Biomedical subjects

S Lautar

Publications and source records attributed to S Lautar.

3 recordsLinked to original sources

PubMed2001

Synthesis of substituted 5[H]phenanthridin-6-ones as potent poly(ADP-ribose)polymerase-1 (PARP1) inhibitors.

1-, 2-, 3-, 4-, 8-, or 10-Substituted 5(H)phenanthridin-6-ones were synthesized and found to be potent PARP1 inhibitors. Among the 28 compounds prepared, some showed not only low IC(50) values (compound 1b, 10 nM) but also desirable water solubility characteristics. These properties, which are superior to the common PARP1 inhibitors such as benzamides and isoquinolin-1-ones, are essential for potential therapeutic usage. The variety of compounds allows SAR analysis of favored substituents and substituted positions on 5(H)phenanthridin-6-one ring.

Enzyme Inhibitors↗

PubMed2000

GPI 6150 prevents H(2)O(2) cytotoxicity by inhibiting poly(ADP-ribose) polymerase.

GPI 6150 (1,11b-dihydro-[2H]benzopyrano[4,3,2-de]isoquinolin-3-one) is a novel inhibitor of poly(ADP-ribose) polymerase (PARP). It has demonstrated efficacy in rodent models of focal cerebral ischemia, traumatic brain injury, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine damage to dopaminergic neurons, regional myocardial ischemia, streptozotocin-induced diabetes, septic shock, and arthritis. Here we report the structure of GPI 6150, its enzymatic characteristics, and biochemical property in cytoprotection. As a competitive PARP inhibitor (K(i) = 60 nM), GPI 6150 protected the P388D1 cells against hydrogen peroxide cytotoxicity, by preventing PARP activation and the depletion of NAD(+), the substrate for PARP. To address the concerns of potential side effects of PARP inhibition, we tested GPI 6150 and found it had no effect on the repair and expression of a plasmid DNA damaged by N-methyl-N'-nitro-N-nitrosoguanidine. Neither did it affect dehydrogenases with NAD co-enzyme. GPI 6150 was much less potent to inhibit mono-ADP-ribosyltransferase. There was no selectivity for GPI 6150 between PARP isozymes. These attributes render GPI 6150 a useful tool to probe the functions of PARP.

ADP Ribose Transferases↗

PubMed1996

A yeast three-hybrid method to clone ternary protein complex components.

The yeast two-hybrid system is a powerful technique to detect binary protein interactions. In order to facilitate ternary complex analysis, we have developed the yeast three-hybrid system. Using epidermal growth factor (EGF) receptor, Grb2 and Sos proteins as an example, we demonstrated the use of the three-hybrid system to detect formation of a three-component complex, i.e., the Grb2-mediated interactions between EGF receptor and Sos. We then used the three-hybrid system to screen a library with Gal4-DNA binding domain -EGF receptor and Gal4 activation domain-Sos fusion proteins and isolated a plasmid encoding Grb2. Thus, the three-hybrid system is useful for characterizing and cloning components of ternary protein complexes.

Adaptor Proteins, Signal Transducing↗