867023-45-8Relevant articles and documents
Lipophilic tail modifications of 2-(hydroxymethyl)pyrrolidine scaffold reveal dual sphingosine kinase 1 and 2 inhibitors
Li, Hao,Sibley, Christopher D.,Kharel, Yugesh,Huang, Tao,Brown, Anne M.,Wonilowicz, Laura G.,Bevan, David R.,Lynch, Kevin R.,Santos, Webster L.
, (2021/01/07)
The sphingosine 1-phosphate (S1P) signaling pathway is an attractive target for pharmacological manipulation due to its involvement in cancer progression and immune cell chemotaxis. The synthesis of S1P is catalyzed by the action of sphingosine kinase 1 or 2 (SphK1 or SphK2) on sphingosine and ATP. While potent and selective inhibitors of SphK1 or SphK2 have been reported, development of potent dual SphK1/SphK2 inhibitors are still needed. Towards this end, we report the structure–activity relationship profiling of 2-(hydroxymethyl)pyrrolidine-based inhibitors with 22d being the most potent dual SphK1/SphK2 inhibitor (SphK1 Ki = 0.679 μM, SphK2 Ki = 0.951 μM) reported in this series. 22d inhibited the growth of engineered Saccharomyces cerevisiae and decreased S1P levels in histiocytic lymphoma myeloid cell line (U937 cells), demonstrating inhibition of SphK1 and 2 in vitro. Molecular modeling studies of 22d docked inside the Sph binding pocket of both SphK1 and SphK2 indicate essential hydrogen bond between the 2-(hydroxymethyl)pyrrolidine head to interact with aspartic acid and serine residues near the ATP binding pocket, which provide the basis for dual inhibition. In addition, the dodecyl tail adopts a “J-shape” conformation found in crystal structure of sphingosine bound to SphK1. Collectively, these studies provide insight into the intermolecular interactions in the SphK1 and 2 active sites to achieve maximal dual inhibitory activity.
Natural Product Neopeltolide as a Cytochrome bc1 Complex Inhibitor: Mechanism of Action and Structural Modification
Zhu, Xiao-Lei,Zhang, Rui,Wu, Qiong-You,Song, Yong-Jun,Wang, Yu-Xia,Yang, Jing-Fang,Yang, Guang-Fu
, (2019/03/19)
The marine natural product neopeltolide was isolated from a deep-water sponge specimen of the family Neopeltidae. Neopeltolide has been proven to be a new type of inhibitor of the cytochrome bc1 complex in the mitochondrial respiration chain. However, its detailed inhibition mechanism has remained unknown. In addition, neopeltolide is difficult to synthesize because of its very complex chemical structure. In the present work, the binding mode of neopeltolide was determined for the first time by integrating molecular docking, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area calculations, which showed that neopeltolide is a Qo site inhibitor of the bc1 complex. Then, according to guidance via inhibitor-protein interaction analysis, structural modification was carried out with the aim to simplify the chemical structure of neopeltolide, leading to the synthesis of a series of new neopeltolide derivatives with much simpler chemical structures. The calculated binding energies (ΔGcal) of the newly synthesized analogues correlated very well (R2 = 0.90) with their experimental binding free energies (ΔGexp), which confirmed that the computational protocol was reliable. Compound 45, bearing a diphenyl ether fragment, was successfully designed and synthesized as the most potent candidate (IC50 = 12 nM) against porcine succinate cytochrome c reductase. The molecular modeling results indicate that compound 45 formed a π-π interaction with Phe274 and two hydrogen bonds with Glu271 and His161. The present work provides a new starting point for future fungicide discovery to overcome the resistance that the existing bc1 complex inhibitors are facing.
PHOSPHONIUM SALTS DERIVATIVES AND THEIR USE AS SOLUBILITY CONTROLLING AUXILIARIES
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Page/Page column 59-60, (2010/02/14)
The present invention relates to the use of compounds of formula (IA) or (IIA): insert formula (IA) and (IIA) from page 15 of the disclosure wherein A represents various substituted or unsubstituted groups such as furyl, phenyl, pyridyl, naphthyl, or thiophenyl; X- represents an anion; and L1 represents a linker, as solubility controlling auxiliaries. These compounds can also be used as solubility controlling fragments of a molecule. The invention also relates to various methods of controlling the solubility of a molecule or a substrate. Moreover, the invention also relates to various phosphonium supported reagents or various phosphonium salts derivatives.
