Synthesis of (aryloxyacetylamino)-isonicotinic/nicotinic acid analogues as potent hypoxia-inducible factor (HIF)-1alpha inhibitors.
We report a new series of HIF-1alpha inhibitors which were obtained through structural modifications of previously reported lead 1. The in vitro inhibitory potencies of newly synthesized compounds were evaluated against hypoxia-induced HIF-1 activation using cell-based reporter assay in three human cancer cell lines including SK-Hep-1, Hep3B, and AGS cells. Several compounds displayed significant inhibitory activity in all the three tested cell lines. In particular, analogue 17 displayed potent inhibition of hypoxia-induced accumulation of HIF-1alpha protein in Hep3B cell line, in addition to the dose-dependent inhibition of HIF-1 target genes VEGF and EPO.
Boovanahalli
Shanthaveerappa K
SK
Molecular Cancer Research Center, KRIBB, Daejeon 305-806, Republic of Korea.
Jin
Xuejun
X
Jin
Yinglan
Y
Kim
Jin Hwan
JH
Dat
Nguyen Tien
NT
Hong
Young-Soo
YS
Lee
Jeong Hyung
JH
Jung
Sang-Hun
SH
Lee
Kyeong
K
Lee
Jung Joon
JJ
D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D007539:Isonicotinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D009525:Niacin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007539:Isonicotinic Acids; D009525:Niacin