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.

Abstract

A rationale for the antitumor activity of 4-methoxy-and 4-amino-8-(I8-D-ribofuranosylamino)pyrimido-[5,4-dlpyrimidine (fJ-MRPP and 13-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 fJ anomers of a series of nucleosides including f-MRPP, 13-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 AMI (Austin model 1) molecular orbital calculations and experimental studies indicating that the antitumor activity of the a anomer of ARPP is probably due to equilibration to the 8 anomer. The AMI calculation of the protonation energy of N5 of pyrimido[5,4-dlpyrimidines, which occupies the same position in space as the Ni of adenosine, gave a direct correlation between the basicity of the nitrogen with a lone pair of electrons and the observed antitumor activity.We recently studied several exocyclic aminoribonucleosides such as 4-methoxy-and 4-amino-8-(,3-D-ribofuranosylamino)-pyrimido [5,tively; compounds la and lb, Fig. 1) and showed these nucleosides to be substrates of mammalian adenosine kinase (1-3). This conclusion was based on the resistance of adenosine kinase-deficient cells to the cytotoxic effects of the nucleosides la-li, 2a, and 2b with associated reductions in both the formation of their cellular monophosphates and the competitive inhibition of adenosine phosphorylation by adenosine kinase. These nucleosides structurally resemble inactive homoadenosine and violate the required spatial relationship between the 2'-OH of the pentofuranosyl and the aglycon moiety as established by Bennett and Hill (4) for a substrate of adenosine kinase. f3-MRPP (la), 13-ARPP (lb), and 4-amino-8-(a-D-ribofuranosylamino)pyrimido[5,4-d]-pyrimidine (2b) showed promising antitumor activity against L1210, WI-L2, and LoVo/L cells in culture and also against L1210 in mice (2). This activity was shown to be due to the inhibition of 5-phosphoribosyl-1-pyrophosphate synthetase (ribose-5-phosphate pyrophosphokinase, EC 2.7.6.1) by the monophosphates of la and lb (3). These results led us to investigate the reason for substrate recognition by adenosine kinase, using a computer-aided receptor modeling method (5, 6, t). In this method the low-energy conformations and atom-based physicochemical properties are exhaustively compared to find the structural similarities between two or more molecule...

In vitro effect of extracellular AMP on MCF‐7 breast cancer cells: Inhibition of glycolysis and cell proliferation

“…Natural adenosine derivatives such as NADH, NAD, ATP, ADP, AMP, and adenosine inhibit cell proliferation in a variety of normal and tumor cells in vitro; inosine, in contrast, is not inhibitory (Green and Chan, 1973;Snyder et al, 1978;Parsons and Hayward, 1983;Rapaport, 1983Rapaport, ,1988Rapaport et al, 1983;Ghose et al, 1989;Lohmann and Hugo, 1989;DiVirgilio et al, 1990). A variety of enzymes exist that degrade various derivatives to adenosine or inosine.…”

“…Intracellular adenosine kinase activity is a n essential prerequisite for an inhibition of cell proliferation (Green and Chan, 1973;Weisman et al, 1988;Ghose et al, 1989). Several investigations have shown that the intracellular accumulation of AMP together with the inhibition of P-ribose-PP synthesis represent the main effects of natural adenosine derivatives .…”

Recent Progress in Pyrimido[5,4-d]pyrimidine Chemistry

“…96CHEC2(7)737, p. 755), ribosides 159b and 160b show antiviral activity by inhibiting viral protein synthesis (85MI2, 89JME629) and antitumor properties by structural "mimicry" of adenosine (89MI1,89PNA8242,93MPH(44)479). Fluoronucleoside 53b inhibits the growth of human leukemic cells (94NN1125).…”

“…The rates of anomerization of ARPP (159b) and MRPP (160b) were measured (89PNA8242). Selective dehalogenation of dichloride 157b (to give 162) and deprotection furnish 6-chloro ARPP (163, Scheme 36) (89JME629), whereas selective amination and subsequent dechlorination lead to nucleosides 164 and 165, respectively.…”

“…Theoretical work in the field of nucleosides is exemplified by the calculation of the protonation energy of N-5 of 8-methylamino PPs 56-58(89PNA8242) and of structural properties of adenosine analogs 159a and…”