Cytotoxic 3,5-bis(benzylidene)piperidin-4-ones and N-acyl analogs displaying selective toxicity for malignant cells.
A series of 3,5-bis(benzylidene)piperidin-4-ones 1, 1-acryloyl-3,5-bis(benzylidene)piperidin-4-ones 2 and adducts of 2 with sodium 2-mercaptoethanesulfonate (mesna), namely series 3, were prepared as candidate cytotoxic agents. These compounds were examined against neoplastic HSC-2, HSC-4 and HL-60 cells as well as HGF, HPC and HPLF normal cell lines and many of the compounds displayed selective toxicity for malignant cells. The CC50 values of the analogs in series 2 towards the cancer cell lines were mainly submicromolar. The relative potencies, selectivity and logP values were in the order of 2>1>3. The sulfonic acid group of a representative compound in series 3 was replaced by a thiol function to produce 4 leading to substantial increases in cytotoxic potencies and hydrophobicity indicating that the presence of a hydrophilic sulfonic acid group was disadvantageous in terms of potency. Molecular modeling suggested that the superior cytotoxicity of various members of series 1-3 over an acyclic analog 5 may have been due to the greater torsion angles theta1 and theta2 created between the arylidene aryl rings and the adjacent olefinic groups in series 1-3.
Pati
Hari N
HN
College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon Saskatchewan S7N 5C9, Canada.
Das
Umashankar
U
Quail
J Wilson
JW
Kawase
Masami
M
Sakagami
Hiroshi
H
Dimmock
Jonathan R
JR
D001597:Benzylidene Compounds / Q000737:chemistry* / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003603:Cytotoxins / Q000737:chemistry* / Q000633:toxicity*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008954:Models, Biological; D009369:Neoplasms / Q000473:pathology*; D010881:Piperidones / Q000737:chemistry* / Q000633:toxicity*; D012680:Sensitivity and Specificity
D001597:Benzylidene Compounds; D003603:Cytotoxins; D010881:Piperidones