Rational design,synthesis and biological evaluation of thiadiazinoacridines: a new class of antitumor agents

A series of potential DNA-binding antitumor agents, 3-[omega-(alkylamino)alkyl]-6-nitro-thiadiazino[3,4,5-kl]acridines 12 and 1,3-di[omega-(alkylamino)alkyl]-6-nitro-thiadiazino[3,4,5-kl]acridines 13, has been prepared by cyclization with SOCl(2) of 1-[[omega-(alkylamino)alkyl]amino]-9-imino-4-nitro-9,10-dihydroacridines 16 or 1-[[omega-(alkylamino)alkyl]amino]-9-[omega-(alkylamino)alkyl]imino-4-nitro-9,10-dihydroacridines 17, respectively. The non-covalent DNA-binding properties of 12, 13 have been examined using a fluorometric technique. In vitro cytotoxic potencies of these derivatives toward six tumor cell lines, including human colon adenocarcinoma (HT29) and human ovarian carcinoma (A2780 sensitive, A2780cisR cisplatin-resistant, CH1, CH1cisR cisplatin-resistant, and SKOV-3) cells, are described and compared to that of reference drugs. In vivo antitumor activity of some selected derivatives, endowed with relevant cytotoxic activity against murine leukemia P388 are reported. The 3-[2-(dimethylamino)ethyl]-6-nitro-2,7-dihydro-3H-2 lambda(4)-thiadiazino[3,4,5-kl]acridin-2-one (12d) has been identified as a new lead in the development of anticancer tetracyclic acridine derivatives.     

Effect of modification of 6-[(aminoalkyl)amino]-7H-benzo[e]-perimidin-7-ones on their cytotoxic activity toward sensitive and multidrug resistant tumor cell lines. Synthesis and biological evaluation

Benzoperimidines, a novel group of antitumor anthracenedione analogues, are of interest due to their ability to overcome multidrug resistance of tumor cells (Stefańska, B., Dzieduszycka, M., Bontemps-Gracz, M. M., Borowski, E., Martelli, S., Supino, R., Pratesi, G., De Cesare, MA., Zunino, F., Ku?nierczyk, H., Radzikowski, Cz. J. Med. Chem. 1999, 42, 3494). Although the structural factor essential for exhibiting this desirable property is the presence in the molecule of a fused heterocyclic ring, the cytotoxicity against resistant cells is highly influenced by the nature and location of the substituents. A series of novel synthetic derivatives, comprising monohydroxylated benzoperimidines and 2-aminobenzoperimidines, allowed the establishment of an in vitro structure-activity relationship for a panel of leukemia sensitive, as well as P-gp dependent multidrug resistance (MDR) and multidrug resistance associated protein dependent resistance (MRP) resistant cell lines. The membrane affinity for the compounds has also been determined.     

Aryloxy substituted N-arylpiperazinones as dual inhibitors of farnesyltransferase and geranylgeranyltransferase-I

A series of aryloxy substituted piperazinones with dual farnesyltransferase/geranylgeranyltransferase-I inhibitory activity was prepared. These compounds were found to have potent inhibitory activity in vitro and are promising agents for the inhibition of Ki-Ras signaling.     

Diaryl ether inhibitors of farnesyl-protein transferase

Imidazolemethyl diaryl ethers are potent inhibitors of farnesyl-protein transferase. The SNAr displacement reaction used to prepare these diaryl ethers was amenable to rapid parallel synthesis of FPTase inhibitors. The use of a broad range of commercially available phenols quickly identified compounds which proved active in cells.     

