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'-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.
Vine
Kara L
KL
School of Biological Sciences, and Department of Chemistry, University of Wollongong, NSW 2522, Australia. klv04@uow.edu.au
Locke
Julie M
JM
Ranson
Marie
M
Pyne
Stephen G
SG
Bremner
John B
JB
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis; D001704:Biopolymers; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D006801:Humans; D007510:Isatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology; D008870:Microtubules / Q000187:drug effects / Q000648:ultrastructure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry
C524271:5,7-dibromo-N-(4-methylbenzyl)isatin; D000970:Antineoplastic Agents; D001704:Biopolymers; D014404:Tubulin; D007510:Isatin; D053148:Caspase 3; D053179:Caspase 7