Phenylcinnamides as novel antimitotic agents.
Compound 8H is a phenylcinnamide that induces G2/M-phase cell cycle arrest and cell death in cancer cell lines. Here we show that 8H exerts its cytotoxic activity through disruption of microtubule dynamics in vitro and in cell culture. A series of cinnamide derivatives were synthesized and evaluated, and several new compounds were identified that improve on the activity of the parent compound, with IC(50) values for induction of cell death ranging from 1 to 10 microM. Notably, these compounds retain potency in the HL-60/VCR leukemia cell line, which is resistant to antimitotic cancer drugs vincrisitine and paclitaxel through up-regulation of P-glycoprotein drug efflux pumps. As P-glycoprotein expression is often responsible for drug resistance in cancer and the exclusion of compounds from the central nervous system, 8H and its derivatives merit further examination as potential antimitotic therapeutics, specifically for brain cancers and cancers that are resistant to standard antimitotic agents.
Leslie
Benjamin J
BJ
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Holaday
Clinton R
CR
Nguyen
Tran
T
Hergenrother
Paul J
PJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D050256:Antimitotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D002417:Cattle; D002934:Cinnamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D016195:G2 Phase / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D010539:Permeability; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020298:U937 Cells
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D050256:Antimitotic Agents; D002934:Cinnamates; D050257:Tubulin Modulators