1342891-34-2Relevant academic research and scientific papers
Examining the structure-activity relationship of benzopyran-based inhibitors of the hypoxia inducible factor-1 pathway
Ferguson, Jalisa,De Los Santos, Zeus,Devi, Narra,Van Meir, Erwin,Zingales, Sarah,Wang, Binghe
, p. 1731 - 1736 (2017/04/03)
Many forms of solid tumor have a characteristic feature known as hypoxia, which describes a low or non-existent presence of oxygen in the cellular microenvironment. This decrease in oxygen causes activation of the hypoxia inducible factor (HIF) pathway, w
Design and synthesis of benzopyran-based inhibitors of the hypoxia-inducible factor-1 pathway with improved water solubility
Ferguson, Jalisa H.,De Los Santos, Zeus,Devi, Saroja N.,Kaluz, Stefan,Van Meir, Erwin G.,Zingales, Sarah K.,Wang, Binghe
, p. 992 - 1001 (2017/08/09)
While progress has been made in treating cancer, cytotoxic chemotherapeutic agents are still the most widely used drugs and are associated with severe side-effects. Drugs that target unique molecular signalling pathways are needed for treating cancer with low or no intrinsic toxicity to normal cells. Our goal is to target hypoxic tumours and specifically the hypoxia inducible factor (HIF) pathway for the development of new cancer therapies. To this end, we have previously developed benzopyran-based HIF-1 inhibitors such as arylsulfonamide KCN1. However, KCN1 and its earlier analogs have poor water solubility, which hamper their applications. Herein, we describe a series of KCN1 analogs that incorporate a morpholine moiety at various positions. We found that replacing the benzopyran group of KCN1 with a phenyl group with a morpholinomethyl moiety at the para positions had minimal effect on potency and improved the water solubility of two new compounds by more than 10-fold compared to KCN1, the lead compound.
Structure-activity relationship of 2,2-dimethyl-2H-chromene based arylsulfonamide analogs of 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl) methyl]-N-phenylbenzenesulfonamide, a novel small molecule hypoxia inducible factor-1 (HIF-1) pathway inhibitor and anti-cancer agent
Mun, Jiyoung,Jabbar, Adnan Abdul,Devi, Narra Sarojini,Liu, Yuan,Van Meir, Erwin G.,Goodman, Mark M.
, p. 4590 - 4597 (2012/08/28)
We have discovered that 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl) methyl]-N-phenylbenzenesulfonamide, a novel small molecule HIF-1 pathway inhibitor, can antagonize tumor growth in animal models of cancer, but the treatment necessitates its delivery in a formulation, due to poor water solubility (15 μg/mL; pH 7.4), evidencing that the chemotype needs further exploration of its amenability to additional chemical modifications for ultimate optimization of function and pharmacology. As a first step towards this goal we investigated the structure-activity relationships of 15 lipophilic 2,2-dimethyl-2H-chromene based arylsulfonamide analogs of 3,4-dimethoxy-N-[(2,2- dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide to find out strategies of modification. A 3,4-dimethoxybenzenesulfonyl group in region 1 showed the strongest inhibition among five arylsulfonyl groups tested. The presence of propan-2-amine in region 2 conferred the strongest inhibitory effect of the compound on HIF-1 activated transcription in a reporter assay. These findings are important as they help define the structural motifs where the 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N- phenylbenzenesulfonamide can be chemically modified to improve its pharmacological properties towards development as a cancer therapeutic.
Design and synthesis of novel small-molecule inhibitors of the hypoxia inducible factor pathway
Mooring, Suazette Reid,Jin, Hui,Devi, Narra S.,Jabbar, Adnan A.,Kaluz, Stefan,Liu, Yuan,Van Meir, Erwin G.,Wang, Binghe
experimental part, p. 8471 - 8489 (2012/02/03)
Hypoxia, a reduction in partial oxygen pressure, is a salient property of solid tumors. Hypoxia drives malignant progression and metastasis in tumors and participates in tumor resistance to radio- and chemotherapies. Hypoxia activates the hypoxia-inducible factor (HIF) family of transcription factors, which induce target genes that regulate adaptive biological processes such as anaerobic metabolism, cell motility, and angiogenesis. Clinical evidence has demonstrated that expression of HIF-1 is strongly associated with poor patient prognosis and activation of HIF-1 contributes to malignant behavior and therapeutic resistance. Consequently, HIF-1 has become an important therapeutic target for inhibition by small molecules. Herein, we describe the design and synthesis of small molecules that inhibit the HIF-1 signaling pathway. Many of these compounds exhibit inhibitory activity in the nanomolar range. Separate mechanistic studies indicate that these inhibitors do not alter HIF-1 levels but interfere with the ability of HIF-1α/HIF-1β to interact with cofactors p300/CBP to form an active transcriptional complex. (Figure presented)
HIF INHIBITORS
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Page/Page column sheet 27, (2008/06/13)
HIF-1 inhibitors and methods of use thereof are provided.
