Studies on the synthesis and biological evaluation of certain pyrrolo[2,3-d] pyrimidine nucleosides and their methylated analogs which are structurally related to the naturally occurring nucleoside Q, nucleoside Q*, and methylated guanosines.

The synthesis of 7-cyano-7-deazguanosine (preQ(,0), 6) has been accomplished in our laboratory via a multi-step synthesis from the nucleoside antibiotic toyocamycin (1). This nucleoside has been subsequently established as a precursor of the naturally occurring nucleosides Q (8) and Q* (9). This finding prompted us to prepare several other preQ(,0) analogs. 7-Cyano-N('2),N('2)-dimethyl-7-deazaguanosine (150) was prepared by the treatment of 2-chloro-5-cyano-7-(2,3,5-tri-O-acetyl-(beta)-D-ribofuranosyl)pyrrolo{2,3,-d}pyrimidin-4-one (149) with ethanolic dimethylamine. The corresponding N('2)-methylguanosine analog 154 was not obtained either by the direct amination or several other alternative approaches. 7-Aminomethyl-7-deazaguanosine (preQ(,1), 7) has been isolated, characterized, and also established as being one of the precursors in the biosynthesis of the naturally occurring nucleosides Q (8) and Q* (9). This prompted us to prepare some closely related preQ(,1) analogs. Hence, 7-aminomethyl-7-deazaguanosine (7) was prepared by a catalytic hydrogenation of the corresponding 7-cyano-7-deazaguanosine derivative 6. The nucleoside preQ(,0) (6) and other closely related 7-cyano-7-deazaguanosine analogs were chemically converted to nucleosides with a carboxamido function at the 7-position. The significance of the proton residing on N-1 and the C-2 amino group of the 7-deazaguanosine derivatives in regards to antileukemic activity could be assessed by blocking the position(s) with methyl group(s). In addition, these derivatives can also be viewed as analogs of a specific class of naturally occurring, modified nucleosides, i.e., 1-methylguanosine (m('1)G) and N('2)-methylated guanosines (m('2)G, m(,2)('2)G). In an effort to expand the knowledge in this area of study, a series of N-1 and/or C-2 amino methylated quanosine derivatives, 7-cyano-7-deazaguanosine, 7-aminomethyl-7-deazaguanosine, and 7-carboxamido-7-deazaguanosine, were prepared by amination of 2-chloro-5-cyano-3-methyl-7-(2,3,5-tri-O-acetyl-(beta)-D-ribofuranosyl)pyrrolo-{2,3-d}pyrimidin-4-one (160). The transformation of cyano group to aminomethyl and carboxamido function by catalytic hydrogenation and with basic hydrogen peroxide, respectively, was also accomplished. The results from the in vitro cytotoxicity testing against leukemia L1210 cell line indicated that the proton residing on N-1 of 7-deazaguanosine analogs is necessary for intrinsic cytotoxicity in this series of compounds. Methylation at an amino group (position-2) decreases the cytotoxicity. The effect of different substituents at purine position-7 of 7-deazaguanosine derivatives was also observed, in general, in the following trend: cyano (TURNEQ) carboxamido >> aminomethyl.