5,6-Dihydroxyindole Tetramers with "Anomalous" Interunit Bonding Patterns by Oxidative Coupling of 5,5',6,6'-Tetrahydroxy-2,7'-biindolyl: Emerging Complexities on the Way toward an Improved Model of Eumelanin Buildup.

Chem. or enzymic oxidn. of 5,6-dihydroxyindole (I) leads to the rapid deposition of a black solid resembling eumelanin pigments by way of a complex oligomerization/polymn. process that proceeds in the early stages via dimers and trimers characterized by 2,4'- and 2,7'-couplings. Despite extensive efforts, the structures of the higher oligomers, which define the structural architecture and physicochem. properties of the eumelanin particles, have so far defied elucidation. Using a dimer-dimer coupling strategy that has recently allowed the first successful entry to a tetramer of I, the authors report now three addnl. tetramers obtained by oxidn. of 5,5',6,6'-tetrahydroxy-2,7'-biindolyl with the peroxidase/H2O2 system. On the basis of extensive 2D NMR and mass spectrometric anal., the products were identified as acetylated II (3%), III (4%), and IV (5%), in which the inner units are linked through unexpected 3,3'-, 4,4'-, and 2,3'-linkages. If verified in further studies, the newly uncovered coupling patterns would entail important consequences for current models of eumelanin structure based on one-dimensional structural chains with extended p-electron conjugation or p-stacked flat oligomer aggregates

Chemical, Pulse Radiolysis and Density Functional Studies of a New, Labile 5,6-Indolequinone and Its Semiquinone.

The chemical and spectroscopic characterization of 5,6-indolequinones and their semiquinones, key transient intermediates in the oxidative conversion of 5,6-dihydroxyindoles to eumelanin biopolymers, is a most challenging task. In the present paper, we report the characterization of a novel, relatively long-lived 5,6-indolequinone along with its semiquinone using an integrated chemical, pulse radiolytic, and computational approach. The quinone was obtained by oxidation of 5,6-dihydroxy-3-iodoindole (1a) with o-chloranil in cold ethyl acetate or aqueous buffer: it displayed electronic absorption bands around 400 and 600 nm, was reduced to 1a with Na2S2O4, and reacted with o-phenylenediamine to give small amounts of 3-iodo-1H-pyrrolo[2,3-b]phenazine (2). The semiquinone exhibited absorption maxima at 380 nm (sh) and 520 nm and was detected as the initial species produced by pulse radiolytic oxidation of 1a at pH 7.0. DFT investigations indicated the 6-phenoxyl radical and the N-protonated radical anion as the most stable tautomers for the neutral and anion forms of the semiquinone, respectively. Calculated absorption spectra in water gave bands at 350 (sh) and 500 nm for the neutral form and at 310 and 360 (sh) nm for the anion. Disproportionation of the semiquinone with fast second-order kinetics (2k = 1.1 x 10(10) M-1 s(-1)) gave a chromophore with absorption bands resembling those of chemically generated 1a quinone. Computational analysis predicted 1a quinone to exist in vacuo as the quinone-methide tautomer, displaying low energy transitions at 380 and 710 nm, and in water as the o-quinone, with calculated absorption bands around 400 and 820 nm. A strong participation of a p orbital on the iodine atom in the 360-380 nm electronic transitions of the o-quinone and quinone-methide was highlighted. The satisfactory agreement between computational and experimental electronic absorption data would suggest partitioning of 1a quinone between the o-quinone and quinone-methide tautomers depending on the medium

Novel bis-platinum complexes endowed with an improved pharmacological profile

Multinuclear platinum complexes are characterized by a peculiar DNA binding mode and higher cytotoxic potency than the mononuclear complexes, and efficacy against a wide range of preclinical tumor models. To reduce the high irreversible plasma protein binding and improve the chemical and metabolic drug stability, novel bis-platinum complexes were designed starting from the parent compound CT-3610. The novel second-generation bis-platinum complexes utilize alkylcarboxylate as leaving groups to improve their pharmacokinetic and pharmacodynamic profiles, thus overcoming the limitations of the previously developed multinuclear compounds. The selected compounds [CT-47518 and CT-47463, respectively (bis-capronate) platinum and (bis-butyrate) platinum], have similar in vitro degradation kinetics in human and murine plasma and, above all, an increased stability when compared to CT-3610, particularly in human plasma. In addition, both compounds exhibited a marked cytotoxic potency as compared with cisplatin and oxaliplatin. Interestingly, they were capable of overcoming resistance mediated by DNA mismatch repair defects in different cellular models. The complexes showed marked antitumor efficacy in Pt-refractory tumor xenografts, with remarkable activity in terms of tumor growth inhibition and tumor growth delay. The improved stability profile in human plasma compared to early bis- and triplatinum complexes together with the marked activity in cellular systems as well as in in vivo models, make CT-47518 and CT-47463 attractive candidates for further development