Structural Mimicry of Adenosine by the Antitumor Agents 4-methoxy- and 4-amino-8-(β -D-ribofuranosylamino)pyrimido[5,4-d]pyrimidine as Viewed by a Molecular Modeling Method

• Published in: Proceedings of the National Academy of Sciences - PNAS 1989-11, Vol.86 (21), p.8242-8246
• Main Authors: Ghose, Arup K., Viswanadhan, Vellarkad N., Sanghvi, Yogesh S., Nord, L. Dee, Willis, Randall C., Revankar, Ganapathi R., Robins, Roland K.
• Format: Article
• Language: English
• Subjects: Adenosine - analogs & derivatives; Antineoplastic Agents; Atoms; Biochemistry; Biological and medical sciences; Electrons; Enzymes; Fundamental and applied biological sciences. Psychology; Hydrogen bonds; Isomerism; Modeling; Models, Molecular; Molecular biophysics; Molecular Conformation; Molecular orbitals; Molecular Structure; Molecules; Nitrogen; Nucleosides; Pyrimidine Nucleosides; Structure in molecular biology; Structure-Activity Relationship; Tridimensional structure
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.86.21.8242

A rationale for the antitumor activity of 4-methoxy- and 4-amino-8-(β -D-ribofuranosylamino)pyrimido[5,4-d]pyrimidine (β -MRPP and β -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 β anomers of a series of nucleosides including β -MRPP, β -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 α anomer of ARPP is probably due to equilibration to the β 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.