Synthesis, pro-apoptotic activity and 2D-QSAR studies of new analogues of fluphenazine.
A series of 10 novel analogues of fluphenazine (FPh) were synthesized. Influence of the synthesized analogues of FPh on frequency of apoptosis and necrosis in cultures of human lymphocytes genotoxically damaged in vitro with benzo[a]pyrene (B[a]P; 7,5 microM, 48 h) was compared with the effect of FPh. Activity of the tested compounds was expressed by ED50 (pro-apoptotic activity) and TD50 (pro-necrotic effect, cytotoxicity). It was noticed that compounds 3-9 and 12 exerted a pro-apoptotic effect markedly stronger than that of FPh. Additionally, compounds 3, 9 and 10 exhibited the weakest influence on frequency of necrotic lymphocyte in cultures. 2D-QSAR analysis was done in order to find quantitative relationship between structures of the tested analogues and their pro-apoptotic activity or pro-necrotic effect in B[a]P-damaged cell cultures. Several statistically significant QSAR models were generated. Information obtained from 2D-QSAR study will be used in further design of analogues of FPh more active in cancer chemoprevention.
Joanna
J
Zyta
Agata
A
Jaszczyszyn
Piotr
P
Swiatek
Kazimierz
K
Gasiorowski
Wiesław
W
Malinka
D000328:Adult; D016588:Anticarcinogenic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D005476:Fluphenazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008297:Male; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship
D016588:Anticarcinogenic Agents; D005476:Fluphenazine