Isatin (1H-indole-2,3-dione) and its derivatives demonstrate a diverse array of biological and pharmacological activities including anticonvulsant, antibacterial, antifungal, antiviral and anticancer properties. This broad spectrum of biochemical targets has been facilitated by the synthetic versatility of isatin, which has allowed the generation of a large number of structurally diverse derivatives including analogues derived from substitution of the aryl ring, and/or derivatisation of the isatin nitrogen and C2/C3 carbonyl moieties. The recent FDA approval of the oxindole sunitinib malate, as a kinase inhibitor for the treatment of advanced renal carcinoma and gastrointestinal stromal tumours, underscores the increasing interest in isatins as a new class of antineoplastic agents. In addition to potent kinase inhibition, the mechanism of action of other isatin derivatives includes the inhibition and/or modulation of proteases, translation initiation, neo-vascularisation and tubulin polymerisation. It was therefore the objective of this review to systematically evaluate the cytotoxic and anticancer properties of various substituted isatins and collate these findings to be used as a guide for future structure-activity relationship and mode of action studies. This is the first review to comprehensively discuss the in vitro and in vivo anticancer activities of isatin and its substituted derivatives.

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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.

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