key: cord-0751674-46nyje11
authors: Piotrowska, Dorota G.; Głowacka, Iwona E.; Schols, Dominique; Snoeck, Robert; Andrei, Graciela; Gotkowska, Joanna
title: Novel Isoxazolidine and γ-Lactam Analogues of Homonucleosides
date: 2019-11-06
journal: Molecules
DOI: 10.3390/molecules24224014
sha: 8a2ca0a9b9108a56a79d6a610c6537102c124697
doc_id: 751674
cord_uid: 46nyje11

Homonucleoside analogues cis-16 and trans-17 having a (5-methoxycarbonyl)isoxazolidine framework were synthesized via the 1,3-dipolar cycloaddition of nucleobase-derived nitrones with methyl acrylate. Hydrogenolysis of the isoxazolidines containing thymine, dihydrouracil, theophylline and adenine moieties efficiently led to the formation of the respective γ-lactam analogues. γ-Lactam analogues having 5-bromouracil and 5-chlorouracil fragments were synthesized by treatment of uracil-containing γ-lactams with NBS and NCS. Isoxazolidine and γ-lactam analogues of homonucleosides obtained herein were evaluated for activity against a broad range of DNA and RNA viruses. None of the compounds that were tested exhibited antiviral or cytotoxic activity at concentrations up to 100 µM. The cytostatic activities of all compounds toward nine cancerous cell lines was tested. γ-Lactams trans-15e (Cl-Ura) and cis-15h (Theo) appeared the most active toward pancreatic adenocarcinoma cells (Capan-1), showing IC(50) values 21.5 and 18.2 µM, respectively. Isoxazolidine cis-15e (Cl-Ura) inhibited the proliferation of colorectal carcinoma (HCT-116).

Nucleoside analogues belong to a group of important antiviral and antitumor drugs [1] [2] [3] [4] . However, resistance to drugs and their toxicity are considered major factors limiting the effectiveness of therapies. Structural modifications of available drugs from a class of nucleoside analogues, including sugar and/or nucleobase residues, resulted in the discovery of a variety of therapeutically-useful antiviral [5] (e.g., azidothymidine (AZT) [6] , carbovir [7] , lobucavir [8] , dioxolane T [9] and lamivudine [10] ) and anticancer [11, 12] (e.g., cladribine [13] , gemcitabine [14] , azacitidine [15] and cytarabine [14, 16] , clofarabine [17] ) agents ( Figure 1 ).

