Abstract
We have previously reported the cytotoxicity and type of cell death induced by twenty trihaloacetylazulenes in human tumor cell lines. We determined for the first time the most-stable chemical structures from their reported structures, using the semiempirical molecular—orbital method (CONFLEX/PM5), and then delineated the relationship between their cytotoxicity (evaluated by 50% cytotoxic concentration, CC50) and a total of twelve parameters. The parameters used are the molecular weight and eleven chemical descriptors: the heat of formation (COSMO, non-COSMO), stability of hydration (=COSMO – nonCOSMO (ΔH)), dipole moment (D), hydrophobicity (log P), highest occupied molecular orbital energy (EHOMO), lowest unoccupied molecular orbital energy (ELUMO), absolute hardness [η=(ELUMO–EHOMO)/2], absolute electron negativity [χ=−(ELUMO+EHOMO)/2], reactivity index (ω=χ2/2η) and surface area (Å2), and volume of the molecule (Å3). There was good correlation between the CC50 value and all descriptors except for absolute hardness in HL-60 cells. There was also a good correlation between the CC50 value and EHOMO, χ, ω, surface area, volume and molecular weight in HSC-2, HSC-3 and HSC-4 cells. The descriptors determined by the present method are useful in evaluating the biological activity of trihaloacetylazulenes.
Quantitative structure-activity relationship (QSAR) represents the quantitative relationship between the structure and biological (pharmaceutical or toxicological) activity of chemical substances. The purpose of QSAR is to predict the pharmacological potency of structurally-related compounds by this mathematical relationship between the two. It is generally accepted that QSAR analyses are performed based on previously published experimental data, and treated as separated papers.
Azulenes have shown antibacterial activity (1), anti-ulcer activity (2), and chemotherapeutic activity against mucous membrane diseases (3). We have previously reported the cytotoxicity and type of cell death induced by twenty trihaloacetylazulenes in human tumor cell lines (4). Using these data, we investigated the physicochemical properties of these twenty compounds using a conventional semiempirical molecular–orbital method (PM5) (5-7) and chemical hardness (8), and performed QSAR analysis to predict the structure of more potent compounds.
Materials and Methods
Calculation. The most stable configuration of twenty trihalo-acetylazulenes (Figure 1) was calculated by CONFLEX 5 (Conflex Co. Ltd., Tokyo). The optimization of the structure was achieved using the PM5 method, using a CAChe Worksystem 4.9 (MOPAC, PM5, non-COSMO, COSMO) (Fujitsu Co. Ltd., Tokyo) (Figure 2).
The following eleven chemical descriptors and one other parameter were used: heat of formation (COSMO, non-COSMO; kcal/mole); stability of hydration (=COSMO–nonCOSMO (ΔH); kcal/mole); dipole moment (D); hydrophobicity (log P); highest occupied molecular orbital energy (EHOMO; eV); lowest unoccupied molecular orbital energy (ELUMO; eV); absolute hardness [η=(EUMO–EHOMO)/2; eV)]; absolute electron negativity [χ=−(ELUMO+EHOMO)/2; eV]; reactivity index (ω=χ2/2η; eV); surface area of the molecule (Å2); volume of the molecule (Å3); and molecular weight.
The QSAR was investigated from each descriptor (determined from molecular structure) and the 50% cytotoxicity concentration (CC50) (plotted as logarithmic scale) (cited from (4)), using a CAChe Worksystem 4.9 project reader.
Cytotoxicity (CC50) and chemical descriptors for trihaloacetylazulenes.
Correlation coefficients (r2) between CC50 and each chemical descriptor in four different cell lines.
Trihaloacetylazulenes used in this study and the most stable structure as determined by CAChe (PM5).
QSAR of trihaloacetylazulenes for CC50.
Correlation between CC50 value (log scale) and each descriptor of trihaloacetylazulenes derivatives against HL-60 cells. The investigated descriptors are a, heat of formation; b, stability of hydration (ΔH); c, dipole moment; d, hydrophobicity (log P); e, EHOMO; f, ELUMO; g, absolute hardness; h, absolute electron negativity; i, reactivity index (ω); j, surface area; k, volume of the molecule, and l, M.W.
Results
Calculations with CONFLEX software demonstrated that the most stable structure of all twenty trihaloacetylazulene derivatives showed the protrusion of substituents on the planar azulene ring (Figures 1 and 2).
The QSAR analysis was performed using data derived from experiments with HL-60, HSC-2, HSC-3 and HSC-4 cells. The CC50 and 11 descriptors are shown in Table I. The previous CC50 values (4) are listed for the calculation of log CC50 as a different expression. The QSAR between the CC50 value logarithmically plotted and each descriptor for HL-60 cells are shown in Figure 3. The correlation coefficients (r2 values) are shown in Table II. For HL-60 cells, there was a good correlation with most descriptors, especially for heat of formation, EHOMO, ELUMO, χ, ω, surface area, volume (r2=0.618-0.841). On the other hand, there was much less correlation with absolute hardness. There was a good correlation with EHOMO, χ, ω, surface area, volume and molecular weight in HSC-2, HSC-3 and HSC-4 cells (Table II) (QSAR figures not shown).
Discussion
Using the values of each parameter that induced the highest cytotoxicity (lowest CC50 values), more potent compounds can be designed. The descriptors determined by the present method are useful in evaluating the biological activity of trihaloacetylazulenes.
Footnotes
- Received September 14, 2009.
- Accepted January 28, 2010.
- Copyright© 2010 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
