Research ArticleExperimental Studies

Estimation of Relationship Between the Structure of 1,2,3,4-Tetrahydroisoquinoline Derivatives Determined by a Semiempirical Molecular-Orbital Method and their Cytotoxicity

MARIKO ISHIHARA, HAJIME HATANO, MASAMI KAWASE and HIROSHI SAKAGAMI
Anticancer Research June 2009, 29 (6) 2265-2271;

Abstract

A semiempirical molecular-orbital method (CAChe 4.9, PM5) was applied to delineate the relationship between the cytotoxicity (evaluated by 50% cytotoxic concentration, CC50) of nineteen 1,2,3,4-tetrahydroisoquinoline derivatives, their molecular weight and the sixteen chemical parameters (descriptors) determined by CONFLEX/PM5 method. There was little or no correlation between the CC50 in HL-60 cells and the heat of formation, stability of hydration (ΔH), dipole moment, electron affinity, ionization potential, highest occupied molecular orbital energy (EHOMO), lowest unoccupied molecular orbital energy (ELUMO), absolute hardness (η, softness and hardness of the molecule) or molecular weight (r2<0.312). On the other hand, there was a good correlation between the CC50 and the hydrophobicity (log P) (r2=0.503), and the descriptors for the molecular size such as surface area (r2=0.771), volume (r2=0.805) and width (r2=0.757). Similar, but not so clear-cut correlation was found in HSC-2, HSC-3 and HSC-4 human oral squamous cell carcinoma cell lines. The present study demonstrates that the cytotoxicity of 1,2,3,4-tetrahydroisoquinoline derivatives depends more on the descriptors for molecular size rather than the physicochemical descriptors.

Tetrahydroisoquinoline have been reported to display antitumor activity (1), anti-inflammatory activity (2) and to prevent Parkinson's disease in an animal model (3). We investigated here the relationship between the cytotoxicity against human oral squamous cell carcinoma cell lines (HSC-2, HSC-3, HSC-4) (evaluated by 50% cytotoxic concentration, CC50) of nineteen 1,2,3,4-tetrahydroisoquinoline derivatives, their molecular weight and the sixteen chemical parameters (descriptors) determined by CONFLEX/PM5 method.

Materials and Methods

Materials. The following chemicals and reagents were obtained from the indicated companies: Dulbecco's modified Eagle's medium (DMEM) (Gibco BRL, Grand Island, NY, USA); fetal bovine serum (FBS) (JRH Bioscience, Lenexa, KS, USA); 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (Sigma Chem. Co., St. Louis, MO, USA). All tetrahydroisoquinolines were provided by Dr. Kawase, Matsuyama University.

Assay for cytotoxicity. Human promyelocytic leukemic cell line (HL-60) and human oral squamous cell carcinoma cell lines (HSC-2, HSC-3, HSC-4) were cultured in RPMI-1640 or DMEM supplemented with 10% heat-inactivated FBS under a humidified 5% CO2 atmosphere, respectively. These cells were incubated for 48 hours with different concentrations of each compound, and the viable cell number was determined by cell counting after staining with trypan blue (for HL-60 cells) or MTT method (for other cell lines) (4). The 50% cytotoxicity (CC50) against these cell lines was determined from the dose-response curve.

Calculation. The most stable configuration of nineteen 1,2,3,4-tetrahydroisoquinoline was calculated by CONFLEX 5 (Conflex Co. Ltd., Tokyo). The optimization of the structure was achieved using a semiempirical molecular-orbital method (PM5), using a CAChe Worksystem 4.9 (MOPAC, PM5, non-COSMO, COSMO) (Fujitsu Co. Ltd., Tokyo). The following descriptors were used: i) heat of formation (COSMO, non-COSMO; kcal/mole); ii) stability of hydration (=COSMO - nonCOSMO (ΔH); kcal/mole); iii) dipole moment (D); iv) electron affinity (eV); v) ionization potential (eV); vi) hydrophobicity (log P); vii) highest occupied molecular orbital energy (EHOMO; eV); viii) lowest unoccupied molecular orbital energy (ELUMO; eV); ix) absolute hardness [η=(EUMO - EHOMO)/2; eV)]; x) absolute electron negativity [χ=-(ELUMO + EHOMO)/2; eV]; xi) reactivity index (ω=χ2/2η; eV); xii) maximum length of the molecule (Å); xiii) distance between N-R3 (Å); xiv) distance between R2-R3 (Å); xv) surface area of the molecule (Å2); xvi) volume of the molecule (Å3) (5-7). The values of xii - xiv were measured using the 3-dimensional pictures of the most stable structure of each molecule. The quantitative structure-activity relationship (QSAR) was investigated from each descriptor (determined from molecular structure) and CC50 value (plotted as logarithmic scale), using a CAChe Worksystem 4.9 project reader.

