Synthesis and cytotoxic evaluation of substituted sulfonyl-N-hydroxyguanidine derivatives as potential antitumor agents.
A series of sulfonyl-N-hydroxyguanidine derivatives was designed and synthesized for cytotoxic evaluation as potential anticancer agents on the basis of the lead compound LY-181984. Replacement of the ureido moiety of the lead compound with hydroxyguanidine provided a stable cytotoxic agent. The conformation of sulfonyl-N-hydroxyguanidine derivatives, such as N-(4-chlorophenyl)-N'-[(benzo[2,1,3]thiadiazol-4-yl)sulfonyl]-N"- hydroxyguanidine (4g), investigated utilizing HMBC NMR, theoretical calculations, and X-ray crystallography, indicated stacking of the two aromatic rings. The derivatives were evaluated for in vitro cytoxicity against five human tumor cell lines, including HepG2, TSGH 8302, COLO 205, KB, and MOLT-4. The cytotoxic activities of the derived compounds against the human tumor cell lines were equal to or greater than that of the lead compound. N-(4-Chlorophenyl)-N'-[[3,5-dichloro-4-(4-nitrophenoxy)phenyl]sulfonyl]- N"- hydroxyguanidine (4n) and N-(4-chlorophenyl)-N'-[[3,5-dichloro-4-(2-chloro-4-nitrophenoxy)phenyl] sulfonyl]-N"-hydroxyguanidine (4o) exhibited the greatest growth inhibition of solid tumor cell lines. Compound 4o was found to possess antitumor activity against murine K1735/M2 melanoma xenografts.
Chern
J W
JW
School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Republic of China. chern@jwc.mc.ntu.edu.tw
Leu
Y L
YL
Wang
S S
SS
Jou
R
R
Lee
C F
CF
Tsou
P C
PC
Hsu
S C
SC
Liaw
Y C
YC
Lin
H M
HM
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D002151:Calorimetry; D002470:Cell Survival / Q000187:drug effects*; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D007624:KB Cells; D009682:Magnetic Resonance Spectroscopy; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D006146:Guanidines; D013449:Sulfonamides