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Isatin (1H-indole-2,3-dione) and its derivatives are responsible for a broad spectrum of biological activities. Among these the cytotoxic and antineoplastic properties have been the most widely reported. The synthetic versatility of the isatin, due to its privileged scaffold, has led to the generation of a large number of structurally diverse derivatives which include analogues derived from either mono-, di-, and trisubstitution of the aryl ring A, and/or those obtained by derivatisation of the isatin nitrogen and C2/C3 carbonyl moieties. These compounds inhibit cancer cell proliferation and tumour growth via interaction with a variety of intracellular targets such as DNA, telomerase, tubulin, P-glycoprotein, protein kinases and phosphatases. Herein we review recent highlights in the development of isatin-based compounds as anticancer agents with a particular focus on the cytotoxicity and structure activity relationships.

To further expand the structure–cytotoxic activity relationships of isatin derivatives and to reduce flexibility in substituent groups at nitrogen, 20 analogues incorporating a ring system between the N1 and C7 atoms of isatin were prepared using a variety of synthetic strategies. This yielded pyrroloindole-, pyrroloquinoline-, pyrroloacridine-, pyrrolophenanthridine- and benzopyrrolophenanthridine-based systems with embedded isatin moieties, the latter possessing a novel carbon skeleton. These compounds were subsequently assessed for their in vitro cytotoxicity against human U937 lymphoma cells, with the brominated pyrroloacridine dione 27 showing the most promising activity (IC50 3.01 μM) after 24 h.

We have previously reported a series of pH-sensitive imine-linked N-alkylisatin prodrugs that are stable at pH 7.4, but readily cleaved at pH 4.5. Herein, one of the most potent prodrugs, 5,7-dibromo-N-(pmethoxybenzyl) isatin (NAI), was functionalized with a para-phenylpropionic acid linker, and the resulting NAI–imine prodrug conjugated to transferrin (Tf) to form a NAI–imine–Tf conjugate. Cytotoxicity assays revealed the conjugate was equipotent to the free drug against MCF-7 breast cancer cells, with clear selectivity patterns based on TfR levels. These results suggest that this novel isatin-based cytotoxin conjugated to a tumor targeting protein via an acid-labile linker warrants further preclinical testing.

Ligand-targeted drug delivery is currently one of the most challenging areas in pharmaceutical research involving the judicious choice of the drug, linker and targeting ligand. A promising new strategy involves conjugating a cytotoxin with a tumour-targeting protein through an acid-labile linker that is stable at physiological pH. Internalisation at the target tumour site via receptor-mediated processes exposes the conjugate to endosomal and lysosomal pH (4.5-6.0), resulting in selective release of the original cytotoxin inside the tumour cell. This thesis describes the synthesis of a new targeted anti-cancer agent and in particular, the development of the drug and linker component. Drug development: Isatin (11) and its derivatives are present in numerous natural products including the Australian marine mollusc, Dicathais orbita. These derivatives possess a broad spectrum of biological properties including anti-cancer activity. New tricyclic and polycyclic derivatives of isatin (11) were prepared since previous research within our group indicated isatin derivatives exhibit highly potent cytotoxic effects against a variety of human cancer cell lines. To expand the cytotoxic structure-relationship activity of isatin derivatives, the N1-C7 region of isatin (11) was investigated through the addition of a 5- or 6-membered ring (i.e. pyrrolo[3,2,1-hi]indole-1,2-dione and pyrrolo[3,2,1-ij]quinoline-1,2-dione derivatives respectively) to yield 23 analogues, 18 of which were novel. In vitro assays revealed the inclusion of the extra ring reduced cytotoxicity compared to the parent molecules. However, a novel brominated tetracyclic acridine-based isatin, 4-bromo-6H-pyrrolo[3,2,1-de]acridine-1,2-dione (144), displayed an IC50 value of 3.01 μM against U937 lymphoma cells and was the most cytotoxic tricyclic/polycyclic isatin derivative synthesised within this project. In general, thetetracyclic and pentacyclic isatins displayed greater activity than the analogous tricyclic deri

In this study a series of isatin-based, pH-sensitive aryl imine derivatives with differing aromatic substituents and substitution patterns were synthesised and their acid-catalysed hydrolysis evaluated. These derivatives were functionalised at the C3 carbonyl group of a potent N-substituted isatin cytotoxin and were stable at physiological pH but readily cleaved at pH 4.5. Observed rates of hydrolysis for the embedded imine-acid moiety were in the order para-phenylpropionic acid>phenylacetic acid (para>meta)>benzoic acid (meta>para). The ability to fine-tune hydrolysis rates in this way has potential implications for optimising imine linked, tumour targeting cytotoxin-protein conjugates

Arange of N-phenethyl,N-phenacyl, and N-(1- and 2-naphthylmethyl) derivatives of 5,7-dibromoisatin 2 were prepared byN-alkylation reactions. Their activity against human monocyte-like histiocytic lymphoma (U937), leukemia (Jurkat), and breast carcinoma (MDA-MB-231) cell lines was assessed. The results allowed further development of structureactivity relationships. The compound 5,7-dibromo-N-(1-naphthylmethyl)-1H-indole-2,3-dione 5a was the most potent against U937 cells with an IC50 value of 0.19 microM.