Isatin Derivatives as Inhibitors of Microtubule Assembly

This thesis describes the rationale, design, and syntheses of derivatives of isatin (1-H-indole-2,3-dione). Isatin was identified, during a high throughput screen of 10,000 compounds, as a potential scaffold for microtubule-destabilizing agents. Additional screening of purchased isatin derivatives gave rise to four substitution patterns of interest, 7-arylisatins, 5-methyl-N¬-alkyl/aryl isatins, 5-chloro-N-alkyl/aryl isatins and 5,7-dichloro-N-alkylated isatins. Series of compounds with the substitutions of interest were synthesized to further probe the structure-activity relationship (SAR) of isatin. The SAR study showed that substitutions in the 5- and 7- positions of the aromatic ring combined with N-substitutions increased the disruption of microtubule assembly. The 7-phenylisatin and N-arylisatin derivatives were inactive in the biological assay. Several of the 5-chloro-N-alkylisatins and the 5,7-dichloro-N-alkylisatins were cytotoxic in both MCF-7 and NCI/ADR-RES cell lines. 5,7-Dichloro-N-(4-bromobenzyl)isatin was the most active compound against MCF-7 cells, IC50 = 2.1 µM. To date the most cytotoxic compound tested is 5-methyl-N-(1-propyl)isatin, with an IC50 value of 52 nM (microtubule assembly IC50 = 2.6 µM) in the drug resistant cancer cell line NCI/ADR-RES