On the other hand, the introduction of a methylene bridge between a nucleobase and the sugar partly led to the formation of homonucleosides, which are known for their resistance to hydrolytic or enzymatic cleavage, as well as for the rotational freedom when compared with the natural nucleosides. Furthermore, it was shown that homonucleosides are substrates for cellular kinases and are able to pair with other nucleosides by Watson-Crick interactions without appreciable modifications of the structure of DNA (or RNA) molecules [18] . 1 -Homonucleosides containing adenine 1 or guanine 2 were found to be active against herpes simplex virus (minimum inhibitory concentration (MIC) = 5-20 µg/mL) and vaccinia virus [19] [20] [21] , while compound 3 (IC 50 = 25.2 µg/mL) showed activity against the influenza type virus AH1N1 ( Figure 2 ) [22] . Homonucleoside analogue of 2 -deoxyuridine 4 has been On the other hand, the introduction of a methylene bridge between a nucleobase and the sugar partly led to the formation of homonucleosides, which are known for their resistance to hydrolytic or enzymatic cleavage, as well as for the rotational freedom when compared with the natural nucleosides. Furthermore, it was shown that homonucleosides are substrates for cellular kinases and are able to pair with other nucleosides by Watson-Crick interactions without appreciable modifications of the structure of DNA (or RNA) molecules [18] . 1′-Homonucleosides containing adenine 1 or guanine 2 were found to be active against herpes simplex virus (minimum inhibitory concentration (MIC) = 5-20 µg/mL) and vaccinia virus [19] [20] [21] , while compound 3 (IC50 = 25.2 µg/mL) showed activity against the influenza type virus AH1N1 ( Figure 2 ) [22] . Homonucleoside analogue of 2′-deoxyuridine 4 has been described as a selective inhibitor of viral uracil-DNA glycosylase (UDG), while exerting only small effect on the human enzymes [23] . Incorporation of the isoxazolidine ring into a nucleoside framework as a sugar part replacer was first proposed by Tronchet and co-workers [24, 25] with the intention to study antiviral [20, [26] [27] [28] [29] [30] [31] , antibacterial [32] and antifungal [33] activities of the compounds. Other research groups then intensively explored this field further. Thus, a compound 5 [34] and phosphonylated derivatives 6 [35] and 7 [36] [37] [38] inhibited the reverse transcriptase activity of avian Moloney virus (AMV) and human immunodeficiency virus (HIV) at a level comparable with that of tenofovir (1 nM) and 10fold higher than that of AZT (10 nM). Moreover, their cytotoxicity was significantly lower (50% cytotoxic concentration (CC50) > 500 µM) in comparison with that of AZT (CC50 = 12.14 µM) ( Figure  3 ). In order to obtain compounds with a sufficient stability for hydrolytic or enzymatic cleavage, analogues of 1′-homonucleosides 8-11 ( Figure 3 ) were also synthesized [39] [40] [41] [42] [43] . On the other hand, the introduction of a methylene bridge between a nucleobase and the sugar partly led to the formation of homonucleosides, which are known for their resistance to hydrolytic or enzymatic cleavage, as well as for the rotational freedom when compared with the natural nucleosides. Furthermore, it was shown that homonucleosides are substrates for cellular kinases and are able to pair with other nucleosides by Watson-Crick interactions without appreciable modifications of the structure of DNA (or RNA) molecules [18] . 1′-Homonucleosides containing adenine 1 or guanine 2 were found to be active against herpes simplex virus (minimum inhibitory concentration (MIC) = 5-20 µg/mL) and vaccinia virus [19] [20] [21] , while compound 3 (IC50 = 25.2 µg/mL) showed activity against the influenza type virus AH1N1 ( Figure 2 ) [22] . Homonucleoside analogue of 2′-deoxyuridine 4 has been described as a selective inhibitor of viral uracil-DNA glycosylase (UDG), while exerting only small effect on the human enzymes [23] . Incorporation of the isoxazolidine ring into a nucleoside framework as a sugar part replacer was first proposed by Tronchet and co-workers [24, 25] with the intention to study antiviral [20, [26] [27] [28] [29] [30] [31] , antibacterial [32] and antifungal [33] activities of the compounds. Other research groups then intensively explored this field further. Thus, a compound 5 [34] and phosphonylated derivatives 6 [35] and 7 [36] [37] [38] inhibited the reverse transcriptase activity of avian Moloney virus (AMV) and human immunodeficiency virus (HIV) at a level comparable with that of tenofovir (1 nM) and 10fold higher than that of AZT (10 nM). Moreover, their cytotoxicity was significantly lower (50% cytotoxic concentration (CC50) > 500 µM) in comparison with that of AZT (CC50 = 12.14 µM) ( Figure  3 ). In order to obtain compounds with a sufficient stability for hydrolytic or enzymatic cleavage, analogues of 1′-homonucleosides 8-11 ( Figure 3 ) were also synthesized [39] [40] [41] [42] [43] . Incorporation of the isoxazolidine ring into a nucleoside framework as a sugar part replacer was first proposed by Tronchet and co-workers [24, 25] with the intention to study antiviral [20, [26] [27] [28] [29] [30] [31] , antibacterial [32] and antifungal [33] activities of the compounds. Other research groups then intensively explored this field further. Thus, a compound 5 [34] and phosphonylated derivatives 6 [35] and 7 [36] [37] [38] inhibited the reverse transcriptase activity of avian Moloney virus (AMV) and human immunodeficiency virus (HIV) at a level comparable with that of tenofovir (1 nM) and 10-fold higher than that of AZT (10 nM). Moreover, their cytotoxicity was significantly lower (50% cytotoxic concentration (CC 50 ) > 500 µM) in comparison with that of AZT (CC 50 = 12.14 µM) ( Figure 3 ). In order to obtain compounds with a sufficient stability for hydrolytic or enzymatic cleavage, analogues of 1 -homonucleosides 8-11 ( Figure 3 ) were also synthesized [39] [40] [41] [42] [43] .

