Synthesis and Investigation of the Antitumor Properties of Novel, Bicyclic Furopyrimidine, Pyrrolopyrimidine and Pyrimidopyridazine Nucleoside Analogues

Abstract

A series of nine hitherto unknown bicyclic pyrimidine nucleoside analogues (BCNAs) bearing bicyclic furo[2,3-d]pyrimidin-2(3H)one, 3H-pyrrolo[2,3-d]pyrimidin-2(7H)-one and 5,6-dihydropyrimido[4,5-c]pyridazin-7(8H)-one bases were prepared in a straightforward approach. Each of the synthesized compounds possesses a β-D-ribofuranose, β-D-2-deoxyribofuranose or β-D-arabinofuranose moiety attached to the heterocyclic ring system. This is one of few examples of the synthesis of pyrrolo[2,3-d]pyrimidin-2(7H)-one and dihydropyrimido[4,5-c]pyridazin-7(8H)-one nucleosides, and the first example of such nucleosides possessing an arabinose moiety. A key synthetic step involved a Sonogashira coupling reaction. For the coupling with 4-phenyl-1-butyne, deprotected 5-iodouridine, 5-iodo-2′-deoxyuridine and 5-iodoarabinouridine were used, and this reaction was followed by cycloisomerization and subsequent conversion of the furan ring into a pyrrole or a pyridazine ring. This approach resulted in the creation of a small library of compounds, which were evaluated for their antiproliferative properties against HL-60 and Jurkat E6.1 cell lines. Of all tested compounds, only 6-(2-phenylethyl)-3-(β-D-ribofuranosyl)furo[2,3-d]pyrimidin-2(3H)-one exhibited weak antiproliferative activity, with IC 50 values of 54 and 81 μM for HL-60 and Jurkat E6.1 cells, respectively.

The 2′-deoxyribofuranoside of 3-phenyltetrahydropyrimido[4,5-c]pyridazin-7-one: a bicyclic nucleoside with sugar residues in N and S conformations, and its molecular recognition

“…Compound 1 has a strong structural relationship to pyrrolo-dC (2) and imidazolo-dC (3) (see Scheme 1), and is decorated with a phenyl ring, as is the case for 2 and 3 (Hudson & Ghorbani-Choghamarani, 2007;Mei et al, 2014). A 3-methylpyrimido[4,5-c]pyridazine nucleoside (Loakes et al, 2003a,b) and a phenylethyl derivative were reported previously (Mieczkowski et al, 2016). Nucleoside 1 was synthesized in our laboratory and incorporated into DNA oligonucleotides employing phosphoramidite chemistry and solid-phase oligonucleotide synthesis (Mei et al, 2015).…”

Extension of furopyrimidine nucleosides with 5-alkynyl substituent: Synthesis, high fluorescence, and antiviral effect in the absence of free ribose hydroxyl groups

“…Despite the persistent synthetic pursuit of furopyrimidine nucleosides, so far only a few and only C-6 substituted have been crystallographically characterized. 20 , 25 , 38 , 40 , 42) , 43) , 44) , 45) , 46) Although nucleosides are often resistant to crystallization, efforts to obtain diffraction quality crystals were successful for compound 4 , using methanol at room temperature. X-Ray crystallography confirmed the structure of the 3',5'-di- O -acetyl-5-iodo-6-( p -tolyl)furopyrimidine ( 4 , Figure 2 ).…”

The halogenation of natural flavonoids, baicalein and chrysin, enhances their affinity to human protein kinase CK2

“…During our research on the design and discovery of novel anticancer compounds based on diverse heterocyclic structures, such as 6 H ‐oxazolo[3,2‐ f ]pyrimidine‐5,7‐dione, 47 1,3,4,12 a ‐tetrahydropyrazino[2,1‐ c ][1,4]benzodiazepine‐6,12(2 H ,11 H )‐dione, 48 as well as nucleoside derivatives 49–52 and natural poliphenolic compounds, 30 we turn our attention to halogenated flavonoid derivatives as possible ligands for tumor‐associated kinase CK2. The compounds used in this study are presented on Figure 1.…”