Investigation of anticancer activity of macrocyclic Schiff bases by means of 4D-QSAR based on simplex representation of molecular structure

Abstract

Influence of the molecular structure of macrocyclic pyridinophanes, their analogues and some other compounds on anticancer activity (Leukemia, central nervous system (CNS) cancer, prostate cancer, breast cancer, melanoma, non-small cell lung cancer, colon cancer, ovarian cancer, renal cancer) was investigated by means of a new 4D-QSAR approach based on the simplex representation of molecular structures (SiRMS).

The number of group (N) is a tuning parameter which can be changed. As a rule N = 3 -- 7.

For all the investigated molecules, the 3D structural models were first created and the set of conformers (fourth dimension) was used. Each conformer was represented as a system of different simplexes (tetratomic fragments of fixed structure, chirality and symmetry).

Statistic characteristics of the QSAR partial least squares (PLS) models were satisfactory (correlation coefficient r = 0.990 - 0.861; cross-validation coefficient {\rm CVR = 0.914 - 0.633} ). The molecular fragments increasing and decreasing anticancer activity were defined. This information may be useful for the design and direct synthesis of novel anticancer agents.

Keywords:

• Anticancer activity
• 4D-QSAR
• Simplex representation
• Molecular design
• Macrocyclic pyridinophanes

Acknowledgements

This study was partially supported by INTAS (INTAS Grant 97-31528). The authors express gratitude to colleagues from the National Cancer Institute (Bethesda, USA) and organic chemists from A.V. Bogatsky Physical–Chemical Institute of NAS of Ukraine for fruitful cooperation.

Notes

The number of group (N) is a tuning parameter which can be changed. As a rule N = 3 -- 7.

Hyperchem 7.0 software. Trial version from http://www.hypercube.com

The number of simplexes of i-th type in the SiRMS approach.