In the isoxazolidine nucleoside/nucleotide analogues described so far, a nucleobase is attached to C5; therefore, the 1,3-dipolar cycloaddition of nitrones and N-vinyl or N-allyl nucleobases has been found a convenient method for their preparation [44] . Recently, we designed isoxazolidine analogues of 1 -homonucleos(t)ides 12 (Figure 3 ), in which nucleobases were attached to C3 to underscore the fundamental difference to the already-described ones [45, 46] . In the synthesis of homonucleosides 12, the 1,3-dipolar cycloaddition was also employed, but in that case, nucleobase-derived nitrones and selected alkenes were applied [45, 46] . Since no significant activity of compounds 12 toward the viruses tested was noticed, we wondered whether the replacement of an isoxazolidine moiety with a γ-lactam ring would lead to an improvement of antiviral properties of newly-designed compounds 15. The idea of incorporation of the γ-lactam moiety has been supported by the presence of this subunit in many natural products (Figure 4) , which showed antiviral [47, 48] , cytotoxic [49] [50] [51] [52] [53] , anti-inflammatory [53] [54] [55] and antimicrobial [56, 57] properties, among others. For this reason the assumption that homonucleoside analogues 15 (Scheme 1) having the γ-lactam moiety could possess interesting biological properties as antiviral or cytotoxic is justified [58] . In the isoxazolidine nucleoside/nucleotide analogues described so far, a nucleobase is attached to C5; therefore, the 1,3-dipolar cycloaddition of nitrones and N-vinyl or N-allyl nucleobases has been found a convenient method for their preparation [44] . Recently, we designed isoxazolidine analogues of 1′-homonucleos(t)ides 12 (Figure 3 ), in which nucleobases were attached to C3 to underscore the fundamental difference to the already-described ones [45, 46] . In the synthesis of homonucleosides 12, the 1,3-dipolar cycloaddition was also employed, but in that case, nucleobase-derived nitrones and selected alkenes were applied [45, 46] . Since no significant activity of compounds 12 toward the viruses tested was noticed, we wondered whether the replacement of an isoxazolidine moiety with a γ-lactam ring would lead to an improvement of antiviral properties of newly-designed compounds 15. The idea of incorporation of the γ-lactam moiety has been supported by the presence of this subunit in many natural products (Figure 4) , which showed antiviral [47, 48] , cytotoxic [49] [50] [51] [52] [53] , antiinflammatory [53] [54] [55] and antimicrobial [56, 57] properties, among others. For this reason the assumption that homonucleoside analogues 15 (Scheme 1) having the γ-lactam moiety could possess interesting biological properties as antiviral or cytotoxic is justified [58] . 

The synthetic strategy for γ-lactam homonucleosides 15 relies on the 1,3-dipolar cycloaddition of nucleobase-derived nitrones 13 with methyl acrylate, followed by the hydrogenolysis of the N-O 

The synthetic strategy for γ-lactam homonucleosides 15 relies on the 1,3-dipolar cycloaddition of nucleobase-derived nitrones 13 with methyl acrylate, followed by the hydrogenolysis of the N-O bond in an isoxazolidine scaffold, which was accompanied by the intramolecular cyclization to transform cycloadducts 14 into compounds 15 (Scheme 1). Nucleobase-derived nitrones 13 were synthesized from N-(2-oxoethyl)nucleobases and Nmethylhydroxylamine, as described previously [45, 46] . The 1,3-dipolar cycloadditions of the nucleobase-derived nitrones 13 to methyl acrylate were carried out at 60 °C in methanol for 24 h (Scheme 2, Table 1 ) and afforded mixtures of diastereoisomeric isoxazolidines cis-14 and trans-14. The cis/trans ratios of the isoxazolidines were calculated from the 1 H-NMR spectra of the crude reaction mixtures by the comparison of diagnostic resonances of the H2C-4 protons in the isoxazolidine ring, as well as the signals of the respective protons of nucleobase moieties. In some cases, differences in resonances of the CH3-N protons for diastereoisomeric isoxazolidines cis-14 and trans-14 were also diagnostic. The crude reaction mixtures of the diastereoisomers were subjected to column chromatography; however, only pure isomeric isoxazolidines cis-14a and trans-14a were isolated (Table 1 , entry a). In the other cases the respective fractions enriched in the isomers cis-14b-14i or Scheme 1. Retrosynthesis of γ-lactam analogues of 1 -homonucleosides 15.

The synthetic strategy for γ-lactam homonucleosides 15 relies on the 1,3-dipolar cycloaddition of nucleobase-derived nitrones 13 with methyl acrylate, followed by the hydrogenolysis of the N-O bond in an isoxazolidine scaffold, which was accompanied by the intramolecular cyclization to transform cycloadducts 14 into compounds 15 (Scheme 1).

