QSAR of Molecular Structure and Cytotoxic Activity of Vitamin K₂ Derivatives with Concept of Absolute Hardness

Abstract

The correlation between the cytotoxicity of seven vitamin K₂ (menaquinone) derivatives and thirteen chemical descriptors determined by CONFLEX5/CAChe Worksystem 4.9 (PM3) was investigated. After determination of the conformation of the seven vitamin K₂ derivatives and approximation to the molecular form present in vivo (biomimetic) by CONFLEX5, the most stable structure was then determined by CAChe Worksystem 4.9 MOPAC (PM3). The vitamin K₂ derivatives with one to three isoprenyl units [1-3] showed an extended form, whereas those with four to seven isoprenyl units [4-7] displayed a spherical form. The human hepatocellular carcinoma HepG₂ cells displayed a good correlation between cytotoxicity and all the descriptors except for the electron affinity and lowest unoccupied molecular orbital energy (E_LUMO). The absolute hardness (η) - absolute electron negativity (χ) activity diagram determined by this calculation method may be useful for estimating the cytotoxic activity of vitamin K₂ derivatives against HepG₂ cells. The human squamous cell carcinoma HSC-2 and HSC-3 cells showed similar correlation. The human promyleocytic leukemia HL-60 cells showed the good correlation between cytotoxicity and molecular length. The present study demonstrates for the first time the best correlation between cytotoxic activity and molecular shape or molecular weight of vitamin K₂ derivatives, regardless of the type of target cells.