Derivatives of Coenzyme F430 with a Covalently Attached α‐Axial Ligand. Part II

Abstract

Dedicated to Professor Duilio Arigoni on the occasion of his 75th birthday Coenzyme F 430 pentamethyl ester 2 was partially hydrolyzed to a mixture of the five F 430 tetramethyl esters 7 ± 11, which were separated by HPLC and identified by means of a full NMR characterization. The tetramethyl ester with a free COOH group at the side chain at C(3) of F 430 was coupled to the N-terminus of the peptidic spacerÀligand construct 12 selected and studied as described before. The UV/VIS and NMR spectra in CH 2 Cl 2 /3,3,3-trifluoroethanol 6 : 1 show that the new derivative, the Ni II (3 3 -dehydroxy-8 3 ,12 2 ,13 3 ,18 2tetra-O-methyl-F 430-3 3 -yl)-l-prolyl-l-prolyl-N p -methyl-l-histidine methyl ester (13), is an intramolecular, pentacoordinate, paramagnetic complex. In the same solvent system, the parent 3 3 ,8 3 ,12 2 ,13 3 ,18 2 -penta-Omethyl-F 430 (2) is four coordinate and diamagnetic even in the presence of equimolar 1H-imidazole. Protonation of the axially coordinating histidine residue of 13 gave the diamagnetic tetracoordinate base-off form, which allowed us to establish the constitution of 13 by NMR.

Discovery of Multiple Modified F 430 Coenzymes in Methanogens and Anaerobic Methanotrophic Archaea Suggests Possible New Roles for F 430 in Nature

“…Neither of these UV spectra is like any of the spectra for the eight different tetrahydro-and hexahydrocorphinoid Ni(II) complexes used to model the F 430 structure (28)(29)(30). The spectra are not consistent with a change in the ␣-axial ligands to the Ni(III), since such ligation is reported to affect the absorbance spectrum to only a small extent (31). The spectrum that we observed for F 430 -3 was, however, comparable to the UV spectrum of the F 330 produced by the reduction of the exocyclic keto group at the 17 3 position of the tetrahydrocorphin with borohydride (32).…”

Methyl‐Coenzyme M Reductase and its Nickel Corphin Coenzyme F 430 in Methanogenic Archaea

“…In the same solvent system, the parent 3 3 ,8 3 ,12 2 ,13 3 ,18 2 -penta-O-methyl-F 430 ester is four coordinate and diamagnetic even in the presence of equimolar 1-H-imidazole. Protonation of the axially coordinating histidine residue gave the diamagnetic tetracoordinate base-off form, which allowed to establish its constitution by NMR [102,103]. Likewise, tetraazamacrocyclic nickel(II) complexes with aliphatic methylthioand methoxy-substituted pendant chains were shown to have a coordination number of 5 and 4, respectively.…”

“…To obtain diastereoselectively coordinated complexes for mechanistic and spectroscopic studies of the free coenzyme in solution as models for F 430 bound within the active site, Bauer and Jaun [102,103] prepared partial-synthetic derivatives of coenzyme F 430 that have a coordinating group attached via a tripeptide linker to one of the propanoic acid side chains. Suitable linkers were evaluated based on molecular mechanics and NMR solution structures and the most promising linker, Pro-Pro-His(π-Me)-OMe was coupled via its N-terminus to the free carboxylate side chain at C(3) of F 430 tetramethyl ester.…”

Design of A Metabolically Stable Tritium‐Tracer of the PI3Kδ‐Inhibitor CDZ173 (Leniolisib) as a Tool to Study Liver Metabolites

“…Further it means that the rotational barrier between both conformers must be at least 81 kJ/mol and slightly lower at body temperature so that one conformer binds to PI3K δ . A similar conformational homogenization upon binding was observed in conformers of small molecule PRO‐ligands upon binding to a cofactor . For the synthetic metabolites 19 – 22 , the same 1:1 ration was observed in the 1 H‐NMR spectra, however a qualitative conformational analysis was not undertaken for these metabolites, i.e .…”

“…A similar conformational homogenization upon binding was observed in conformers of small molecule PRO-ligands upon binding to a cofactor. [35] For the synthetic metabolites 19 -22, the same 1:1 ration was observed in the 1 H-NMR spectra, however a qualitative conformational analysis was not undertaken for these metabolites, i.e. analytical data of these conformers are reported as 'conformer A' and 'conformer B' in the Experimental Section In the biologically relevant X-ray structure of CDZ173 bound to PI3Kd, [2] [36] the backbone of CDZ173 is cis, the oxygen is neither cis nor trans relative to the axial C(3 0 ) substituent and the pyrroldine puckering corresponds to the conformer IV in Scheme 4, while the carbonyl side chain is in plane with the pyrrolidine.…”