Design, Synthesis, Antiviral, and Cytostatic Evaluation of Novel Isoxazolidine Analogs of Homonucleotides

Abstract

Moderate diastereoselectivities (d.e. 2-62%) of isoxazolidine homonucleotides were observed for cycloadditions between N-methyl-C-(diethoxyphosphoryl)nitrone and N-allyl nucleobases, with trans-isoxazolidines predominating. The stereochemistry of the substituted isoxazolidines was established based on 2D NOE experiments performed for uracil-containing cycloadducts. The cis- and trans-isoxazolidine phosphonates obtained herein were evaluated in vitro for activity against a broad range of DNA and RNA viruses. None of the compounds were endowed with antiviral activity at subtoxic concentrations, but some of them were found to inhibit the proliferation of L1210 cells with IC50 values in the range of 33-100 µM.

Synthesis, anti-varicella-zoster virus and anti-cytomegalovirus activity of quinazoline-2,4-diones containing isoxazolidine and phosphonate substructures

“…As previously reported [25], N 1 -allyl-N 3 -benzoylquinazoline-2,4-dione 18a was obtained in three steps in 20% overall yield starting from quinazoline-2,4-dione employing bis-N 1 ,N 3 -benzoylation with benzoyl chloride followed by the selective N 1 -debenzoylation and subsequent allylation. However, this procedure appeared tedious and the N 1 -debenzylation step was the least effective.…”

“…Recently, we successfully accomplished the syntheses of homonucleoside analogues 11 which proved inactive against a broad spectrum of DNA and RNA viruses while some of them appeared slightly cytostatic toward several cancerous cell lines [25]. However, later on they were additionally screened for inhibition of VZV and HCMV replication and two compounds 11a (B ¼ N-benzoyluracil) and 12a (R ¼ benzoyl, R 0 ¼ methyl) showed noticeable activity toward VZV (Table 3).…”

Design, Synthesis, Anti-Varicella-Zoster and Antimicrobial Activity of (Isoxazolidin-3-yl)Phosphonate Conjugates of N1-Functionalised Quinazoline-2,4-Diones

“…The relative configurations of the isoxazolidine cycloadducts trans - 20 and cis - 20 or trans - 21 and cis - 21 were established by taking in account our previous studies on the stereochemistry of cycloaddition of N-substituted C -diethyoxyphosphonylated nitrones 22 and 23 with allylated derivatives of various (hetero)aromatic compounds [ 21 , 22 ], including N3-substituted N1-allylquinazoline-2,4-diones [ 18 ]. Since modification of the substituents in quinazoline-2,4-dione moiety, including the relocation of substituents at N1 and N3, has no influence on the stereochemical outcome of the cycloaddition of nitrones 22 and 23 to N-allylquinazoline-2,4-dione dipolarophiles, configurations of all major isoxazolidines 20 and 21 were assigned trans , while minor isomers were assigned cis , by analogy to previously established configurations of trans - and cis -isoxazolidines 12a–c [ 18 ].…”

Design, antiviral and cytostatic properties of isoxazolidine-containing amonafide analogues

“…3 Hz, J H4b-P = 15.7-16.1 Hz, J H4a-H5 = 5.5-5. 33 9 Hz] extracted from the respective 1 H and 13 C NMR spectra.…”