Antitumor Trans Platinum Adducts of GMP and AMP

Recently it has been shown that several analogues of the clinically ineffective trans-DDP exhibit antitumor activity comparable to that of cis-DDP. The present paper describes the binding of antitumor trans-[PtCl2(E-iminoether)2] (trans-EE) to guanosinemonophosphate (GMP) and adenosinemonophosphate (AMP). We have used HPLC and H1 and N15 NMR to characterize the different adducts. In the case of a 1:1 mixture of trans-EE and GMP, at an early stage of the reaction, a monofunctional adduct is formed which, subsequently, is partly converted into a monosolvated monofunctional species. After about 70 hours an equilibrium is established between chloro and solvato monofunctional adducts at a ratio of 30/70. In the presence of excess GMP (4:1) the initially formed monofunctional adducts react further to give two bifunctional adducts, one with the iminoether ligands in their original E configurations and the other with the iminoether ligands having one E and the other, Z configurations. The coordination geometry obtained by energy minimization calculations is in qualitative agreement with 2D NMR data.

Photochemical and photobiological properties of furocoumarins and homologues drugs

Furocoumarins are natural photosensitizing drugs used in PUVA photochemotherapy and in photopheresis. Their therapeutic effectiveness is connected to the lesions they induce to various cell components, membranes, ribosomes, mitochondria, and in particular to DNA, damaged by formation of monofunctional adducts and of inter-strand cross-links (ISC). ISC represent a severe damage, mainly correlated to the main side effects observed in photochemotherapy, skin phototoxicity and genotoxicity. Searching for new monofunctional derivatives, two tetramethylfuroquinolinones, 1,4,6,8-tetramethyl-2H-furo[2,3-h]quinolin-2- one (FQ) and 4,6,8,9-tetramethyl-2H-furo[2,3-h]-quinolin-2-one (HFQ) were studied. Both compounds are very active; however while FQ produced many chromosomal aberrations and strong skin erythemas, HFQ practically did not induce such side effects. FQ and HFQ formed high levels of monoadducts but no ISC in DNA, but both provoked many DNA-protein cross-links (DPC). FQ induced these lesions by a biphotonic reaction: at first a furan-side monoadduct is formed, which is then converted into a DPC; thus the FQ molecule seemed to form the bridge between DNA and proteins. HFQ formed DPC by a single step (DPC at zero length, like UVC). For these features, HFQ appears to be the first molecule belonging to a new class of active but not phototoxic drugs for photomedicine.

Steric Determinants of Pt/DNA Interactions and Anticancer Activity

Studies directed at establishing the structural features that control Pt/DNA interactions and the anticancer activity of Pt drugs are described. [H1,N15]-HSQC 2D NMR spectroscopic studies of the reactions of cisplatin with oligonucleotides containing ApG and GpA binding sites reveal dramatic differences in the rates of formation of monofunctional adducts at the two sites. When the reactant is cis-[Pt(NH3)2(OH2)2]2+ no such differences are observed suggesting that outer-sphere interactions between the reactant and the oligonucleotide may play a substantial role in determining the rates. Rates of closure to the bifunctional adducts are similar to those observed for cisplatin. Studies of the adduct profiles formed by sterically bulky and/or optically active complexes reveal that steric interactions play a major role in mediating the binding of Pt(ll) to DNA but that hydrogen bonds play less of a role. In vitro cytotoxic activities for these complexes do not always follow the trends that would be expected on the basis of the adduct profiles.

Pd(II) and Pt(II) Complexes of Schiff Thiobases Derived From 2-Carbonylpyridine

Pd(ll) and Pt(ll) complexes of three series of Schiff thiobases derived from 2- carbonylpyridine have been synthesized and characterized. The crystal structure of the Pt(ll) derivative of methyl-3-(2-pyridylmethylene)hydrazinecarbodithioate (HFp) was resolved. The ligand coordinates the platinum ion in tridentate fashion by heterocycle and imine nitrogen and thiocarbonyl sulfur. The fourth ligand is a chloride ion. The structure of the complexes is suitable for the formation of monofunctional adducts with DNA. Studies on the interaction of the complexes with Calf thymus DNA by CD reveal modifications in the B form of lineal DNA. Interaction with plasmid DNA was also confirmed in the images obtained by atomic force microscopy.