Quantitative structure activity relationships of cytotoxicity effect on various cancer cells of some imidazo[1,2-?]pyrazine derivatives

We have investigated the quantitative structure activity relationships (QSARs) between quantum chemical parameters and logIC50-1 being as values of cytotoxicity effect on various cancer cells of seventeen imidazo[1,2-?]pyrazine derivatives. All of the quantum chemical parameters except for hydrophobic parameter and molar refractivity was calculated by using DFT/B3LYP method and 6-31G (d,p) basis set. The complex, strong, descriptive and interpretable models for QSAR is derived using multiple linear regression analysis as a statistical method. QSAR models show that molecular volume, ionization potential, molecular softness, dipole moment, molar refractivity and hydrophobic parameter are important parameters that can affect the inhibitor activities on cancer cells division of investigated molecules. QSAR models found the regression coefficients for MDAMB-231, MCF-7, Hep G2 and SK-N-SH cells as 1.000, 0.984, 0.926 and 0.997, respectively.

Keywords:

Cytotoxicity, Imidazo[1, 2-?]pyrazine, inhibition concentration QSAR, Quantum chemical parameters,

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Abignente E, Arena F, De Caprariis P, Nuzzetti R, Marmo E, Lampa E, Rosatti E, Ottavo R (1981). Research on heterocyclic compounds. x - Imidazo[1,2-a]pyrazine derivatives: synthesis and antiinflammatory activity. Farmaco Sci 36, 61-80.
Adamczyk M, Akireddy SR, Johnson DD, Mattingly PG, Pan Y, Reddy RE (2003). Synthesis of 3,7- dihydroimidazo[1,2a]pyrazine-3-ones and their chemiluminescent properties. Tetrahedron 59, 8129- 8142.
Arrault A, Dubuisson M, Gharbi S, Marchand C, Verbeuren T, Rupin A, Cordi A, Bouskela E, Rees JF, Marchand-Bynaert J (2003). Synthesis and evaluation of near-infrared fluorescent sulfonamide derivatives for imaging of hypoxia-induced carbonic anhydrase IX expression in tumors Bioorg Med Chem Lett 13, 653- 657.
Barraclough P, Black JW, Cambridge D, Gerskowitsch VP, Giles HR, Glen C, Hull RAD, Iyer R, King WR (1993). Synthesis and pharmacological properties of BW315C and other inotropic 2-arylimidazo[1,2-a]pyrazines. Bioorg Med Chem Lett 3, 509-514.
Boiani M, Cereçetto H, Gonzalez M (2004). Cytotoxicity of furoxans: quantitative structure-activity relationships study. II Farmaco 59, 405-412.
Bonnet PA, Michel A, Laurent F, Sablayrolles C, Rechencq E, Mani JC, Boucard MJ, Chapat P (1992). Synthesis and antibronchospastic activity of 8-alkoxy- and 8- (alkylamino)imidazo[1,2-a]pyrazines. J Med Chem 35, 3353-3358.
Brown A, Heenderson A, Lane C, Lansdell M, Maw G, Monaghan S (2006) Small molecule inhibitors of IgE synthesis Bioorg Med Chem Lett 16, 4697-4699.
Consonni V, Todeschini R, Pavan M (2002). Structure/response correlations and similarity/diversity analysis by GETAWAY descriptors. 2. Application of the novel 3D molecular descriptors to QSAR/QSPR studies. J Chem Inf Comput Sci 42, 693-705.
Contour-Galcera MO, Piotout L, Moinet C, Morgan B, Gordon T, Roubert P, Thurieau C (2001) Synthesis of substituted imidazopyrazines as ligands for the human somatostatin receptor subtype 5. Bioorg Med Chem Lett 11, 741-745.
Demirayak S, Kayagil I (2005) Synthesis of some 6,8- Diarylimidazo[1,2-a]pyrazine derivatives by using either reflux or microwave irradiation method and investigation their anticancer activities, J Heterocyclic Chem 42, 319-325.
Dewar MJS, Zoebisch EG, Healy EF, Stewart JJP (1985). AM1: A new general purpose quantum mechanical model. J Am Chem Soc 107, 3902-3909.
Frisch et al., Gaussian 09W Revision A.02, Gaussian Inc., Wallingford CT, PA, 2009.
Guha R, Serra JR, Jurs PC (2004). Generation of QSAR sets with a self-organizing map. J Mol Graph Model 23, 1-14.
Gupta S, Singh M, Madan AK (1999). Superpendentic index: a novel topological descriptor for predicting biological activity. J Chem Inf Comput Sci 39, 272-277.
