title: Synthesis and Biological Evaluation of Manassantin Analogues for Hypoxia-Inducible Factor 1α Inhibition.
abstract: To cope with hypoxia, tumor cells have developed a number of adaptive mechanisms mediated by hypoxia-inducible factor 1 (HIF-1) to promote angiogenesis and cell survival. Due to significant roles of HIF-1 in the initiation, progression, metastasis, and resistance to treatment of most solid tumors, a considerable amount of effort has been made to identify HIF-1 inhibitors for treatment of cancer. Isolated from Saururus cernuus, manassantins A (1) and B (2) are potent inhibitors of HIF-1 activity. To define the structural requirements of manassantins for HIF-1 inhibition, we prepared and evaluated a series of manassantin analogues. Our SAR studies examined key regions of manassantin's structure in order to understand the impact of these regions on biological activity and to define modifications that can lead to improved performance and drug-like properties. Our efforts identified several manassantin analogues with reduced structural complexity as potential lead compounds for further development. Analogues MA04, MA07, and MA11 down-regulated hypoxia-induced expression of the HIF-1α protein and reduced the levels of HIF-1 target genes, including cyclin-dependent kinase 6 (Cdk6) and vascular endothelial growth factor (VEGF). These findings provide an important framework to design potent and selective HIF-1α inhibitors, which is necessary to aid translation of manassantin-derived natural products to the clinic as novel therapeutics for cancers.
authors.affiliation: Department of Chemistry, Duke University , Durham, North Carolina 27708, United States.
authors.forename: Do-Yeon
authors.initials: DY
authors.lastname: Kwon
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University , 80 Daehak-ro, Buk-gu, 702-701 Daegu, Republic of Korea.
authors.forename: Hye Eun
authors.initials: HE
authors.lastname: Lee
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Weitzel
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University , 80 Daehak-ro, Buk-gu, 702-701 Daegu, Republic of Korea.
authors.forename: Kyunghye
authors.initials: K
authors.lastname: Park
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University , 80 Daehak-ro, Buk-gu, 702-701 Daegu, Republic of Korea.
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Chen-Ting
authors.initials: CT
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Duke University , Durham, North Carolina 27708, United States.
authors.forename: Tesia N
authors.initials: TN
authors.lastname: Stephenson
authors.affiliation: Department of Chemistry, Duke University , Durham, North Carolina 27708, United States.
authors.forename: Hyeri
authors.initials: H
authors.lastname: Park
authors.affiliation: Department of Chemistry, Duke University , Durham, North Carolina 27708, United States.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fitzgerald
authors.forename: Jen-Tsan
authors.initials: JT
authors.lastname: Chi
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mook
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University , 80 Daehak-ro, Buk-gu, 702-701 Daegu, Republic of Korea.
authors.forename: You Mie
authors.initials: YM
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Duke University , Durham, North Carolina 27708, United States.
authors.forename: Jiyong
authors.initials: J
authors.lastname: Hong
mesh_terms: D060326:Chemistry Techniques, Synthetic; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000737:chemistry; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020128:Inhibitory Concentration 50; D017705:Lignans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure
chemical_list: D003432:Cross-Linking Reagents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017705:Lignans; C054895:manassantin A