View this table:
Table I.

CC50 and chemical descriptors for 1,2,3,4-tetrahydroisoquinoline derivatives.

Results and Discussion

Calculation with CONFLEX soft ware demonstrated that the most stable structure of all nineteen 1,2,3,4-tetrahydroisoquinoline derivatives showed the protrusion of substituents on the planar backbone (Figures 1 and 2).

The QSAR analysis was performed using HL-60 cells. The CC50 value, 16 descriptors and molecular weight of each compound are shown in Table I. QSAR between the CC50 value logarithmically plotted and each descriptor of HL-60 cells are shown in Table II and Figure 3. There was a good correlation between the CC50 value and hydrophobicity (r2=0.503, Figure 3f), the maximum length of molecule (r2=0.445, Figure 1l), distance between N-R3 (r2=0.471, Figure 3m), distance between R2-R3 (r2=0.757, Figure 3n), surface area of the molecule (r2=0.771, Figure 3o) and the volume of the molecule (r2=0.803, Figure 3p). However, there was no correlation between the CC50 value and the other descriptors.

View this table:
Table II.

Correlation coefficients between CC50 and each chemical descriptor in four different cell lines.

The QSAR between the CC50 value and the electron state of the molecule can be estimated by ΕHOMO or ELUMO (Figure 3 g and h, respectively) which are the indicators of electron donating and electron attracting capability, respectively, with an increase in ΕHOMO, the electron donating capability is enhanced, while a decrease in ELUMO, the electron attracting capability is enhanced. ΕHOMO also reflects the ionization potential, hence no correlation existed between the CC50 and the ionization potential. In a QSAR analysis of endocrine disruptors, positive correlation has been reported between biological activity and chemical hardness (8-10). These papers showed that the biological activity of endocrine disruptors are well fitted to the η value. In contrast, the present results demonstrate the lack of positive correlation between the CC50 value of 1,2,3,4-tetrahydroisoquinoline and the η value (Table II, Figure 3).

We then performed the QSAR analysis using HSC-2, HSC-3 and HSC-4 cells. There was a good correlation between the CC50 values and the surface area of the molecule and the volume of the molecule (r2=0.805~0.375) (Table II, Figure 4). These results show that descriptors xiv-xvi can be utilized to estimate the cytotoxicity of 1,2,3,4-tetrahydroisoquinoline related compounds.

Figure 1.
Figure 1.

The structure of 1,2,3,4-tetrahydroisoquinoline derivatives.

In conclusion, the present QSAR analysis demonstrates that the CC50 value of 1,2,3,4-tetrahydroisoquinoline depends on their molecular size (surface area, volume, width), but not on the most of the other electronic factors. The molecular size determined by the CONFLEX/PM5 method is useful to evaluate the biological activity of 1,2,3,4-tetrahydroisoquinoline.

Figure 2.
Figure 2.

The most stable conformation of 1,2,3,4-tetrahydroisoquinoline derivatives used.

Figure 3.
Figure 3.

Correlation between CC50 value (log scale) and each descriptor of 1,2,3,4-tetrahydroisoquinoline derivatives against HL-60 cells. The investigated descriptors are a, heat of formation; b, stability of hydration (ΔH); c, dipole moment; d, electron affinity; e, ionization potential; f, hydrophobicity (log P); g, EHOMO; h, ELUMO; i, absolute hardness; j, absolute electron negativity; k, reactivity index (ω); l, maximum length; m, distance between N-R3; n, distance between R2-R3; o, surface area; p, volume of the molecule and q, MW.

Figure 4.
Figure 4.

Correlation between CC50 value (log scale) and selective descriptors of 1,2,3,4-tetrahydroisoquinoline derivatives against HSC-2 (left column), HSC-3 (center column) and HSC-4 cells (right column). Only descriptors that were found to show higher correlation coefficients in HL-60 cells (Figure 3) were selected.

Acknowledgements

This study was supported in part by a Grant-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan (Ishihara, No. 15659444; Sakagami, No. 19592156).

  • Received February 24, 2009.
  • Revision received April 8, 2009.
  • Accepted April 21, 2009.

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Estimation of Relationship Between the Structure of 1,2,3,4-Tetrahydroisoquinoline Derivatives Determined by a Semiempirical Molecular-Orbital Method and their Cytotoxicity
MARIKO ISHIHARA, HAJIME HATANO, MASAMI KAWASE, HIROSHI SAKAGAMI
Anticancer Research Jun 2009, 29 (6) 2265-2271;
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