Molecular modeling of 3-arylisoquinoline antitumor agents active against A-549. A comparative molecular field analysis study.
A series of 58 3-arylisoquinoline antitumor agents were investigated for defining the pharmacophore model using comparative molecular field analysis (CoMFA) program. The studied compounds related to bioisostere of benzophenanthridine alkaloid were synthesized and evaluated for antitumor cytotoxicity against human lung tumor cell (A 549). In order to perform the systematic molecular modeling study of these compounds, the conformational search was carried out based on the single X-ray crystallographic structure of 7,8-dimethoxy-3-phenylisoquinolin-(2H)-one (2). Interestingly, two types of structures having different dihedral angles between the isoquinoline ring and 3-aryl ring were found in the crystals. Therefore, CoMFA was performed two different, overlapping ways. The alignments of the structures were based on the common isoquinoline ring and 3-aryl ring. The 3-D-quantitative structure-activity relationship study resulted in significant cross-validated, conventional r(2) values equal to 0.715 and 0.927, respectively.
College of Pharmacy, Chonnam National University, Yongbong-dong Buk-gu, Kwangju 500-757, Republic of Korea. wjcho@chonnam.ac.kr
Won-Jea
WJ
Cho
Eui-Ki
EK
Kim
Il Yeong
IY
Park
Eun Young
EY
Jeong
Tae Sung
TS
Kim
Thanh Nguyen
TN
Le
Dae-Duk
DD
Kim
Eung-Seok
ES
Lee
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D012984:Software; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007546:Isoquinolines