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

J Med Chem. 2007 Oct 18;50(21):5109-17. doi: 10.1021/jm0704189. Epub 2007 Sep 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / 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*
  • Isatin / chemical synthesis*
  • Isatin / pharmacology
  • Lymphocytes / drug effects
  • Lymphocytes / pathology
  • Microtubules / drug effects
  • Microtubules / ultrastructure
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tubulin / chemistry


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