PubMed · 14858571
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G BOSIS. 1951. [Aromatic diamidine].. https://pubmed.ncbi.nlm.nih.gov/14858571/
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A series of platinum(II) amidine complexes were previously prepared with the aim of obtaining a new class of platinum-based antitumour drugs. This series includes compounds of the type cis--[PtCl2{Z-HN=C(NHMe)Me}2] and trans-[PtCl2{Z-HN=C(NHMe)Me}2] (1, 2), cis-[PtCl2{E-HN=C(NMe2)Me}2] and trans-[PtCl2{E-HN=C(NMe2)Me}2] (3, 4), cis-[PtCl2{Z-HN=C(NHMe)Ph}2] and trans-[PtCl2{Z-HN=C(NHMe)Ph}2] (5, 6), and cis-[PtCl2{HN=C(NMe2)Ph}2] and trans-[PtCl2{HN=C(NMe2)Ph}2] (7, 8). The reactions with dimethyl sulfoxide were studied for complexes 5-8; the formation of cationic species containing coordinated dimethyl sulfoxide was demonstrated by NMR experiments and electrospray ionization mass spectrometry. In this work, the amidine platinum(II) complexes were tested for their in vitro cytotoxicity on a panel of various human cancer cell lines. The results indicate that the benzamidine complex 8 was the most effective derivative also circumventing acquired cisplatin resistance as demonstrated by chemosensitivity tests performed on cisplatin-sensitive and cisplatin-resistant cell lines. The studies concerning the cellular DNA damage on both parental chemosensitive and resistant sublines suggest for the new trans-amidine complex a different mechanism of action compared with that exhibited by cisplatin.
This study examined the role of changes in renal interstitial pressure on the renal levels of cytochrome P450 metabolites of arachidonic acid and compared the effects of inhibition of the formation of 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids with 1-aminobenzotriazole on the pressure-natriuretic response versus that seen after administration of HET0016, a more selective inhibitor of the formation of 20-HETE. Renal interstitial pressure rose by 3.4+/-0.3 mm Hg, and the levels of 20-HETE in renal cortical tissue doubled when renal perfusion pressure was increased from 100 to 160 mm Hg. Removal of the renal capsule prevented the increase in renal interstitial pressure and 20-HETE levels after an elevation in renal perfusion pressure. Urine flow and sodium excretion increased 5-fold when renal perfusion pressure was increased from 106 to 160 mm Hg. The administration of 1-aminobenzotriazole (50 mg/kg, IP) or HET0016 (10 mg/kg IV bolus plus 1 mg/kg per hour of infusion) decreased the pressure-natriuretic response by 50% and inhibited the renal formation of 20-HETE and epoxyeicosatrienoic acids by 90% and 50%, respectively. Administration of a lower dose of HET0016 (1 mg/kg per hour, IV) selectively reduced the formation of 20-HETE by 80% without inhibiting renal epoxygenase activity and blunted the pressure-natriuretic response by 42%. These results indicate that elevations in renal perfusion pressure increase 20-HETE levels in the kidney secondary to a rise in renal interstitial pressure. They also suggest that 20-HETE, rather than epoxyeicosatrienoic acids, modulates the pressure-natriuretic response, because selective blockade of the formation of 20-HETE with HET0016 blunts the response to the same extent as that seen after inhibition of the formation of 20-HETE and epoxyeicosatrienoic acids with 1-aminobenzotriazole.
The identification of transformation products of pesticides in foodstuffs is a crucial task difficult to tackle, due to the lack of standards and scarce information available. In this work, we describe a methodology for the identification and structural elucidation of pesticide transformation products in food. The proposed strategy is based on the use of liquid chromatography electrospray time-of-flight mass spectrometry (LC/TOFMS): accurate mass measurements of (molecule and fragment) ions of interest are used in order to establish relationships between fragmentation of the parent pesticides in the instrument (in-source CID fragmentation) and possible degradation products of these pesticides in food. Examples of this strategy showing the potential of LC/TOFMS to determine unknown pesticides in food are described in two different real samples, suggesting that pesticides often are transformed into degradation products in the same fashion that they are fragmented in the instrument. Using the proposed approach and without using standards a priori, based solely on accurate mass measurements of ions and "fragmentation-degradation" relationships, we have identified two parent pesticides (amitraz and malathion) along with six degradation products, m/z 253 (N,N'-bisdimethylphenylformamidine), 163 (N-2,4-dimethylphenyl-N-methyl formamidine), 150 (2,4-dimethylformamidine), and 122 (2,4-dimethylaniline) from amitraz, and m/z 317 and 303, due to ether hydrolysis of methyl and ethyl groups from malathion. Structures for these species were proposed, and the potential of the proposed approach was critically discussed.