Toward the Design of Photoresponsive Conditional Antivitamins B₁₂: A Transient Absorption Study of an Arylcobalamin and an Alkynylcobalamin

Abstract

Cobalamins are of widespread importance in biology. Both of the cofactors essential for human metabolism, the organocobalamins coenzyme B and methylcobalamin, are highly photolabile, as are other alkylcobalamins. The alkynylcobalamin phenylethynylcobalamin (PhEtyCbl) and the arylcobalamin 4-ethylphenylcobalamin (EtPhCbl) with "atypical" Co-C-bonds to unsaturated carbons, were recently designed as metabolically inert cobalamins, classified as "antivitamins B". The further development of an ideal light-activated or "conditional" antivitamin B would require it to be readily converted by light into an active B vitamin form. Very photolabile "antivitamins B" would also represent particularly useful scaffolds for therapeutic light-activated reagents. Here, the photoactive arylcobalamin EtPhCbl and the remarkably photostable alkynylcobalamin PhEtyCbl are examined using femtosecond to picosecond UV-visible transient absorption spectroscopy. PhEtyCbl undergoes internal conversion to the ground state with near unit quantum yield on a time scale < 100 ps and an activation energy of 12.6 ± 1.4 kJ/mol. The arylcobalamin EtPhCbl forms an excited state with a ca. 247 ps lifetime. This excited state branches between internal conversion to the ground state and formation of a long-lived base-off species with a quantum yield of ∼9%. Anaerobic steady state photolysis of "light-sensitive" EtPhCbl results in the formation of cob(II)alamin, but only with quantum yield <1%. Hence, our studies suggest that suitably modified arylcobalamins may be a rational basis for the design of photoresponsive "antivitamins B".

Antivitamin B12 Inhibition of the Human B12‐Processing Enzyme CblC: Crystal Structure of an Inactive Ternary Complex with Glutathione as the Cosubstrate

“…As reported earlier for ethynyl-Cbl [14] and for 2 , [11–12] solutions of 3 were stable to sunlight (SI, Figure S8). In aqueous solution, 3 underwent slow pH-dependent hydrolysis to H 2 OCbl.…”

“…Vitamin B 12 (cyanocobalamin, CNCbl) and other cobalamins (Cbls) are indispensable for the mammalian metabolism [1] on account of the essential cofactor activities of coenzyme B 12 (AdoCbl) and methylcobalamin (MeCbl). [2] To provide mammalian cells with AdoCbl and MeCbl, natural Cbls are first transformed into cob(II)alamin (Cbl II )b ythe Cblprocessing chaperone CblC (also named MMACHC,f or methylmalonic aciduria type Ca nd homocystinuria).…”

“…[3] CblC binds Cbls base-off and removes their axial Co b ligand [3c, 4] to furnish Cbl II ,t he relevant biosynthetic precursor of AdoCbl and MeCbl. [3c] Cbls that are transported into cells,but are not deligated there by CblC,remain metabolically inert and have been classified as B 12 antivitamins. [5] Such inert vitamin B 12 derivatives induce symptoms of B 12 deficiencyi nl aboratory animals, [6] as does ad ysfunctional CblC in humans.…”

“…[3c] Cbls that are transported into cells,but are not deligated there by CblC,remain metabolically inert and have been classified as B 12 antivitamins. [5] Such inert vitamin B 12 derivatives induce symptoms of B 12 deficiencyi nl aboratory animals, [6] as does ad ysfunctional CblC in humans. [3b] To clarify still puzzling roles of Cbls in humans, [1,7] B 12 deficiencyisstudied in laboratory animals.The application of B 12 antivitamins [5,8] is ar ather animal-friendly means in such studies.…”

Alpha‐ and Beta‐Diastereoisomers of Phenylcobalamin from Cobalt‐Arylation with Diphenyliodonium Chloride

“…However, when compared to alkylcobalamins, such as MeCbl , the two isomeric phenyl‐Cbls, PhCbl and αPhCbl , underwent light‐induced interconversion rather slowly. In line with the apparent comparable stability of PhCbl and αPhCbl , recent fsec laser pulse studies with EtPhCbl , indicated this aryl‐Cbl to be far less light‐sensitive than MeCbl and AdoCbl , and to exhibit a low quantum yield of Co−C bond homolysis (<1 %) due to fast internal conversion of the singlet excited state(s) of EtPhCbl to the ground state.…”