The syntheses of tricyclic analogues of O6-methylguanine

The syntheses and properties of tricyclic pyrrolo[2,3-d]pyrimidine analogues of S6-methylthioguanine and O6-methylguanine

“…Previously, compounds 3a and 3b were obtained in two steps from the appropriate 5-substituted pyrimidine precursors 8 and 9, respectively. 9 Compounds 8 13 and 9 9 were obtained via Michael addition of 2,6-diamino-4(3H)pyrimidinone to the appropriate nitroalkenes which were in turn prepared in 4 steps from 1,3propanediol or 1,4-butanediol respectively. Compounds 8 and 9 were subsequently converted (in 4 steps) to the desired tricyclic pyrrolopyrimidines 3a and 3b.…”

“…Compounds 8 and 9 were subsequently converted (in 4 steps) to the desired tricyclic pyrrolopyrimidines 3a and 3b. 9 In order to develop a more efficient synthesis of 3b that could also be applied to obtaining the novel sulfur-containing analogues 4a and 4b, we considered an alternative route to 5-substituted pyrrolo [2,3-d]pyrimidines that has been used in the synthesis of the queuine base. 14 This method, which involves the reaction of an a-bromoaldehyde with 2,6-diamino-4(3H)pyrimidinone, allowed the preparation of compounds 10 and 11 in three steps from the respective diols (Scheme 1).…”

“…In contrast compound 3b is relatively stable and displays an IC 50 of approximately 1 mM in a standard MGMT assay. 9 Previous studies have shown that synthetic oligonucleotide substrates containing S 6 -methylthioand Se 6 -methylselenoguanine analogues are also repaired by MGMT 10 which has encouraged us to prepare the corresponding thio analogues of 3a and 3b.…”

The Synthesis and Properties of Tricyclic Analogues of S 6–Methylthioguanineand O 6-Methylguanine

“…Compound 1 was a weak inactivator (IC 50 1mM) suggesting that it is likely to be recognised as a substrate by the protein. [4] While the analogues are designed as cross-linking agents rather than optimal inactivators of MGMT this demonstrates at least for compound 1 that recognition in DNA is likely and infact is expected to be much better following incorporation into DNA. [1] …”

“…[4] Compounds 6 [5] and 7 [4] were prepared via Michael addition of 2,6-diamino-4(3H)pyrimidinone to the appropriate nitroalkenes which were in turn obtained in four steps from 1,3-propanediol or 1,4-butanediol respectively. The tricyclic pyrrolopyrimidines 4a-b, were prepared via an alternative route in which an appropriate α-bromoaldehyde was condensed with 2,6-diamino-4(3H)pyrimidinone, and the resulting 5-substituted pyrrolopyrimidines subject to thiation at the 4-oxo position and cyclisation via the Mitsunobu reaction.…”