Sequential cytotoxicity: a theory evaluated using novel 2-[4-(3-aryl-2-propenoyloxy)phenylmethylene]cyclohexanones and related compounds.
Five series of novel compounds were synthesized in order to evaluate the theory of sequential cytotoxicity which seeks to exploit the view that various cancer cells are particularly susceptible to successive attacks by cytotoxic agents. The compounds prepared were various 2-[4-(3-aryl-2-propenoyloxy)phenylmethylene]cyclohexanone s 1 and the related Mannich bases 2. In addition the analogues 3-5 lacking an olefinic bond in the ester group were also synthesized, which were predicted to be less cytotoxic than the compounds of series 1 and 2. The atomic charges at the potential sites for interaction with cellular constituents were determined by molecular modeling calculations. The biodata obtained from murine and human neoplastic cells revealed that the predictions made regarding the viability of the theory were fulfilled in approximately two-thirds of the cases indicating that further investigation of this hypothesis is warranted. In addition, the significant potencies of some of the Mannich bases toward human tumor cell lines, in particular coupled to their selective toxicity toward human leukemic and colon cancer cells, confirms their usefulness in serving as lead molecules for further development. A preliminary investigation into the mode of action of representative compounds revealed their ability to induce apoptosis and inhibit the biosyntheses of ribonucleic acid and proteins.
Dimmock
J R
JR
College of Pharmacy and Nutrition and Departments of Biochemistry and Chemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5C9, Canada. dimmock@skyway.usask.ca
Kandepu
N M
NM
Nazarali
A J
AJ
Motaganahalli
N L
NL
Kowalchuk
T P
TP
Pugazhenthi
U
U
Prisciak
J S
JS
Quail
J W
JW
Allen
T M
TM
LeClerc
R
R
Santos
C L
CL
De Clercq
E
E
Balzarini
J
J
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D018360:Crystallography, X-Ray; D003512:Cyclohexanones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008352:Mannich Bases / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003512:Cyclohexanones; D008352:Mannich Bases; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm