Proton speciation and microspeciation of vinpocetine and related compounds in aqueous and biomimetic media.
OBJECTIVE
The determination of protonation macroconstants of twelve compounds in the vincamine drug family and the determination of protonation microconstants of cis- and trans-apovincaminic acid in media of various solvent composition to characterise their site-specific basicity and to estimate the concentration of the membrane-penetrating and receptor-binding forms.


METHODS
UV-pH titrations have been used to determine the protonation macroconstants in 10-43 wt% methanol/water mixtures. Yasuda-Shedlovsky extrapolation was applied to obtain aqueous logK values for compounds sparingly soluble in water. Protonation microconstants were also determined by deductive methods for compounds of free carboxylic group.


RESULTS
In the case of the two water-soluble compounds the extrapolated and the directly measured aqueous logK values were in good agreement, verifying all other extrapolated data. Compounds of cis-D/E ring anellation are 0.4-0.8 logK units more basic than their epimeric, trans counterparts. The pH-dependent distribution of apovin-caminic acid microspecies in aqueous and membrane-like media is depicted in microspeciation diagrams.


CONCLUSIONS
The N(4) nitrogen is more shielded by the adjacent ethyl group in trans-D/E ring anellation eburnanes than in cis ones, as reflected by the protonation constants. Solvent-dependent basicity data predict superiority of trans isomers in lipophilicity and membrane-penetrating ability.
Mazák
K
K
Semmelweis University, Institute of Pharmaceutical Chemistry, Budapest, Hungary.
Nemes
A
A
Noszál
B
B
D006863:Hydrogen-Ion Concentration; D000432:Methanol / Q000737:chemistry*; D008954:Models, Biological; D011485:Protein Binding; D011522:Protons; D013237:Stereoisomerism; D017186:Titrimetry; D014466:Ultraviolet Rays; D014748:Vinca Alkaloids / Q000737:chemistry*; D014749:Vincamine / Q000031:analogs & derivatives* / Q000737:chemistry*; D014867:Water / Q000737:chemistry*
D011522:Protons; D014748:Vinca Alkaloids; D014867:Water; C032858:apovincaminic acid; C013983:vinpocetine; D014749:Vincamine; D000432:Methanol