Synthesis and pharmacological evaluation of N-(3-(1H-indol-4-yl)-5-(2-methoxyisonicotinoyl)phenyl)methanesulfonamide (LP-261), a potent antimitotic agent.
The synthesis and optimization of a series of orally bioavailable 1-(1H-indol-4-yl)-3,5-disubstituted benzene analogues as antimitotic agents are described. A functionalized dibromobenzene intermediate was used as a key scaffold, which when modified by sequential Suzuki coupling and Buchwald-Hartwig amination provided a flexible entry to 1,3,5-trisubstituted phenyl compounds. A 1H-indol-4-yl moiety at the 1-position was determined to be a critical feature for optimal potency. The compounds have been shown to induce cell cycle arrest at the G2/M phase and demonstrate efficacy in both cell viability and cell proliferation assays. The primary site of action for these agents is revealed by their colchicine competitive inhibition of tubulin polymerization, and a computational model has been developed for the association of these compounds to tubulin. An optimized lead LP-261 significantly inhibits growth of a human non-small-cell lung tumor (NCI-H522) in a mouse xenograft model.
Ansaris, Four Valley Square, Blue Bell, Pennsylvania 19401, United States. rshetty@ansarisbio.com
Rupa S
RS
Shetty
Younghee
Y
Lee
Bin
B
Liu
Arifa
A
Husain
Rhoda W
RW
Joseph
Yixin
Y
Lu
David
D
Nelson
John
J
Mihelcic
Wenchun
W
Chao
Kristofer K
KK
Moffett
Andreas
A
Schumacher
Dietmar
D
Flubacher
Aleksandar
A
Stojanovic
Marina
M
Bukhtiyarova
Ken
K
Williams
Kyoung-Jin
KJ
Lee
Alexander R
AR
Ochman
Michael S
MS
Saporito
William R
WR
Moore
Gary A
GA
Flynn
Bruce D
BD
Dorsey
Eric B
EB
Springman
Ted
T
Fujimoto
Martha J
MJ
Kelly
D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003078:Colchicine / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D016195:G2 Phase; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007539:Isonicotinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D007211:Indoles; D007539:Isonicotinic Acids; C562240:N-(3-(1H-indol-4-yl)-5-(2-methoxyisonicotinoyl)phenyl)methanesulfonamide; D013449:Sulfonamides; D014404:Tubulin; D050257:Tubulin Modulators; D003078:Colchicine