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

Xiaoxiang Zhu, Qian sheng Yu, Roy G. Cutler, Carsten W. Culmsee, Harold W. Holloway, Debomoy Lahiri, Mark P. Mattson, Nigel H. Greig

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

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-α (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.

Original languageEnglish
Pages (from-to)5090-5097
Number of pages8
JournalJournal of Medicinal Chemistry
Volume45
Issue number23
DOIs
StatePublished - Nov 7 2002

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Cell death
Cell Death
Pharmacology
Derivatives
Tumor Suppressor Protein p53
Camptothecin
Tissue culture
PC12 Cells
Neuroprotective Agents
Drug-Related Side Effects and Adverse Reactions
Neurodegenerative Diseases
Up-Regulation
Stroke
Apoptosis
DNA
Pharmaceutical Preparations
Proteins
pifithrin
Alzheimer disease type 2

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

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. / Zhu, Xiaoxiang; Yu, Qian sheng; Cutler, Roy G.; Culmsee, Carsten W.; Holloway, Harold W.; Lahiri, Debomoy; Mattson, Mark P.; Greig, Nigel H.

In: Journal of Medicinal Chemistry, Vol. 45, No. 23, 07.11.2002, p. 5090-5097.

Research output: Contribution to journalArticle

Zhu, Xiaoxiang ; Yu, Qian sheng ; Cutler, Roy G. ; Culmsee, Carsten W. ; Holloway, Harold W. ; Lahiri, Debomoy ; Mattson, Mark P. ; Greig, Nigel H. / 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. In: Journal of Medicinal Chemistry. 2002 ; Vol. 45, No. 23. pp. 5090-5097.
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