Synthesis of Polycyclic Hetero-Fused 7-Deazapurine Heterocycles and Nucleosides through C–H Dibenzothiophenation and Negishi Coupling

Abstract

A new approach for synthesizing polycyclic heterofused 7-deazapurine heterocycles and the corresponding nucleosides was developed based on C–H functionalization of diverse (hetero)aromatics with dibenzothiophene-S-oxide followed by the Negishi cross-cooupling with bis(4,6-dichloropyrimidin-5-yl)zinc. This cross-coupling afforded a series of (het)aryl-pyrimidines that were converted to fused deazapurine heterocycles through azidation and thermal cyclization. The fused heterocycles were glycosylated to the corresponding 2′-deoxy- and ribonucleosides, and a series of derivatives were prepared by nucleophilic substitutions at position 4. Four series of new polycyclic thieno-fused 7-deazapurine nucleosides were synthesized using this strategy. Most of the deoxyribonucleosides showed good cytotoxic activity, especially for the CCRF-CEM cell line. Phenyl- and thienyl-substituted thieno-fused 7-deazapurine nucleosides were fluorescent, and the former one was converted to 2′-deoxyribonucleoside triphosphate for enzymatic synthesis of labeled oligonucleotides.

Synthesis and Biological Profiling of Benzofuro‐Fused 7‐Deazapurine Nucleosides

“…As the 2’‐deoxyribonucleosides bearing bulky bases behave differently in the biological activity profiling, [14] here we decided to prepare both series of the benzofuro‐fused 2’‐deoxyribonucleosides and ribonucleosides bearing different substituents at the position 10 and to systematically study their biological activities. The glycosylation of nucleobase 10 with the Hoffer's chlorosugar [19] under basic condition gave the nucleoside 11 in moderate 33 % yield (Scheme 2).…”

“…As most of the previously reported (hetero)aryl‐fused nucleosides [11,12,13,14] exerted interesting fluorescence properties with potential for construction of fluorescent DNA probes, [24] we studied the photophysical properties of the title benzofuro‐fused 7‐deazapurine nucleosides 14 a – d and 16 a – d . All the compounds were found to be fluorescent in DMF with emission maxima in a broad range between 358–482 nm and moderate to good quantum yields (0.2–0.42, Table 2).…”

“…In all cases, the active compounds were only ribonucleosides, corresponding 2'‐deoxyribonucleosides were always completely inactive. However, in the case of nucleosides based on the 7‐deazapurine fused with bulky heteroaromatic rings 5 and 6 , only 2'‐deoxyribonucleosides displayed potent anti‐cancer activities, [14] which suggested that the mode of action of this class of nucleosides is probably different from all the previously reported heteroaryl‐fused 7‐deazapurine ribonucleosides. All these results indicate that structure‐based design is very difficult for this class of compounds due to the complex mechanism of action and diversity of possible biological targets.…”

“…The heteroaryl-fused 7-deazapurine nucleobases can be prepared through two main strategies: 1) multistep heterocyclization of chloronitro-(hetero)aryls, [10,11,15] 2) thermal or photochemical cyclization of azido-biaryls. [8,13,14,16] Due to the availability of the starting material and shorter reaction sequence, the second approach was applied to synthesize the target benzofuro-fused 7-deazapurines.…”

“…As most of the previously reported (hetero)aryl-fused nucleosides [11,12,13,14] exerted interesting fluorescence properties with potential for construction of fluorescent DNA probes, [24] we studied the photophysical properties of the title benzofuro-fused 7-deazapurine nucleosides 14 a-d and 16 a-d. All the compounds were found to be fluorescent in DMF with emission maxima in a broad range between 358-482 nm and moderate to good quantum yields (0.2-0.42, Table 2). The substituent in position 10 has significant effect both on emission maxima and quantum yield, both 2-furyl derivatives 14 b and 16 b showed the brightest fluorescence with good quantum yields 0.34 and 0.42, respectively.…”