title: Antitumor agents. 163. Three-dimensional quantitative structure-activity relationship study of 4'-O-demethylepipodophyllotoxin analogs using the modified CoMFA/q2-GRS approach.
abstract: Analogs of 4'O-demethylepipodophyllotoxin are considered as potential anticancer agents. We have applied comparative molecular field analysis (CoMFA) and a novel CoMFA/q2-GRS technique recently developed in our group to identify the essential structural requirements for increasing the ability of these compounds to form cellular protein-DNA complex. In addition, a new method to incorporate different types of probe atoms as part of q2-GRS routine has been developed. The best final model with 101 compounds using a combination of four different sets of probe atoms and charges [C (sp3, +1), C (sp3, 0), H (+1), and O (sp3, -1)] yielded a q 2 of 0.584 and the standard error of prediction of 0.660 at 5 principal components. The steric and electrostatic contour plots of the final model were compared with the DNA phosphate backbone environment of the DNA-4'O-demethylepipodophylltoxin analog complex, which was generated using the X-ray structure of the DNA-nogalamycin complex. The comparison reveals that the CoMFA steric and electrostatic fields are compatible with stereochemical properties of the DNA backbone. The results obtained from this study shall guide our future synthetic efforts.
authors.affiliation: Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, 27599, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Cho
authors.forename: A
authors.initials: A
authors.lastname: Tropsha
authors.forename: M
authors.initials: M
authors.lastname: Suffness
authors.forename: Y C
authors.initials: YC
authors.lastname: Cheng
authors.forename: K H
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D003196:Computer Graphics; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004247:DNA; D004264:DNA Topoisomerases, Type I; D011034:Podophyllotoxin; C072088:4'-demethylepipodophyllotoxin