An Investigation into the Cytotoxicity and Mode of Action of Some Novel N-Alkyl-Substituted Isatins

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‘-methoxyeth...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2007-10, Vol.50 (21), p.5109-5117
Main Authors: Vine, Kara L, Locke, Julie M, Ranson, Marie, Pyne, Stephen G, Bremner, John B
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Apoptosis
Biological and medical sciences
Biopolymers
Caspase 3 - metabolism
Caspase 7 - metabolism
Cell Cycle - drug effects
Cell Line, Tumor
Drug Screening Assays, Antitumor
Enzyme Activation
General aspects
Humans
Isatin - analogs & derivatives
Isatin - chemical synthesis
Isatin - pharmacology
Lymphocytes - drug effects
Lymphocytes - pathology
Medical sciences
Microtubules - drug effects
Microtubules - ultrastructure
Pharmacology. Drug treatments
Stereoisomerism
Structure-Activity Relationship
Tubulin - chemistry
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Summary: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 μM. 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0704189