novobiocin and benzamide

Hsp90 represents a promising target for the development of both anti-cancer and neuroprotective agents. Structure-activity relationship studies on novobiocin and novobiocin analogues, led to the development of KU-32 and recently, KU-596, as lead compounds for the potential treatment of neurodegenerative diseases. Similar to KU-32, we have demonstrated that upon replacement of the acetamide side chain present in KU-32 with a benzamide, this neuroprotective agent was transformed into a scaffold that manifests anti-proliferative activity. To assess structure-activity relationships for this new scaffold, a library of benzamide-containing novologues was prepared and evaluated against two breast cancer cell lines. Compound 14a manifested the most potent anti-proliferative activity from these studies and induced Hsp90-dependent client protein degradation in a concentration-dependent manner.

Topics: Antineoplastic Agents; Benzamides; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HSP90 Heat-Shock Proteins; Humans; MCF-7 Cells; Molecular Structure; Structure-Activity Relationship

A soluble arginine-specific mono(ADP-ribosyl)transferase was detected in dormant spores of Phycomyces blakesleeanus. Soluble proteins incubated with [32P]NAD revealed, after a two dimensional electrophoretic separation, three major ADP-ribosylated substrates with molecular weights of 38, 37, and 36 kDa and pI values of 6.9, 8.1 and 4.6, respectively. The addition of MgCl2 stimulated the (ADP-ribosyl)transferase activity. This enzymatic activity was stimulated by 250 microM NO-releasing agent sodium nitroprusside and inhibited with 8 mM benzamide, 0.4 mM meta-IodoBenzylGuanidine (MIBG), and 0.5 mM novobiocin. The three ADP-ribosylation inhibitors affected the germination of Phycomyces spores. The concentrations necessary to inhibit 50% of the spore germination of Phycomyces were 0.05 mM, 0.2 mM, and 8 mM for novobiocin, MIBG, and benzamide, respectively. All the above inhibitors affected the germination process to the same extent, that is, they inhibited the tube protuberation, leaving the spores as swollen cells. These data suggest that ADP-ribosylation may be involved in the germination process of Phycomyces, particularly in germ-tube formation.

Topics: 3-Iodobenzylguanidine; Adenosine Triphosphate; ADP Ribose Transferases; Benzamides; Enzyme Inhibitors; Guanosine Triphosphate; Iodobenzenes; Magnesium Chloride; Nitroprusside; Novobiocin; Phycomyces

A simple and sensitive procedure for testing various chemicals affecting DNA repair is presented. Cells, either labelled with [3H]thymidine or [14C]thymidine, were drug-treated or used as references cells. Both cell populations were irradiated with 5 Gy. The number of DNA breaks were determined, after mixing of drug-treated and reference cells of different labelling, at various intervals by the DNA unwinding technique and the drug-dependent DNA breaks were calculated. The drugs benzamide, 3-aminobenzamide, novobiocin and 9-beta-D-arabinofuranosyladenine (araA), all known to affect DNA repair, were used to study their effect on the number of DNA strand breaks with the presented technique. It was found that the assay improved the accuracy in determining the influence of DNA repair inhibitors compared to indirect measurements.

Topics: Animals; Benzamides; Carbon Radioisotopes; Cell Line; Cytarabine; DNA; DNA Damage; DNA Repair; DNA Replication; Kinetics; Novobiocin; Radioisotope Dilution Technique; Thymidine; Tritium