title: Imino-tetrahydro-benzothiazole derivatives as p53 inhibitors: discovery of a highly potent in vivo inhibitor and its action mechanism.
abstract: Several neurological disorders manifest symptoms that result from the degeneration and death of specific neurons. p53 is an important modulator of cell death, and its inhibition could be a therapeutic approach to several neuropathologies. Here, we report the design, synthesis, and biological evaluation of novel p53 inhibitors based on the imino-tetrahydrobenzothiazole scaffold. By performing studies on their mechanism of action, we find that cyclic analogue 4b and its open precursor 2b are more potent than pifithrin-alpha (PFT-alpha), which is known to block p53 pro-apoptotic activity in vitro and in vivo without acting on other pro-apoptotic pathways. Using spectroscopic methods, we also demonstrate that open form 2b is more stable than 4b in biological media. Compound 2b is converted into its corresponding active cyclic form through an intramolecular dehydration process and was found two log values more active in vivo than PFT-alpha. Thus, 2b can be considered as a new prodrug prototype that prevents in vivo p53-triggered cell death in several neuropathologies and possibly reduces cancer therapy side effects.
authors.affiliation: Developmental Biology Institute of Marseille, Université. de la Mediterranée, Inserm UMR623, CNRS, INSERM, Campus de Luminy-Case 907, Marseille Cedex 09, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pietrancosta
authors.forename: Anice
authors.initials: A
authors.lastname: Moumen
authors.forename: Rosanna
authors.initials: R
authors.lastname: Dono
authors.forename: Paul
authors.initials: P
authors.lastname: Lingor
authors.forename: Veronique
authors.initials: V
authors.lastname: Planchamp
authors.forename: Fabienne
authors.initials: F
authors.lastname: Lamballe
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Kraus
authors.forename: Flavio
authors.initials: F
authors.lastname: Maina
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D019771:Axotomy; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D015195:Drug Design; D004355:Drug Stability; D005047:Etoposide / Q000633:toxicity; D007097:Imines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D019579:Neocortex / Q000166:cytology; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009900:Optic Nerve / Q000502:physiology; D010766:Phosphorylation; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014822:Vitreous Body
chemical_list: C512077:1-(4-nitrophenyl)-2-(4,5,6,7-tetrahydro-2-imino-3(2H)-benzothiazolyl)ethanone; D000970:Antineoplastic Agents; D052160:Benzothiazoles; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007097:Imines; D018696:Neuroprotective Agents; D011355:Prodrugs; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; D005047:Etoposide; C121565:pifithrin