Discovery of (E)-3-((styrylsulfonyl)methyl)pyridine and (E)-2-((styrylsulfonyl)methyl)pyridine derivatives as anticancer agents: synthesis, structure-activity relationships, and biological activities.
ON01910.Na is a highly effective anticancer agent that induces mitotic arrest and apoptosis. Clinical studies with ON01910 in cancer patients have shown efficacy along with an impressive safety profile. While ON01910 is highly active against cancer cells, it has a low oral availability and requires continuous intravenous infusion or multiple gram doses to ensure sufficient drug exposure for biological activity in patients. We have identified two novel series of styrylsulfonyl-methylpyridines. Lead compounds 8, 9a, 18 and 19a are highly potent mitotic inhibitors and selectively cytotoxic to cancer cells. Impressively, these compounds possess excellent pharmaceutical properties and two lead drug candidates 9a and 18 demonstrated antitumor activities in animal models.
Centre for Drug Discovery and Development, Sansom Institute for Health Research and School of Pharmacy and Medical Sciences, University of South Australia , Adelaide, South Australia 5001, Australia.
Tiangong
T
Lu
Aik Wye
AW
Goh
Mingfeng
M
Yu
Julian
J
Adams
Frankie
F
Lam
Theodosia
T
Teo
Peng
P
Li
Ben
B
Noll
Longjin
L
Zhong
Sarah
S
Diab
Osama
O
Chahrour
Anran
A
Hu
Abdullahi Y
AY
Abbas
Xiangrui
X
Liu
Shiliang
S
Huang
Christopher J
CJ
Sumby
Robert
R
Milne
Carol
C
Midgley
Shudong
S
Wang
D000631:Aminopyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D017304:Annexin A5; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019540:Area Under Curve; D001682:Biological Availability; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D055808:Drug Discovery; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006207:Half-Life; D007202:Indicators and Reagents; D053208:Kaplan-Meier Estimate; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D051381:Rats; D013329:Structure-Activity Relationship; D013343:Styrenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
C000588582:3-methoxy-6-(((2,4,6-trimethoxystyryl)sulfonyl)methyl)pyridin-2-amine; D000631:Aminopyridines; D017304:Annexin A5; D000970:Antineoplastic Agents; D007202:Indicators and Reagents; C000588581:N-(2-methoxy-5-(((2,4,6-trimethoxystyryl)sulfonyl)methyl)pyridin-3-yl)methanesulfonamide; D013343:Styrenes; D013449:Sulfonamides; D013450:Sulfones; C507134:ON 01910; D005998:Glycine