H-p-Chloro-Phe-D-Cys-β-(3-pyridyl)-Ala-D-Trp-Lys-tBu-Gly-Cys-2-Nal-NH2

We report the elusive metallic anion [EtAl(3-py)3]-(3-py = 3-pyridyl) (1), the first member of the anionic tris(3-pyridyl) family. Unexpectedly, the lithium complex 1Li shows substantial protic stability against water and alcohols, unlike related tris(2-pyridyl)aluminate analogues. This stability appears to be related to the inability of the [EtAl(3-py)3]-anion to chelate Li+, which precludes a decomposition pathway involving Li/Al cooperativity.

Naturally occurring and synthetic isothiocyanates are among the most effective chemopreventive agents known. A wide variety of isothiocyanates prevents cancer in the rat lung, mammary gland, esophagus, liver, small intestine, colon, and bladder. Mechanistic studies have shown that this chemopreventive activity is due to favorable modification of phase I and phase II carcinogen metabolism, resulting in increased carcinogen excretion or detoxification and decreased carcinogen DNA interactions. Most studies reported that the isothiocyanate must be present at carcinogen exposure in order to effect tumorigenesis inhibition. Our studies focus on naturally occurring isothiocyanates phenethyl isothiocyanate (PEITC) and benzyl isothiocyanate (BITC) as lung cancer inhibitors. These studies employed the major lung carcinogens in tobacco smoke, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo(a)pyrene (BaP). Combining chemopreventive agents that inhibit tumorigenesis by NNK and BaP in rodents may be effective in addicted smokers. PEITC inhibits lung tumor induction by NNK in F-344 rats and A/J mice, while BITC inhibits BaP-induced lung tumorigenesis in A/J mice; combining the two inhibits lung tumorigenesis by combined NNK and BaP in A/J mice. PEITC selectively inhibits metabolic activation of NNK in the rodent lung, while inducing glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), one of the major NNK metabolites. Thus, PEITC decreases DNA and hemoglobin adduct formation by NNK while increasing the amounts of NNAL and its glucuronide excreted in the urine. Presently available data indicate that non-toxic doses of PEITC can inhibit the metabolic activation and carcinogenicity of NNK in rat and mouse lung; BITC has similar effects on BaP activation and tumorigenicity in mouse lung. Thus, combinations of chemopreventive agents active against different carcinogens in tobacco smoke may be useful in the chemoprevention of lung cancer.

The International Agency for Research on Cancer has classified the tobacco-specific nitrosaminesN'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as "carcinogenic to humans" (Group 1). To exert its carcinogenicity, NNN requires metabolic activation to form reactive intermediates which alkylate DNA. Previous studies have identified cytochrome P450-catalyzed 2'-hydroxylation and 5'-hydroxylation of NNN as major metabolic pathways, with preferential activation through the 5'-hydroxylation pathway in some cultured human tissues and patas monkeys. So far, the only DNA adducts identified from NNN 5'-hydroxylation in rat tissues are 2-[2-(3-pyridyl)-N-pyrrolidinyl]-2'-deoxyinosine (Py-Py-dI), 6-[2-(3-pyridyl)-N-pyrrolidinyl]-2'-deoxynebularine (Py-Py-dN), andN6-[4-hydroxy-1-(pyridine-3-yl)butyl]-2'-deoxyadenosine (N6-HPB-dAdo) after reduction. To expand the DNA adduct panel formed by NNN 5'-hydroxylation and identify possible activation biomarkers of NNN metabolism, we investigated the formation of dAdo-derived adducts using a new highly sensitive and specific liquid chromatography-nanoelectrospray ionization-high-resolution tandem mass spectrometry method. Two types of NNN-specific dAdo-derived adducts,N6-[5-(3-pyridyl)tetrahydrofuran-2-yl]-2'-deoxyadenosine (N6-Py-THF-dAdo) and 6-[2-(3-pyridyl)-N-pyrrolidinyl-5-hydroxy]-2'-deoxynebularine (Py-Py(OH)-dN), were observed for the first time in calf thymus DNA incubated with 5'-acetoxyNNN. More importantly, Py-Py(OH)-dN was also observed in relatively high abundance in the liver and lung DNA of rats treated with racemic NNN in the drinking water for 3 weeks. These new adducts were characterized using authentic synthesized standards. Both NMR and MS data agreed well with the proposed structures ofN6-Py-THF-dAdo and Py-Py(OH)-dN. Reduction of Py-Py(OH)-dN by NaBH3CN led to the formation of Py-Py-dN bothin vitroandin vivo, which was confirmed by its isotopically labeled internal standard [pyridine-d4]Py-Py-dN. The NNN-specific dAdo adducts Py-THF-dAdo and Py-Py(OH)-dN formed by NNN 5'-hydroxylation provide a more comprehensive understanding of the mechanism of DNA adduct formation by NNN.

Introduction:The gasotransmitter hydrogen sulphide (H2S), an endogenous ubiquitous signalling molecule, is known for its beneficial effects on different mammalian systems. H2S exhibits cardioprotective activity against ischemia/reperfusion (I/R) or hypoxic injury.Methods:A library of forty-five isothiocyanates, selected for their different chemical properties, has been evaluated for its hydrogen sulfide (H2S) releasing capacity. The obtained results allowed to correlate several factors such as steric hindrance, electronic effects and position of the substituents to the observed H2S production. Moreover, the chemical-physical profiles of the selected compounds have been studied by an in silico approach and from a combination of the obtained results, 3-pyridyl-isothiocyanate (25) has been selected as the most promising one. A detailed pharmacological characterization of its cardioprotective action has been performed.Results:The results herein obtained strongly indicate 3-pyridyl-isothiocyanate (25) as a suitable pharmacological option in anti-ischemic therapy. The cardioprotective effects of compound 25 were tested in vivo and found to exhibit a positive effect.Conclusion:Results strongly suggest that isothiocyanate-based H2S-releasing drugs, such as compound 25, can trigger a ''pharmacological pre-conditioning" and could represent a suitable pharmacological option in antiischemic therapy.