title: Synthesis and biological evaluation of 1,2-dithiol-3-thiones and pyrrolo[1,2-a]pyrazines as novel hypoxia inducible factor-1 (HIF-1) inhibitor.
abstract: Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor which is strongly associated with tumor survival, progression, and therapeutic resistance. Accordingly, it has been suggested that the inhibition of the HIF-1 pathway can suppress tumor, and it has become an important therapeutic target. In present study, oltipraz, its metabolite M2, and their derivatives were synthesized and evaluated as HIF-1α inhibitors. Among the synthesized, benzyl-substituted pyrrolo[1,2-a]pyrazine 2g most potently inhibited HIF-1α protein accumulation (81% at 10μM) and VEGF, GLUT-1 transcription (77% and 92% at 10μM, respectively).
authors.affiliation: Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul 02447, Republic of Korea.
authors.forename: Young Hun
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Sang Geon
authors.initials: SG
authors.lastname: Kim
authors.affiliation: Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul 02447, Republic of Korea; Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address: kyslee@khu.ac.kr.
authors.forename: Yong Sup
authors.initials: YS
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051272:Glucose Transporter Type 1 / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013871:Thiones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D011719:Pyrazines; D013871:Thiones; D013876:Thiophenes; D042461:Vascular Endothelial Growth Factor A; C026209:oltipraz; C049325:1,2-dithiol-3-thione
keywords: GLUT-1; Hypoxia inducible factor-1; Oltipraz; Pyrrolopyrazine; VEGF