Anti-tumour imidazotetrazines. Part XXI. Mitozolomide and temozolomide: probes for the major groove of DNA.
The structural and electronic properties of the major groove-binding anti-tumour imidazotetrazinones, mitozolomide and temozolomide were studied using molecular orbital techniques. Structure-activity relationships of mitozolomide derivatives emphasized the importance of a hydrogen bond donor on the C8-substituent and showed that good activity would be expected for derivatives carrying a small C8-substituent with restricted negative potential. The coplanarity of the carboxamide substituent in mitozolomide is unlikely to be disrupted by hydrogen bonding in the major groove. Semi-empirical M.O. calculations gave a very high partial positive charge on C4, indicating an enhanced susceptibility to nucleophilic attack leading to ring opening at this position and the formation of a triazene alkylating agent.
Clark
A S
AS
Pharmaceutical Sciences Institute, Aston University, Birmingham, UK.
Stevens
M F
MF
Sansom
C E
CE
Schwalbe
C H
CH
D000970:Antineoplastic Agents / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D008958:Models, Molecular; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000077204:Temozolomide
D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D003606:Dacarbazine; D004247:DNA; C040369:mitozolomide; D000077204:Temozolomide