Novel p53 inactivators with neuroprotective action: syntheses and pharmacological evaluation of 2-imino-2,3,4,5,6,7-hexahydrobenzothiazole and 2-imino-2,3,4,5,6,7-hexahydrobenzoxazole derivatives.
Tumor suppressor protein, p53, is an intracellular protein that is critical within the biochemical cascade that leads to cell death via apoptosis. Recent studies identified the tetrahydrobenzothiazole analogue, pifithrin-alpha (2), as a p53 inhibitor that was effective in protecting neuronal cells against a variety of lethal insults and reducing the side effects of anticancer drugs. As up-regulation of p53 has been described as a common feature of several neurodegenerative disorders, including Alzheimer's disease, 2 and novel analogues (3-16) were synthesized to (i) assess the value of tetrahydrobenzothiazole analogues as neuroprotective agents and (ii) define the structural requirements for p53 inactivation. Not only did 2 exhibit neuroprotective activity in both tissue culture and in vivo stroke models but also compounds 6, 7, 10, 13, 15, and 16 proved to be highly potent in protecting PC12 cells and compounds 3, 4, and 6 were highly potent in protecting primary hippocampal cells against death induced by the DNA-damaging agent, camptothecin.
Zhu
Xiaoxiang
X
Laboratory of Neurosciences, Gerontology Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, Maryland 21224, USA.
Yu
Qian-Sheng
QS
Cutler
Roy G
RG
Culmsee
Carsten W
CW
Holloway
Harold W
HW
Lahiri
Debomoy K
DK
Mattson
Mark P
MP
Greig
Nigel H
NH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002166:Camptothecin / Q000633:toxicity; D046508:Culture Techniques; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D007097:Imines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
D001583:Benzoxazoles; D007097:Imines; D018696:Neuroprotective Agents; D013844:Thiazoles; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D002166:Camptothecin