3D-QSAR Study on
1,3-diarylidene-2-tetralone, 2,6-bis(arylidene)cyclohexanone and
3,5-bis(arylidene)-4-piperidone Series of Cytotoxic
Compounds
Maulik R. Patel, Department of
Pharmaceutical Sciences, College of Pharmacy and Allied Health
Professions
Tanaji T. Talele, Department of
Pharmaceutical Sciences, College of Pharmacy and Allied Health
Professions
Jonathan R. Dimmock, College of
Pharmacy and Nutrition, University of Saskatchewan, Saskatoon,
Sask., Canada
Abstract
In a continuing effort to develop more potent cytotoxic
compounds in our laboratory, we developed 3D-QSAR models for
1,3-diarylidene-2-tetralone, 2,6-bis(arylidene)cyclohexanone and
3,5-bis(arylidene)-4-piperidone analogues previously shown to
exhibit cytotoxic activity in L1210, Molt4 C/8, and CEM cells
(Dimmock et al., J. Med. Chem. 2001, 44, 586–593; Eur. J. Med.
Chem. 2000, 35, 967-977; Eur. J. Med. Chem. 2002, 37, 813-824; Eur.
J. Med. Chem. 2003, 38, 169-177). The CoMFA models with
steric and electrostatic fields provided satisfactory statistical
data (r2cv 0.485, r2ncv 0.834, r2pred 0.591), (r2cv 0.532, r2ncv
0.850, r2pred 0.729), and (r2cv 0.561, r2ncv 0.864, r2pred 0.666)
for cytotoxicity in L1210, Molt4 C/8, and CEM cells,
respectively. The CoMSIA models with steric, electrostatic,
hydrophobic, and H-bond donor fields exhibited r2cv 0.513, r2ncv
0.833, and r2pred 0.562 for cytotoxicity in L1210 cells while best
CoMSIA model was obtained by combination of steric, electrostatic,
and hydrophobic fields yielding statistically significant data
(r2cv 0.531, r2ncv 0.828, r2pred 0.652) and (r2cv 0.560, r2ncv
0.841, r2pred 0.729) for cytotoxicity in Molt4 C/8 and CEM cells,
respectively. The information obtained from CoMFA and CoMSIA
3D contour maps can be used in the design of more potent compounds
as cancer chemotherapeutics.