Synthesis of N3- and 2-NH₂-substituted 6,7-diphenylpterins and their use as intermediates for the preparation of oligonucleotide conjugates designed to target photooxidative damage on single-stranded DNA representing the bcr–abl chimeric gene

Abstract

Two 17-mer oligodeoxynucleotide-5'-linked-(6,7-diphenylpterin) conjugates, 2 and 3, were prepared as photosensitisers for targeting photooxidative damage to a 34-mer DNA oligodeoxynucleotide (ODN) fragment 1 representing the chimeric bcr-abl gene that is implicated in the pathogenesis of chronic myeloid leukaemia (CML). The base sequence in the 17-mer was 3'G G T A G T T A T T C C T T C T T5'. In the first of these ODN conjugates (2) the pterin was attached at its N3 atom, via a -(CH2)3OPO(OH)- linker, to the 5'-OH group of the ODN. Conjugate 2 was prepared from 2-amino-3-(3-hydroxypropyl)-6,7-diphenyl-4(3H)-pteridinone 10, using phosphoramidite methodology. Starting material 10 was prepared from 5-amino-7-methylthiofurazano[3,4-d]pyrimidine 4 via an unusual highly resonance stabilised cation 8, incorporating the rare 2H,6H-pyrimido[6,1-b][1,3]oxazine ring system. In the characterisation of 10 two pteridine phosphazenes, 15 and 29, were obtained, as well as new products containing two uncommon tricyclic ring systems, namely pyrimido[2,1-b]pteridine (20 and 24) and pyrimido[1,2-c]pteridine (27). In the second ODN conjugate the linker was -(CH2)5CONH(CH2)6OPO(OH)- and was attached to the 2-amino group of the pterin. In the preparation of 3, the N-hydroxysuccinimide ester 37 of 2-(5-carboxypentylamino)-6,7-diphenyl-4(3H)-pteridinone was condensed with the hexylamino-modified 17-mer. Excitation of 36 with near UV light in the presence of the single-stranded target 34-mer, 5'T G A C C A T C A A T A A G14 G A A G18 A A G21 C C C T T C A G C G G C C3' 1 caused oxidative damage at guanine bases, leading to alkali-labile sites which were monitored by polyacrylamide gel electrophoresis. Cleavage was observed at all guanine sites with a marked preference for cleavage at G14. In contrast, excitation of ODN-pteridine conjugate 2 in the presence of 1 caused oxidation of the latter predominantly at G18, with a smaller extent of cleavage at G15 and G14 (in the double-stranded portion) and G21. These results contrast with our previous observation of specific cleavage at G21 with ruthenium polypyridyl sensitisers, and suggest that a different mechanism, probably one involving Type 1 photochemical electron transfer, is operative. Much lower yields were found with the ODN-pteridine conjugate 3, perhaps as a consequence of the longer linker between the ODN and the pteridine in this case.

Lipophilic Decyl Chain–Pterin Conjugates with Sensitizer Properties

“…Oligodeoxynucleotides have been covalently bound to 6,7diphenylpterin and used as photosensitizers. 12 Nucleoside analogues have been synthesized as pterin derivatives. 13 In the presence of oxygen, aromatic pterins act as photosensitizers through both type I (generation of radicals via electron transfer or hydrogen abstraction) and type II (production of 1 O 2 ) mechanisms; 10,14 the former species (such as hydroxyl radicals) have very short diffusion distances, but the latter species 1 O 2 can diffuse one hundred or more nanometers in biological media.…”

“…Oligodeoxynucleotides have been covalently bound to 6,7-diphenylpterin and used as photosensitizers . Nucleoside analogues have been synthesized as pterin derivatives .…”

The Activity of Novel BCR-ABL Small-Molecule Degraders Containing Pyrimidine Rings and Their Role in Overcoming Drug Resistance

“…On the basis of previous studies, we explored various structures and prepared a lead compound, DMP11, a linker containing a pyrimidine ring with stable physicochemical properties and high activity. As a “privileged scaffold,” the pyrimidine ring is widely used in the field of new drug research and development, and its unique mode of action with the receptor greatly improves the selectivity of drug molecules and anticancer activity and can reduce toxic and side effects [ 22 , 23 ]. PROTAC can effectively inhibit the target protein at a low dose and quickly degrade and clear it, providing an efficient strategy with high safety, antidrug resistance, and broad application prospects [ 24 ].…”