Purification and characterization of phenoloxidase from the hemocytes of Eurygaster integriceps (Hemiptera: Scutelleridae)

Insects protect themselves from microbial invaders by two main immune activities, namely the cellular and humoral reactions. Phenoloxidases are oxidative enzymes that have an important role in both cell-mediated and humoral immunity. In this study, the purification and biochemical characterization of a phenoloxidase from the hemocytes of the Sunn pest Eurygaster integriceps Puton (Hemiptera: Scutelleridae) were carried out. After the final purification step, the enzyme was purified 7.31-fold with a recovery of 3.94% and a specific activity of 4.95U/mg protein. Results of the biochemical characterization showed that the purified phenoloxidase has a maximum activity at pH 6 and at 30-35°C and is stable for 24-36h. Divalent cations such as Ca(2+) and Cu(2+) significantly increased the enzymatic activity and synthetic inhibitors such as phenylthiourea significantly decreased it. The purified phenoloxidase has a molecular mass of 22kDa. The current paper represents a further step towards the characterization of humoral immunity of E. integriceps in order to develop new strategies for the biological control of the Sunn pest.     

rRNA pseudouridylation defects affect ribosomal ligand binding and translational fidelity from yeast to human cells

How pseudouridylation (Ψ), the most common and evolutionarily conserved modification of rRNA, regulates ribosome activity is poorly understood. Medically, Ψ is important because the rRNA Ψ synthase, DKC1, is mutated in X-linked dyskeratosis congenita (X-DC) and Hoyeraal-Hreidarsson (HH) syndrome. Here, we characterize ribosomes isolated from?a yeast strain in which Cbf5p, the yeast homolog of DKC1, is catalytically impaired through a D95A mutation (cbf5-D95A). Ribosomes from cbf5-D95A cells display decreased affinities for tRNA binding to the A and P sites as well as the cricket paralysis virus internal ribosome entry site (IRES), which interacts with both the P and the E sites of the ribosome. This biochemical impairment in ribosome activity manifests as decreased translational fidelity and IRES-dependent translational initiation, which are also evident in mouse and human cells deficient for DKC1 activity. These findings uncover specific roles for Ψ modification in ribosome-ligand interactions that are conserved in yeast, mouse, and humans.     

Identification of QTL for resistance to plum pox virus strains M and D in Lito and Harcot apricot cultivars

Sharka is a severe apricot viral disease caused by the plum pox virus (PPV) and is responsible for large crop losses in many countries. Among the known PPV strains, both PPV-D (Dideron) and PPV-M (Marcus) are virulent in apricot, the latter being the most threatening. An F1 apricot progeny derived from Lito, described in the literature as resistant, crossed to the susceptible selection BO81604311 (San Castrese × Reale di Imola) was used to study the genetic control of resistance to PPV. A population of 118 individuals was phenotyped by inoculating both PPV-D and PPV-M strains in replicated seedlings and scored for 3 years. An additional set of 231 seedlings from the same cross was also phenotyped for 2 years. SSR-based linkage maps were used for quantitative trait locus (QTL) analysis. A major QTL of resistance to both PPV-M and PPV-D strains was found in the top half of the Lito linkage group 1, where a QTL was previously described in Stark Earli-Orange, the donor of Lito resistance. The LOD score was considerably enhanced when the recovery of plants from infection was taken into account. The results obtained in Lito were compared with those observed in a second apricot cross progeny (Harcot × Reale di Imola) in which QTL of resistance to sharka were also mapped in the same linkage group 1 for both PPV strains. Several models of resistance to sharka disease are discussed considering the segregation frequencies, the QTL alignment in the two maps and the information gathered from the literature.     

Genome size, GC percentage and 5mC level in the Indonesian coelacanth Latimeria menadoensis

The living fossil Latimeria menadoensis is important to understand sarcopterygian evolution. To gain further insights into this fish species we studied its genome size, GC% and 5mC level. The genome size and the GC% of the Indonesian coelacanth seem to be very similar to those of the African coelacanth. Moreover the GC%, the CpG frequency and the 5mC level of L. menadoensis are more similar to those of fish and amphibians than to those of mammals, birds and reptiles and this is in line with the hypothesis that two different DNA methylation and CpG shortage equilibria arose during vertebrate evolution. Our results suggest that the genome of L. menadoensis has remained unchanged for several million years, maybe since the origin of the lineage which from lobe-finned fish led to tetrapods. These data fit a conservative evolutionary landscape and suggest that the genome of the extant crossopterygians may be a sort of evolutionarily frozen genome.