An investigation into the cytotoxicity and mode of action of some novel N-alkyl-substituted isatins.

Abstract

A range of substituted N-alkylisatins were synthesized and their cytotoxicity evaluated against several cancer cell lines in vitro. SAR studies indicated that the introduction of an aromatic ring with a one or three carbon atom linker at N1 enhanced the activity from that of the allyl, 2'-methoxyethyl, and 3'-methylbutyl N-substituted isatins. Furthermore, electron-withdrawing groups substituted at the meta or para position of the ring were favored over the ortho orientation. Of the 24 compounds screened, nine displayed sub-micromolar IC50 values and in general demonstrated greater selectivity toward leukemia and lymphoma cell lines over any of the carcinoma cell lines tested. 5,7-Dibromo-N-(p-methylbenzyl)isatin (6) was the most active compound, inhibiting the metabolic activity of both U937 and Jurkat cancer cell lines at 0.49 muM. Various N-alkylisatins were also found to dramatically alter lymphocyte morphology, destabilize microtubules, inhibit tubulin polymerization, induce G2/M cell cycle arrest, and activate the effector caspase-3 and -7.

• Authors: Kara L Vine, Julie M Locke, Marie Ranson, Stephen G Pyne, John B Bremner
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 50 Issue 21 Pg. 5109-17 (Oct 18 2007) ISSN: 0022-2623 [Print] United States
• PMID: 17887662 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5,7-dibromo-N-(4-methylbenzyl)isatin
• Antineoplastic Agents
• Biopolymers
• Tubulin
• Isatin
• Caspase 3
• Caspase 7

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology)
• Apoptosis
• Biopolymers
• Caspase 3 (metabolism)
• Caspase 7 (metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Drug Screening Assays, Antitumor
• Enzyme Activation
• Humans
• Isatin (analogs & derivatives, chemical synthesis, pharmacology)
• Lymphocytes (drug effects, pathology)
• Microtubules (drug effects, ultrastructure)
• Stereoisomerism
• Structure-Activity Relationship
• Tubulin (chemistry)