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Structure activity analysis of the pro-apoptotic, antitumor effect of nitrostyrene adducts and related compounds.
- Source :
-
Biochemical pharmacology [Biochem Pharmacol] 2003 Feb 15; Vol. 65 (4), pp. 603-10. - Publication Year :
- 2003
-
Abstract
- In the present study, we outlined the part of the molecule mediating the prominent pro-apoptotic effect of the Michael adduct of ascorbic acid with p-chloro-nitrostyrene, a new synthetic phosphatase inhibitor. The nitrostyrene (NS) moiety was identified as the structure essential for apoptosis induction. NS and its ascorbic acid adducts displayed LC(50) values of 10-25 microM with no significant reduction of potency in okadaic acid resistant cells overexpressing the MDR1 P-glycoprotein. Induction of apoptosis by NS derivatives and the protein phosphatase 2A inhibitor cantharidic acid was proven by the analysis of caspase-3 activation and subsequent fragmentation of DNA. Further structure activity analysis revealed the necessity of the nitro group at the beta-position of the side chain. The pro-apoptotic potential of adducts of NS with pyrimidine- or pyridine-derivatives varied between NS and a progressive reduction in potency up to a nearly complete loss of cytotoxicity. Substitutions at the benzene core of NS suggested a prominent enhancement of toxicity only by substitutions at the 2- or 3-position. Heterocyclic aromatics can substitute for the benzene ring of NS albeit with a 2-3-fold reduced potency. In conclusion, nitrostyrene was identified as the core structure mediating the pro-apoptotic effect of a new synthetic phosphatase inhibitor. Further studies defined a nitrovinyl side chain attached to an aromatic ring as the pharmacophore structure of a new group of pro-apoptotic agents. These observations present the basis for the development of a new group of anticancer drugs.
- Subjects :
- Animals
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Apoptosis
Cell Survival drug effects
DNA Fragmentation drug effects
Rats
Structure-Activity Relationship
Styrenes chemical synthesis
Styrenes chemistry
Tumor Cells, Cultured
Antineoplastic Agents pharmacology
Styrenes pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0006-2952
- Volume :
- 65
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Biochemical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 12566088
- Full Text :
- https://doi.org/10.1016/s0006-2952(02)01618-0