Substituted benzocyloheptenes as potent and selective alpha(v) integrin antagonists

A novel series of potent and specific alpha(v) integrin antagonists has been obtained by aminoalkyl substitutions on benzocyloheptene acetic acids as a rigid GD bioisostere. The preferred compounds 1-2, 1-3 and 1-8, showed nano- to subnanomolar IC(50) values on alpha(v)beta(3) and alpha(v)beta(5) integrins, with favorable pharmacokinetics.     

Gamma irradiation and cellular damage in Kocuria rosea: investigation by one- and two-dimensional infrared spectroscopy

Fourier transform infrared (FT-IR) spectroscopy was used to investigate the radiation-induced effects on Kocuria rosea. Bacterial suspensions at the stationary phase were exposed to increasing doses of gamma radiation. In the region 1350-840cm(-1), assigned to phosphodiester backbone, nucleic acids, and sugar rings, the radical damaging effects were dose-dependent, with the first threshold at 2.75kGy and the second at 13.75kGy inducing more striking spectral variations. Postirradiation reincubation did not significantly affect the biomolecular response, except in the spectral range 1100-1000cm(-1). These observations suggest the occurrence of new phylogenetic characteristics for K. rosea following irradiation. Moreover, two-dimensional analysis was used to highlight correlated evolutions of molecular species as radical aggression increased. The results point to an evolutionary scheme during the time course of irradiation. Thus, one- and two-dimensional IR analyses are convenient means of investigating the metabolic events following oxidative stress generated by either chemical or physical agents.     

The Drosophila orphan nuclear receptor DHR38 mediates an atypical ecdysteroid signaling pathway

Ecdysteroid pulses trigger the major developmental transitions during the Drosophila life cycle. These hormonal responses are thought to be mediated by the ecdysteroid receptor (EcR) and its heterodimeric partner Ultraspiracle (USP). We provide evidence for a second ecdysteroid signaling pathway mediated by DHR38, the Drosophila ortholog of the mammalian NGFI-B subfamily of orphan nuclear receptors. DHR38 also heterodimerizes with USP, and this complex responds to a distinct class of ecdysteroids in a manner that is independent of EcR. This response is unusual in that it does not involve direct binding of ecdysteroids to either DHR38 or USP. X-ray crystallographic analysis of DHR38 reveals the absence of both a classic ligand binding pocket and coactivator binding site, features that seem to be common to all NGFI-B subfamily members. Taken together, these data reveal the existence of a separate structural class of nuclear receptors that is conserved from fly to humans.     

Transition metal complexes of buparvaquone as potent new antimalarial agents. 1. Synthesis,X-ray crystal-structures,electrochemistry and antimalarial activity against Plasmodium falciparum

New Cu(II), Ni(II), Co(II), Fe(II), and Mn(II) metal complexes of buparvaquone [3-trans(4-tert.-butylcyclohexyl)methyl-2-hydroxy-1,4-naphthoquione] (L1H) have been synthesized and characterized using IR, electron paramagnetic resonance (EPR) spectroscopy, microanalytical methods and single crystal X-ray diffraction methods. The single crystal structures were determined for ligand L1H [space group P-1 with a=6.2072(14) A, b=10.379 (2) A, c=13.840 (3) A, V=878.7(3) A(3), Z=2, D(calcd.)=1.234 mg/m(3)] and copper complex [Cu(L1)(2)(C(2)H(5)OH)(2)] C1 [space group I2/a with a=17.149(14) A, b=9.4492(8) A, c=26.946(3) A, V=4335.3(7)A(3), Z=4, D(calcd.)=1.233 mg/m(3)]. All the metal complexes along with the parent ligand have been studied for their electrochemical properties using cyclic voltammetric techniques. The compounds were tested for their in vitro antimalarial activity against Plasmodium falciparum strains. A correlation between the antimalarial activity and the redox property of these complexes is presented. The copper complex C1 exhibits significantly higher growth inhibitory activity both in vitro and in vivo than the parent ligand.