3699-71-6Relevant academic research and scientific papers
Identification of the Privileged Position in the Imidazo[1,2-a]pyridine Ring of Phosphonocarboxylates for Development of Rab Geranylgeranyl Transferase (RGGT) Inhibitors
Ka?mierczak, Aleksandra,Kusy, Damian,Niinivehmas, Sanna P.,Gmach, Joanna,Joachimiak, ?ukasz,Pentik?inen, Olli T.,Gendaszewska-Darmach, Edyta,B?azewska, Katarzyna M.
, p. 8781 - 8800 (2017)
Members of the Rab GTPase family are master regulators of vesicle trafficking. When disregulated, they are associated with a number of pathological states. The inhibition of RGGT, an enzyme responsible for post-translational geranylgeranylation of Rab GTPases represents one way to control the activity of these proteins. Because the number of molecules modulating RGGT is limited, we combined molecular modeling with biological assays to ascertain how modifications of phosphonocarboxylates, the first reported RGGT inhibitors, rationally improve understanding of their structure-activity relationship. We have identified the privileged position in the core scaffold of the imidazo[1,2-a]pyridine ring, which can be modified without compromising compounds' potency. Thus modified compounds are micromolar inhibitors of Rab11A prenylation, simultaneously being inactive against Rap1A/Rap1B modification, with the ability to inhibit proliferation of the HeLa cancer cell line. These findings were rationalized by molecular docking, which recognized interaction of phosphonic and carboxylic groups as decisive in phosphonocarboxylate localization in the RGGT binding site.
KINETIC STUDY OF THE HORNER-REACTION. II
Larsen, Rolf Olaf,Aksnes, Gunnar
, p. 229 - 238 (2007/10/02)
The results of the kinetic study of the Horner-reaction between m- and p-substituted benzaldehydes and two 2-carbethoxymethyl-substituted phosphinates (III and IV), and corresponding phosphine oxides (V and VI) in ethanolic sodium ethoxide are reported.The kinetics of the reactions are overall third order, first order in aldehyde, ethoxide and phosphinate, or phosphine oxide.The rates of the reaction are found to be increased by electron-withdrawing substituents in the benzaldehydes, in accordance with a rate-determining addition of the phosphoryl stabilized carbanion to the carbonyl group in the aldehydes.Phosphinate (III) are found to react about 35 times faster than the analogous phosphine oxide (V), in spite of the nearly equal pK-values of the two compounds.This rate effect is discussed in terms of their ability, in the reactions with aldehydes, to form a pentacoordinated intermediate.Within each group of compounds, the rate of the reaction is found to increase with increasing basicity of the phosphoryl stabilized carbanion.
