Replacement of a thiourea-S with an amidine-NH donor group in a platinum-acridine antitumor compound reduces the metal's reactivity with cysteine sulfur.
The reactivity of two DNA-targeted platinum-acridine conjugates with cysteine sulfur was studied. The conjugate containing an amidine-NH donor group cis to the chloride leaving group showed considerably reduced reactivity with N-acetylcysteine compared to the prototypical derivative containing a thiourea-S linkage. The opposite scenario has been observed previously in reactions with nucleobase nitrogen. Possible consequences of the unique target-selective tuning of the substitution chemistry for the pharmacodynamic properties and biological activity of these agents are discussed.
Ma
Zhidong
Z
Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina 27109, USA.
Rao
Lu
L
Bierbach
Ulrich
U
D000166:Acridines / Q000737:chemistry / Q000494:pharmacology; D000578:Amidines / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D003545:Cysteine / Q000737:chemistry; D004247:DNA / Q000378:metabolism*; D017671:Platinum Compounds / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000737:chemistry
D000166:Acridines; D000578:Amidines; D000970:Antineoplastic Agents; D017671:Platinum Compounds; D004247:DNA; D013890:Thiourea; D003545:Cysteine