Structural mimicry of adenosine by the antitumor agents 4-methoxy- and 4-amino-8-(beta-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidine as viewed by a molecular modeling method.
A rationale for the antitumor activity of 4-methoxy- and 4-amino-8-(beta-D-ribofuranosylamino)pyrimido-[5,4-d]pyrimidine (beta-MRPP and beta-ARPP, respectively) was studied by a molecular modeling method. Although these nucleoside analogues are structurally different from adenosine, they act as substrates for adenosine kinase. The molecular modeling method, which considered the three-dimensional structure and atom-based physicochemical properties of the nucleosides to quantify the molecular similarities, showed that certain low-energy conformations of the beta anomers of a series of nucleosides including beta-MRPP, beta-ARPP, and their 4-hydroxy, 4-amino-6-chloro, 4-methylthio-2,6-dichloro, 4,6-diamino, 4-dimethylamino, 4-methylamino, and 4-hydroxy-2,6-dichloro analogues have remarkable structural similarity to adenosine. The method also suggested that the selection of the reference compound adenosine in the structural comparison is of primary importance to gain insight into the observed antitumor activity. The success of the present method led to AM1 (Austin model 1) molecular orbital calculations and experimental studies indicating that the antitumor activity of the alpha anomer of ARPP is probably due to equilibration to the beta anomer. The AM1 calculation of the protonation energy of N5 of pyrimido[5,4-d]pyrimidines, which occupies the same position in space as the N1 of adenosine, gave a direct correlation between the basicity of the nitrogen with a lone pair of electrons and the observed antitumor activity.
Ghose
A K
AK
ICN Nucleic Acid Research Institute, Costa Mesa, CA 92626.
Viswanadhan
V N
VN
Sanghvi
Y S
YS
Nord
L D
LD
Willis
R C
RC
Revankar
G R
GR
Robins
R K
RK
D000241:Adenosine / Q000031:analogs & derivatives*; D000970:Antineoplastic Agents; D007536:Isomerism; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011741:Pyrimidine Nucleosides; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; C011650:NSC 283867; D011741:Pyrimidine Nucleosides; C061494:4-methoxy-8-(ribofuranosylamino)pyrimido(5,4-d)pyrimidine; D000241:Adenosine