Sulfonate derivatives of naphtho[2,3-b]thiophen-4(9H)-one and 9(10H)-anthracenone as highly active antimicrotubule agents. Synthesis, antiproliferative activity, and inhibition of tubulin polymerization.
Benzenesulfonate derivatives of naphtho[2,3-b]thiophen-4(9H)-one and 9(10H)-anthracenone were prepared and found to inhibit microtubule formation by an in vitro tubulin polymerization assay. Several analogues showed potent cytotoxic activity in an assay based on K562 leukemia cells with IC50 values of <100 nM. The methylamino analogue 14i was the most active compound in this assay (14i, IC50 K562: 0.05 muM). Antiproliferative activities of selected compounds were additionally evaluated against a panel of 12 tumor cell lines, including multi-drug-resistant phenotypes. All resistant cell lines were sensitive to these compounds. Concentration-dependent flow cytometric studies showed that KB/HeLa cells treated with selected compounds were arrested in the G2/M phases of the cell cycle. In competition experiments, these compounds strongly displaced radiolabeled colchicine from its binding site in the tubulin, showing IC50 values lower than that of colchicine. The results demonstrate that the antiproliferative activity is related to the inhibition of tubulin polymerization.
Zuse
Anne
A
Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, CancerCare Manitoba, ON6010-675 McDermot Avenue, Winnipeg, Canada.
Schmidt
Peter
P
Baasner
Silke
S
Böhm
Konrad J
KJ
Müller
Klaus
K
Gerlach
Matthias
M
Günther
Eckhard G
EG
Unger
Eberhard
E
Prinz
Helge
H
D000873:Anthracenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003078:Colchicine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015739:Nocodazole / Q000494:pharmacology; D011034:Podophyllotoxin / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000873:Anthracenes; D009281:Naphthalenes; D013876:Thiophenes; D014404:Tubulin; D050257:Tubulin Modulators; D011034:Podophyllotoxin; D015739:Nocodazole; D003078:Colchicine