Discovery of novel 2-N-aryl-substituted benzenesulfonamidoacetamides: orally bioavailable tubulin polymerization inhibitors with marked antitumor activities.
The discovery and optimization of a series of 2-N-aryl-substituted benzenesulfonamidoacetamides as novel tubulin polymerization inhibitors are described. Pharmacophore exploration of hit compound AH-487 identified the optimal structure of N-heteroaryl-2-(4-methoxy-N-(3-(trifluoromethyl)phenyl)phenylsulfonamido)acetamide as a potent antimitotic agent. Subsequent lead compounds 4b and 4c, with N-4-aminophenyl and N-1H-indol-5-yl substitutions at the acetamide position, respectively, were shown to induce cell-cycle arrest at the G(2) /M phase and lead to an accumulation of HeLa cells in the sub-G(1) phase. More significantly, these lead compounds (3c, 4b, and 4c) exhibit impressive cytotoxicity against a panel of cancer cells including P-glycoprotein-overexpressing MDR-positive cells, with potency greater than or equal to clinically studied benzenesulfonamide E7010. Mechanistic studies demonstrated that derivatives of AH-487 disrupt mitotic spindles by inhibiting microtubule polymerization and induce apoptosis via induction of Bcl-2 phosphorylation in tumor cells. The optimized leads 4b and 4c strongly inhibited the growth of human hepatocellular carcinoma cells in a mouse xenograft model.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Zulong
Z
Liu
Zuyu
Z
Zhou
Wei
W
Tian
Xing
X
Fan
Ding
D
Xue
Long
L
Yu
Qiang
Q
Yu
Ya-Qiu
YQ
Long
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000627:Aminophenols / Q000494:pharmacology; D000818:Animals; D050256:Antimitotic Agents / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001682:Biological Availability; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018432:Drug Resistance, Multiple; D016195:G2 Phase / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000096926:Benzenesulfonamides
D018435:ATP Binding Cassette Transporter, Subfamily B; D000627:Aminophenols; D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D050257:Tubulin Modulators; C079199:E 7010; D000096926:Benzenesulfonamides