O6-(alkyl/aralkyl)guanosine and 2'-deoxyguanosine derivatives: synthesis and ability to enhance chloroethylnitrosourea antitumor action.
A series of O6-(alkyl/aralkyl)guanosines and 2'-deoxyguanosine analogs extended to peracetyl and N2-acetyl derivatives, potentially water soluble, was synthesized. Each was associated with N'-(2-chloroethyl)-N-[2-(methylsulfonyl)ethyl]-N'-nitrosourea for in vitro evaluation on M4Beu melanoma cells of their ability to enhance the cytotoxic effect of this chloroethylnitrosourea, which is frequently reduced by repairs performed by O6-alkylguanine-DNA-alkyltransferase. Structure-activity analysis revealed that (i) benzyl and 4-halobenzyl are the O6-substituents required to afford a significant activity, (ii) 2'-deoxyguanosine derivatives demonstrate greater potency than guanosine analogs, (iii) acetylation, especially at the N2 position, generally results in compounds with moderate ability but may prevent incorporation of such nucleosides into DNA. Accordingly, O6-(4-iodobenzyl)-N2-acetylguanosine (3b) and O6-benzylperacetyl-2'-deoxyguanosine (2a), as well as O6-benzyl-N2-acetylguanosine (1b) and O6-benzyl-N2-acetyl-2'-deoxyguanosine (2b), by far the most water soluble, exhibit a good profile for further in vivo trials by the intravenous route.
Mounetou
E
E
INSERM Unité 71, Clermont-Ferrand, France.
Debiton
E
E
Buchdahl
C
C
Gardette
D
D
Gramain
J C
JC
Maurizis
J C
JC
Veyre
A
A
Madelmont
J C
JC
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D004357:Drug Synergism; D005038:Ethylnitrosourea / Q000031:analogs & derivatives* / Q000633:toxicity; D006151:Guanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D055672:Static Electricity; D013329:Structure-Activity Relationship
D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D007202:Indicators and Reagents; D006151:Guanosine; C017139:1-(2-chloroethyl)-1-nitrosourea; D003849:Deoxyguanosine; D005038:Ethylnitrosourea