925442-73-5Relevant articles and documents
Discovery and evaluation of nNav1.5 sodium channel blockers with potent cell invasion inhibitory activity in breast cancer cells
Dutta, Shilpa,Lopez Charcas, Osbaldo,Tanner, Samuel,Gradek, Frédéric,Driffort, Virginie,Roger, Sébastien,Selander, Katri,Velu, Sadanandan E.,Brouillette, Wayne
, p. 2428 - 2436 (2018/04/23)
Voltage-gated sodium channels (VGSC) are a well-established drug target for anti-epileptic, anti-arrhythmic and pain medications due to their presence and the important roles that they play in excitable cells. Recently, their presence has been recognized in non-excitable cells such as cancer cells and their overexpression has been shown to be associated with metastatic behavior in a variety of human cancers. The neonatal isoform of the VGSC subtype, Nav1.5 (nNav1.5) is overexpressed in the highly aggressive human breast cancer cell line, MDA-MB-231. The activity of nNav1.5 is known to promote the breast cancer cell invasion in vitro and metastasis in vivo, and its expression in primary mammary tumors has been associated with metastasis and patient death. Metastasis development is responsible for the high mortality of breast cancer and currently there is no treatment available to specifically prevent or inhibit breast cancer metastasis. In the present study, a 3D-QSAR model is used to assist the development of low micromolar small molecule VGSC blockers. Using this model, we have designed, synthesized and evaluated five small molecule compounds as blockers of nNav1.5-dependent inward currents in whole-cell patch-clamp experiments in MDA-MB-231 cells. The most active compound identified from these studies blocked sodium currents by 34.9 ± 6.6% at 1 μM. This compound also inhibited the invasion of MDA-MB-231 cells by 30.3 ± 4.5% at 1 μM concentration without affecting the cell viability. The potent small molecule compounds presented here have the potential to be developed as drugs for breast cancer metastasis treatment.
Metal-Free Enantioselective Oxidative Arylation of Alkenes: Hypervalent-Iodine-Promoted Oxidative C?C Bond Formation
Shimogaki, Mio,Fujita, Morifumi,Sugimura, Takashi
, p. 15797 - 15801 (2016/12/16)
The enantioselective oxyarylation of (E)-6-aryl-1-silyloxylhex-3-ene was achieved using a lactate-based chiral hypervalent iodine(III) reagent in the presence of boron trifluoride diethyl etherate. The silyl ether promotes the oxidative cyclization, and enhances the enantioselectivity. In addition, the corresponding aminoarylation was achieved.
Targeting an Aromatic Hotspot in Plasmodium falciparum 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase with β-Arylpropyl Analogues of Fosmidomycin
Sooriyaarachchi, Sanjeewani,Chofor, René,Risseeuw, Martijn D. P.,Bergfors, Terese,Pouyez, Jenny,Dowd, Cynthia S.,Maes, Louis,Wouters, Johan,Jones, T. Alwyn,Van Calenbergh, Serge,Mowbray, Sherry L.
, p. 2024 - 2036 (2016/10/22)
Blocking the 2-C-methyl-d-erythrithol-4-phosphate pathway for isoprenoid biosynthesis offers new ways to inhibit the growth of Plasmodium spp. Fosmidomycin [(3-(N-hydroxyformamido)propyl)phosphonic acid, 1] and its acetyl homologue FR-900098 [(3-(N-hydroxyacetamido)propyl)phosphonic acid, 2] potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this biosynthetic pathway. Arylpropyl substituents were introduced at the β-position of the hydroxamate analogue of 2 to study changes in lipophilicity, as well as electronic and steric properties. The potency of several new compounds on the P. falciparum enzyme approaches that of 1 and 2. Activities against the enzyme and parasite correlate well, supporting the mode of action. Seven X-ray structures show that all of the new arylpropyl substituents displace a key tryptophan residue of the active-site flap, which had made favorable interactions with 1 and 2. Plasticity of the flap allows substituents to be accommodated in many ways; in most cases, the flap is largely disordered. Compounds can be separated into two classes based on whether the substituent on the aromatic ring is at the meta or para position. Generally, meta-substituted compounds are better inhibitors, and in both classes, smaller size is linked to better potency.
Identifying structural features on 1,1-diphenyl-hexahydro-oxazolo[3,4-a]pyrazin-3-ones critical for Neuropeptide S antagonist activity
Zhang, Yanan,Gilmour, Brian P.,Navarro, Hernan A.,Runyon, Scott P.
body text, p. 4064 - 4067 (2009/04/06)
A series of 7-substituted 1,1-diphenyl-hexahydro-oxazolo[3,4-a]pyrazin-3-ones were synthesized and tested for Neuropeptide S (NPS) antagonist activity. A concise synthetic route was developed, which features a DMAP catalyzed carbamate formation. 4-Fluorob
