Effect of linkage geometry on biological activity in thiourea- and guanidine-substituted acridines and platinum-acridines.
Novel thiourea- and guanidine-modified acridine-4-carboxamides (4, 7) and a corresponding platinum-intercalator conjugate (4') have been synthesized and evaluated as cytotoxic agents in human promyelocytic leukemia, HL-60, and a non-small cell lung cancer, NCI-H460. Modification of thiourea sulfur in derivative 4 with a DNA platinating moiety, giving 4', resulted in a pronounced cytotoxic enhancement, and the conjugate proved to be the most active of the newly synthesized compounds in NCI-H460 cells. Conjugate 4' represents a new chemotype with potential applications in the treatment of chemoresistant tumors.
Department of Chemistry, Wake Forest University, Winston-Salem, NC 27109, USA.
Zhidong
Z
Ma
Gilda
G
Saluta
Gregory L
GL
Kucera
Ulrich
U
Bierbach
D000166:Acridines / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D019791:Guanidine / Q000031:analogs & derivatives* / Q000737:chemistry; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D010984:Platinum / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000737:chemistry*; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry
D000166:Acridines; D000970:Antineoplastic Agents; C029280:guanidine carboxamide; D010984:Platinum; D014508:Urea; D013890:Thiourea; D019791:Guanidine