) was also characterized by an X-ray diffraction study. Complexes 1a-6a have been tested against a panel of human tumor cell lines in order to evaluate their cytotoxic activity. cis-Isomers were significant more potent than the corresponding trans-isomers against all tumor cell lines tested; moreover, complexes 1a and 5a showed IC(50) values from about 2-fold to 6-fold lower than those exhibited by cisplatin, used as reference platinum anticancer drug.

T4 Phage Photoinactivation by Linear Furocoumarins and Angular Furoquinolinones

Linear furocoumarins (psoralens) are active sensitizers that can damage numerous cell components such as nucleic acids, 2] proteins, and lipids. 5] However, DNA is the main cellular target in which various lesions can be introduced: monofunctional adducts with pyrimidine bases (MA) and bifunctional adducts, cross-links between two adjacent pyrimidine bases (interstrand cross-links; ISC), and covalent linkages between DNA and proteins (DNA–protein cross-links; DPC). Furocoumarins are widely used in photomedicine (PUVA therapy) for the treatment of various skin diseases and in photopheresis to prevent rejection in organ transplantation. Recently, furocoumarins have also been proposed as sterilizing agents for blood preparations because they provide various advantages over conventional techniques; indeed, furocoumarins affect a wide spectrum of microorganisms, including viruses, with a decreased capacity for affecting blood components. Whereas the mechanism of furocoumarin sensitization on mammalian cells, yeast, and bacteria has been extensively studied, only a few reports concerning the furocoumarin mechanism of virus inactivation have been published. The studies reported herein have addressed some aspects of this problem by using the simple and well-known T4 bacteriophage model ; we checked the sensitivity of T4 in both its mature virion and vegetative forms. Three very active photosensitizing derivatives were chosen: a well-known linear furocoumarin, 4,5’,8-trimethylpsoralen (TMP) and two angular furoquinolinones: 1,4,6,8-tetramethyl-2H-furo ACHTUNGTRENNUNG[2,3-h]quinolin-2one (FQ) and 4,6,8,9-tetramethyl-2H-furo ACHTUNGTRENNUNG[2,3-h]quinolin-2one (HFQ) (Figure 1). These compounds were selected for their different capacities for inducing various lesions in DNA, in particular bifunctional adducts, ISCs, and/or DPCs. Furocoumarins and their homologues form C4-cycloadducts with pyrimidine bases (MA) through the double bonds at either the 3,4 position or on the furan group; adducts formed through the latter process can absorb light and thus further react with an another pyrimidine group to yield an ISC. Alternatively, this second reaction can involve a protein to form a DPC. All three derivatives chosen can form various MAs in DNA, but TMP is known to be capable of inducing numerous ISCs and DPCs as well. FQ and HFQ efficiently form DPCs, but not ISCs, a behavior common to all furocoumarins with an angular molecular structure. In fact, FQ and HFQ are potentially bifunctional molecules, but for geometric reasons they behave as monofunctional reactive compounds when intercalated into DNA. We initially studied the response of mature T4 virions and T4 in its vegetative form (phage DNA injected into recipient bacteria, blocked by starvation), that is, before and after the infection process, respectively. Under suitably selected mild experimental conditions, all compounds showed a strong killing activity toward T4 virions but not the vegetative form (Figure 2).

Mechanism of action of 4-hydroxymethyl-1,6,8-trimethylfuro[2,3-h]quinolin-2(1H)-one, a very active angular furocoumarin-like sensitizer.

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 (DPCL>0) was replaced by an efficient production of DNA–protein cross-links at zero length (DPCL=0), probably via guanine damage. Because of its angular molecular structure, HOFQ does not form interstrand cross-links (ISC): therefore, DPCL=0 and MA represent the main lesions induced by HOFQ in DNA. In comparison with FQ (which induces MA and DPCL>0) and 8-methoxypsoralen (8-MOP) (MA, ISC, DPCL>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.