Glucopyranosylidene-spiro-imidazolinones, a New Ring System: Synthesis and Evaluation as Glycogen Phosphorylase Inhibitors by Enzyme Kinetics and X-ray Crystallography
<p></p><p>We
have discovered and studied a <i>tele</i>substitution reaction in a
biologically important heterocyclic ring system. Conditions that favour
the <i>tele</i>-substitution pathway were identified: the use of increased
equivalents of the nucleophile or decreased equivalents of base, or the use of
softer nucleophiles, less polar solvents and larger halogens on the
electrophile. Using results from X-ray crystallography and isotope labelling
experiments a mechanism for this unusual transformation is proposed. We focused
on this triazolopyrazine as it is the core structure of the <i>in
vivo </i>active anti-plasmodium compounds of Series 4 of the Open Source
Malaria consortium.</p>
<p> </p>
<p>Archive
of the electronic laboratory notebook with the description of all conducted
experiments and raw NMR data could be accessed via following link <a href="https://ses.library.usyd.edu.au/handle/2123/21890">https://ses.library.usyd.edu.au/handle/2123/21890</a> .
For navigation between entries of laboratory notebook please use file
"Strings for compounds in the article.pdf" that works as a reference
between article codes and notebook codes, also this file contain SMILES for
these compounds. </p><br><p></p>
Structure-based design and synthesis of two biphenyl-N-acyl-β-d-glucopyranosylamine derivatives as well as their assessment as inhibitors of human liver glycogen phosphorylase (hlGPa, a pharmaceutical target for type 2 diabetes) is presented. X-ray crystallography revealed the importance of structural water molecules and that the inhibitory efficacy correlates with the degree of disturbance caused by the inhibitor binding to a loop crucial for the catalytic mechanism. The in silico-derived models of the binding mode generated during the design process corresponded very well with the crystallographic data.
A survey has been made of the X-ray crystallography of some eighty sterol derivatives belonging mainly to the cholesterol and ergosterol series but including also calciferol and other photoderivatives of ergosterol and some higher plant and animal sterols. The measurements are recorded in four tables and include determinations of unit cell size, space group and some data on the crystal morphology and optics. In three cases, cholesteryl chloride, bromide and cholesteryl chloride hydrochloride, Patterson projections have also been derived from the intensities of the X-ray reflexions of the
hOl
planes. These confirm earlier deductions on the shape and size of the sterol molecules, proving that these are roughly lath-shaped, 20 x 7 x 4 A, and the details of the patterns can also to some degree be correlated with the actual arrangement of the carbon atoms in the sterol ring system and with the positions of the chlorine and bromine atoms. The arrangement of the molecules in the crystal units is closely that given by the preliminary examination from the optic orientation, and this has therefore been employed to suggest in each of the remaining sterol crystal structures the probable molecular arrangement
Di-tert-butylsilylene, generated by photolysis of hexa-tert-butylcyclotrisilane, reacts with the triple bond of adamantane-1-carbonitrile to furnish the 1,3-diaza-2,5-disilacyclohexa-3,6-diene 5. However, treatment of 2,2-dimethylpropanenitrile with dimesitylsilylene affords the azadisilacyclobutene ring system 6. The structures of 5 and 6 were determined by X-ray crystallography.Key words: silicon, silylene, silaheterocycles, X-ray crystallography.
Structure-based design and synthesis of two biphenyl-N-acyl-β-D-glucopyranosylamine derivatives as well as their assessment as inhibitors of human liver glycogen phosphorylase (hlGPa, a pharmaceutical target for type 2 diabetes) is presented. X-ray crystallography revealed the importance of structural water molecules and that the inhibitory efficacy correlates with the degree of disturbance caused by the inhibitor binding to a loop crucial for the catalytic mechanism. The in silico derived models of the binding mode generated during the design process corresponded very well with the crystallographic data.
Molecular insights into the mechanism of 4‐hydroxyphenylpyruvate dioxygenase inhibition: enzyme kinetics, X‐ray crystallography and computational simulations