Guyton AC (1991). Textbook of Medical Physiology (8th ed.) Philadelphia: WB Saunders. ISBN 0-7216-3994-1.
Gülseven Sıdır Y, Sıdır İ, Taşal E, Öğretir C (2011). A Theoretical study on electronic structure and structure–activity properties of novel drug precursor 6-acylbenzothiazolon derivatives. Inter J Quan Chem 111, 3616-3629.
Hansch C, Kurup A, Garg R, Gao H (2001). ChemBioinformatics and QSAR. A review of QSAR lacking positive hydrophobic terms. Chem Rev 101, 619-672.
Horvarth D, Mao B (2003). Neighborhood behavior fuzzy molecular descriptors and their influence between structural similarity and property similarity. QSAR Comb Sci 22, 498-509.
Jalali-Heravi M, Parastar F (2000). The Use of artificial Neural Network in QSAR Study of anti-HIV activity for a large group of HEPT derivatives. J Chem Inf Comput Sci 40, 147-154.
Lumma WC, Randall WC, Cresson EL, Huff JR, Hartman RD, Lyon TF (1983). Piperazinylimidazo[1,2- a]pyrazines with selective affinity for in vitro alphaadrenergic receptor subtypes. J Med Chem 26, 357- 363.
Mccapra F, Roth M (1972). Cyclisation of a dehydropeptide derivative: a model for cypridina luciferin biosynthesis. J Chem Soc Chem Commun 15, 894-895.
Meurer LC, Tolman RL, Chapin EW, Saperstein R, Vicario PP, Zrada MM, MacCoss M (1992). Synthesis and hypoglycemic activity of substituted 8-(1- piperazinyl)imidazo[1,2-a]pyrazines. J Med Chem 35, 3845-3857.
Michel A, Laurent F, Chapat JP, Boucard M, Bonnet PA (1995). Pharmacological activities of imidazo[1,2- a]pyrazine derivatives. Arzneimittelforschung 45, 1288-1293.
Myadaraboina S, Alla M, Saddanapu V, Bommena VR, Addlagatta A (2010). Structure activity relationship studies of imidazo[1,2-a]pyrazine derivatives against cancer cell lines. Eur J Med Chem 45, 5208-5216.
Putta S, Eksterowicz J, Lemmen C, Stanton R (2003). A novel subshape molecular descriptor. J Chem Inf Comput Sci 435, 1623-1635.
Rival Y, Grassy G, Michel G (1992). Synthesis and antibacterial activity of some imidazo[1,2- a]pyrimidine derivatives. Chem Pharm Bull 40, 1170- 1176.
Sablayrolles C, Cros GH, Milhavet JC, Rechenq E, Chapat JP, Boucard MJ, Serrano J, McNeill JH (1984) Synthesis of imidazo[1,2-a]pyrazine derivatives with uterinerelaxing, antibronchospastic, and cardiac-stimulating properties. J Med Chem 27, 206-212.
Schmidi H (1997). Multivariate prediction for QSAR. Chemom Intell Lab Sys 37, 125-134.
Spitzer WA, Victor F, DonPollock G, Hayes JS (1988). Imidazo[1,2-a]pyrimidines and imidazo[1,2- a]pyrazines: The role of nitrogen position in inotropic activity. J Med Chem 31, 1590-1595.
Sumi S, Shoji I, Toshoi G (1970). Synthesis of cypridina luciferin and related compounds. IV. : Synthesis of 3, 7-Dihydroimidazo[1, 2-α]pyrazin-3-ones. Yakugaku Zasshi 90, 423-430.
Toshio G, Shoji I, Sumi S (1968). Cypridina bioluminescence IV. Synthesis and chemiluminescence of 3,7-dihydroimidazo[1,2-a]pyrazin-3-one and its 2- methyl derivative. Tetrahedron Lett 36, 3873-3876.
Vitse O, Laurent F, Pocock TM, Benezech V, Zanik L, Elliott KRF, Subra G, Portet K, Chapat JP, Small RC, Michel A, Bonnet PA (1999). New Imidazo[1,2- a]pyrazine derivatives with bronchodilatory and Cyclic Nucleotide Phosphodiesterase Inhibitory Activities. Bioorg Med Chem 7, 1059-1065.
Vitse O, Bonnet PA, Bompart J, Viols H, Subra G, Chapat JP, Grassy GJ (1997). Nitration in the imidazo[1,2- a]pyrazine series. Experimental and computational results. Heterocycl Chem 34, 701-707.
Winkler DA (2002). The role of quantitative structure - activity relationships (QSAR) in biomolecular discovery. Briefings in Bioformatics 3, 73-86.
Wold S, Trygg J, Berglund A, Antii H (2001) Some recent developments in PLS modeling. Chemom Intell Lab Syst 58, 131-150.
Yoshito K, Sumi S, Shoji I, Toshoi G (1969). Synthesis of cypridina luciferin and related compounds. III. : Synthesis of cypridina luciferin. Yakugaku Zasshi 89, 1657-1660