DFT analysis of Co-alkyl and Co-adenosyl vibrational modes in B12-cofactors

Density functional theory (DFT)-based normal mode calculations have been carried out on models for B12-cofactors to assign reported isotope-edited resonance Raman spectra, which isolate vibrations of the organo-Co group. Interpretation is straightforward for alkyl-Co derivatives, which display prominent Co-C stretching vibrational bands. DFT correctly reproduces Co-C distances and frequencies for the methyl and ethyl derivatives. However, spectra are complex for adenosyl derivatives, due to mixing of Co-C stretching with a ribose deformation coordinate and to activation of modes involving Co-C-C bending and Co-adenosyl torsion. Despite this complexity, the computed spectra provide a satisfactory re-assignment of the experimental data. Reported trends in adenosyl-cobalamin spectra upon binding to the methylmalonyl CoA mutase enzyme, as well as on subsequent binding of substrates and inhibitors, provide support for an activation mechanism involving substrate-induced deformation of the adenosyl ligand.NRC publication: Ye

Preparation of titanocene-gold compounds based on highly active gold(I)-N-heterocyclic carbene anticancer agents: Preliminary in vitro studies in renal and prostate cancer cell lines

Heterometallic titanocene-based compounds containing gold(I)-phosphane fragments have been extremely successful against renal cancer in vitro and in vivo. The exchange of phosphane by N-heterocyclic carbene ligands to improve or modulate their pharmacological profile afforded bimetallic complexes effective against prostate cancer, but less effective against renal cancer in vitro. Herein we report the synthesis of new bimetallic Ti-Au compounds by the incorporation of two previously reported highly active gold(I)-N-heterocyclic carbene fragments derived from 4,5-diarylimidazoles. The two new compounds [(η5 -C5 H5 )2 TiMe(μ-mba)Au(NHC)] (where NHC=1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene, NHC-Bn 2 a; or 1,3-diethyl-4,5-diphenylimidazol-2-ylidene, NHC-Et 2 b) with the dual linker (-OC(O)-p-C6 H4 -S-) containing both a carboxylate and a thiolate group were evaluated in vitro against renal and prostate cancer cell lines. The compounds were found to be more cytotoxic than previously described Ti-Au compounds containing non-optimized gold(I)-N-heterocyclic fragments. We present studies to evaluate their effects on cell death pathways, migration, inhibition of thioredoxin reductase (TrxR) and vascular endothelial growth factor (VEGF) in the PC3 prostate cancer cell line. The results show that the incorporation of a second metallic fragment such as titanocene into biologically active gold(I) compounds improves their pharmacological profile.This work was supported by the US National Cancer Institute and the US National Institute for General Medical Sciences (NIGMS) grants 1SC1CA182844 and 2SC1GM127278‐05A1 (to M.C.). N.C. acknowledges a postdoctoral fellowship from the Fundación Alfonso Martín Escudero (Spain). N.G. thanks the Universidad de la Rioja (Spain) for a doctoral fellowship and a travel scholarship. M.A. thanks the Ministerio de Economía y Ciencia (MINECO, Spain) for a doctoral fellowship and a travel scholarship.Peer reviewe

Mode Recognition in UV Resonance Raman Spectra of Imidazole: Histidine Monitoring in Proteins

The imidazole side-chains of histidine residues perform key roles in proteins, and spectroscopic markers are of great interest. The imidazole Raman spectrum is subject to resonance enhancement at UV wavelengths, and a number of UVRR markers of structure have been investigated. We report a systematic experimental and computational study of imidazole UVRR spectra, which elucidates the band pattern, and the effects of protonation and deprotonation, of H/D exchange, of metal complexation, and of addition of a methyl substituent, modeling histidine itself. A consistent assignment scheme is proposed, which permits tracking of the bands through these chemical variations. The intensities are dominated by normal mode contributions from stretching of the strongest ring bonds, C₂N and C₄C₅, consistent with enhancement via resonance with a dominant imidazole π–π* transition