Allosteric inhibitors of Akt1 and Akt2: a naphthyridinone with efficacy in an A2780 tumor xenograft model

A series of naphthyridine and naphthyridinone allosteric dual inhibitors of Akt1 and 2 have been developed. These compounds have been optimized to have potent dual activity against the activated kinase as well as the activation of Akt in cells. One molecule in particular, compound 17, has potent inhibitory activity against Akt1 and 2 in vivo in a mouse lung and efficacy in a tumor xenograft model.     

Differential maintenance and de novo methylating activity by three DNA methyltransferases in aging and immortalized fibroblasts.

Genomic methylation, which influences many cellular processes such as gene expression and chromatin organization, generally declines with cellular senescence although some genes undergo paradoxical hypermethylation during cellular aging and immortalization. To explore potential mechanisms for this process, we analyzed the methylating activity of three DNA methyltransferases (Dnmts) in aging and immortalized WI-38 fibroblasts. Overall maintenance methylating activity by the Dnmts greatly decreased during cellular senescence. In immortalized WI-38 cells, maintenance methylating activity was similar to that of normal young cells. Combined de novo methylation activity of the Dnmts initially decreased but later increased as WI-38 cells aged and was strikingly elevated in immortalized cells. To further elucidate the mechanisms for changes in DNA methylation in aging and immortalized cells, the individual Dnmts were separated and individually assessed for maintenance and de novo methylating activity. We resolved three Dnmt fractions, one of which was the major maintenance methyltransferase, Dnmt1, which declined steadily in activity with cellular senescence and immortalization. However, a more basic Dnmt, which has significant de novo methylating activity, increased markedly in activity in aging and immortalized cells. We have identified this methyltransferase as Dnmt3b which has an important role in neoplastic transformation but its role in cellular senescence and immortalization has not previously been reported. An acidic Dnmt we isolated also had increased de novo methylating activity in senescent and immortalized WI-38 cells. These studies indicate that reduced genome-wide methylation in aging cells may be attributed to attenuated Dnmt1 activity but that regional or gene-localized hypermethylation in aging and immortalized cells may be linked to increased de novo methylation by Dnmts other than the maintenance methyltransferase.     

Do bright colors at nests incur a cost due to predation?

Summary Birds show much interspecific variation in the coloration and brightness of their plumage. I examine the hypothesis that selection due to predation on incubating birds and their nest contents can explain part of this diversity. First, I argue that rather than using absolute rates of nest predation to make predictions about the costs of conspicuous colours, we should measure experimentally whether increases in plumage conspicuousness elevate rates of nest predation. Second, I present experimental data investigating the cost of red and brown colour at ground and tree nests. These data provide the first evidence that bright colours do attract predators to nests and that, in addition, this cost varies according to the nesting site. Natural selection seems to most strongly oppose the evolution of conspicuous colours in ground-nesting birds.     

The preparation and biological activity of novel amino acid analogs of butirosin

The aminoglycoside antibiotic butirosin (1) has been chemically modified in its amino acid side-chain. The (S)-()-4-amino-2-hydroxybutyryl side-chain was removed by alkaline hydrolysis of the tetrakis(5,5-dimethyl-3-oxo-1-cyclohexen-1-yl) derivative. The resulting deacylated, trisubstituted derivative 3 was reacylated with a wide variety of mono and polyfunctional amino acids. The cyclohexenyl protecting groups were then removed by chlorine gas and the new analogs isolated chromatographically. Structure-activity relationships were determined with five microorganisms, including Pseudomonas aeruginosa. The specific side-chain structures that exhibited maximum potency against Pseudomonas are identified.Butirosin¹, a new aminoglycoside antibiotic complex produced by mucoid strains of Bacillus circulans NRRL B-3312 and B-3313, is the first example of the aminocyclitol class of compounds to contain an amino acid in its chemical structure. Complete structural assignments for butirosin A and B have been described² and are shown in formula 1. The amino acid, which is connected by an amide linkage to N¹ of the deoxystreptamine moiety, was found to be the unique (S)-()-4-amino-2-hydroxybutyric acid². The butirosins have marked activity against Gram-positive and Gram-negative bacteria, including Pseudomonas aeruginosa, both in vitro and in vivo, as well as low toxicity in mammalian species^3,4. They were therefore likely candidates for structural-modification studies.