Antitumor imidazotetrazines. 25. Crystal structure of 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (temozolomide) and structural comparisons with the related drugs mitozolomide and DTIC.
The antitumor imidazotetrazinone, temozolomide (5), C6H6N6O2, forms crystals with unit cell dimensions a = 17.332 (3), b = 7.351 (2), c = 13.247 (1), beta = 109.56 (1) degree and space group P21/c. A doubly hydrogen-bonded dimer constitutes the asymmetric unit. One carboxamide group forms an additional intermolecular NH...O hydrogen bond; in both molecules the carboxamide group is coplanar with the heterocycle and its NH2 group interacts with the imidazole nitrogen atom N(7). Molecular orbital calculations show the carbonyl carbon C(4) to be the most electron deficient atom, with relatively weak N(3)-C(4) and C(4)-N(5) bonds confirming that temozolomide should ring-open at this position in solution. The energy barrier to carboxamide group rotation of approximately 20 kJ mol-1 should permit interconversion between rotamers. In temozolomide and the related drug mitozolomide (4), N(7) is more negatively charged than N(1), which favors the formation of hydrogen bonds to the former atom in spite of their poor geometry. The relevance of these structural features to the action of temozolomide as a major-groove-directed prodrug of the alkylating agent MTIC (3) is discussed.
Lowe
P R
PR
Pharmaceutical Sciences Institute, Aston University, Birmingham, U.K.
Sansom
C E
CE
Schwalbe
C H
CH
Stevens
M F
MF
Clark
A S
AS
D000970:Antineoplastic Agents / Q000737:chemistry*; D003461:Crystallography; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D009588:Nitrogen Mustard Compounds / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000077204:Temozolomide
D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D003606:Dacarbazine; C040369:mitozolomide; D000077204:Temozolomide