Cytotoxic 2-benzylidene-6-(nitrobenzylidene)cyclohexanones which display substantially greater toxicity for neoplasms than non-malignant cells.
Various 2-benzylidene-6-(nitrobenzylidene)cyclohexanones were prepared as candidate cytotoxins in which the nitro group was located in the ortho, meta and para positions leading to series 1-3, respectively. The CC(50) values towards human HSC-2 and HSC-4 oral squamous cell carcinomas as well as human HL-60 promyelocytic leukemic cells are in the low micromolar range in general. On the other hand, most of the compounds afforded clear evidence of being far less toxic towards human HGF gingival fibroblasts, HPC pulp cells and HPLF periodontal ligament fibroblasts which are non-malignant cells. Selectivity index (SI) figures were generated which are the ratios of the average CC(50) values towards normal cells and the CC(50) figure towards a malignant cell line. Huge SI values were obtained for many of the compounds. In particular 1c, 2f, 3c and 3g which have average SI values of >76, >38, 124 and 341, respectively, are clearly lead molecules affording direction for amplification of this area of study. A lead compound 1c caused internucleosomal DNA fragmentation and activation of caspase-3 in HL-60 cells but not in HSC-2 carcinomas. In a short-term toxicity study, doses up to and including 300 mg/kg of the majority of the compounds prepared in this study did not cause any mortalities to mice. Some guidelines for development of these tumor-selective cytotoxins are presented.
Das
Umashankar
U
Drug Design and Discovery Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, Canada S7N 5C9.
Doroudi
Alireza
A
Drug Design and Discovery Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, Canada S7N 5C9.
Inci Gul
H
H
Drug Design and Discovery Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, Canada S7N 5C9.
Pati
Hari N
HN
Drug Design and Discovery Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, Canada S7N 5C9.
Kawase
Masami
M
Faculty of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Maysuyama, Ehime 790-8578, Japan.
Sakagami
Hiroshi
H
Division of Pharmacology, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry, Saitama 350-0238, Japan.
Chu
Qing
Q
Division of Pharmacology, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry, Saitama 350-0238, Japan.
Stables
James P
JP
National Institute of Neurological Disorders and Stroke, 6001 Executive Boulevard, Rockville, MD 20852, USA.
Dimmock
Jonathan R
JR
Drug Design and Discovery Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, Canada S7N 5C9.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D003512:Cyclohexanones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005347:Fibroblasts / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D003512:Cyclohexanones