Nucleobase-derived nitrones 13 were synthesized from N-(2-oxoethyl)nucleobases and N-methylhydroxylamine, as described previously [45, 46] . The 1,3-dipolar cycloadditions of the nucleobase-derived nitrones 13 to methyl acrylate were carried out at 60 • C in methanol for 24 h (Scheme 2, Table 1 ) and afforded mixtures of diastereoisomeric isoxazolidines cis-14 and trans-14. The cis/trans ratios of the isoxazolidines were calculated from the 1 H-NMR spectra of the crude reaction mixtures by the comparison of diagnostic resonances of the H 2 C-4 protons in the isoxazolidine ring, as well as the signals of the respective protons of nucleobase moieties. In some cases, differences in resonances of the CH 3 -N protons for diastereoisomeric isoxazolidines cis-14 and trans-14 were also diagnostic. The crude reaction mixtures of the diastereoisomers were subjected to column chromatography; however, only pure isomeric isoxazolidines cis-14a and trans-14a were isolated (Table 1 , entry a). In the other cases the respective fractions enriched in the isomers cis-14b-14i or trans-14b-14i were collected. The subsequent separation of diastereoisomeric mixture of isoxazolidines cis-14b-14h or trans-14b-14h on an HPLC column allowed us to obtain pure isomers cis-14b-14h and trans-14b-14h (Table 1 , entry b-h), and the amounts, however small, were sufficient to perform a full characterization of the newly-synthesized compounds and their further biological screening. Unfortunately, the attempts at separating diastereoisomeric isoxazolidines cis-14i and trans-14i appeared fruitless, even with HPLC. trans-14b-14i were collected. The subsequent separation of diastereoisomeric mixture of isoxazolidines cis-14b-14h or trans-14b-14h on an HPLC column allowed us to obtain pure isomers cis-14b-14h and trans-14b-14h (Table 1 , entry b-h), and the amounts, however small, were sufficient to perform a full characterization of the newly-synthesized compounds and their further biological screening. Unfortunately, the attempts at separating diastereoisomeric isoxazolidines cis-14i and trans-14i appeared fruitless, even with HPLC. The relative configurations of isoxazolidines cis-14a and trans-14a have already been established [45] . As we have recently described, (5-methoxycarbonyl)isoxazolidine cis-14a was reduced with sodium borohydride in ethanol to the known (5-hydroxymethyl)isoxazolidine cis-16 [45] (Scheme 3). During this transformation, the structure of the isoxazolidine skeleton remains unchanged, and The relative configurations of isoxazolidines cis-14a and trans-14a have already been established [45] . As we have recently described, (5-methoxycarbonyl)isoxazolidine cis-14a was reduced with sodium borohydride in ethanol to the known (5-hydroxymethyl)isoxazolidine cis-16 [45] (Scheme 3). The relative configurations of isoxazolidines cis-14a and trans-14a have already been established [45] . As we have recently described, (5-methoxycarbonyl)isoxazolidine cis-14a was reduced with The relative configurations of isoxazolidines cis-14a and trans-14a have already been established [45] . As we have recently described, (5-methoxycarbonyl)isoxazolidine cis-14a was reduced with sodium borohydride in ethanol to the known (5-hydroxymethyl)isoxazolidine cis-16 [45] (Scheme 3). During this transformation, the structure of the isoxazolidine skeleton remains unchanged, and therefore, a relative configuration of the isoxazolidine cis-14a was unambiguously established. Consequently, the isomeric (5-methoxycarbonyl)isoxazolidine was identified as trans-14a. Since similar spectral patterns for the respective isoxazolidine protons (H3, H4α, H4β and H5) were observed in series of cis-14b-14i and trans-14b-14i when compared to those observed for cycloadducts cis-14a and trans-14a, their configurations were analogously assigned. The relative configurations of isoxazolidines cis-14a and trans-14a have already been established [45] . As we have recently described, (5-methoxycarbonyl)isoxazolidine cis-14a was reduced with sodium borohydride in ethanol to the known (5-hydroxymethyl)isoxazolidine cis-16 [45] (Scheme 3). During this transformation, the structure of the isoxazolidine skeleton remains unchanged, and therefore, a relative configuration of the isoxazolidine cis-14a was unambiguously established. Consequently, the isomeric (5-methoxycarbonyl)isoxazolidine was identified as trans-14a. Since similar spectral patterns for the respective isoxazolidine protons (H3, H4ɑ, H4β and H5) were observed in series of cis-14b-14i and trans-14b-14i when compared to those observed for cycloadducts cis-14a and trans-14a, their configurations were analogously assigned. Figure 5, structure 18) . Surprisingly, the preferred conformations for dihydrouacil-containing isoxazolidines cis-14g and trans-14g could not be assigned, and sets of couplings indicate the existence of conformational equilibrium of isoxazolidine ring. Figure 5, structure 18) . Surprisingly, the preferred conformations for dihydrouacil-containing isoxazolidines cis-14g and trans-14g could not be assigned, and sets of couplings indicate the existence of conformational equilibrium of isoxazolidine ring. For the either cis or trans isoxazolidines containing uracil or substituted uracil residues 14a-14f, we also noticed that diastereotopic hydrogen atoms in CH2-base units which resonate at a lower field (4.05-3.89 ppm) showed significantly smaller vicinal coupling constants to H-C3 (3.3-3.9 Hz) than those associated with higher field signals (3.59-3.32 ppm) when values of 9.1-9. 7 Hz were observed. One may conclude that high-field hydrogens are antiperiplanar to H-C3, while low-field ones are oriented gauche, as depicted by the Newman projection 19 ( Figure 5 ). Although real reasons for the restricted rotation around C3-CH2Base bond remain obscure to us at the moment, they may simply reflect repulsive interactions of sterically bulky CH2-base groups with Me-N and Hβ-C4-Hα fragments.

Finally, attempts at transformation of isoxazolidine cycloadducts cis-14/trans-14 into γ-lactam derivatives trans-15/cis-15 were made, following the procedure applied previously for transformation For the either cis or trans isoxazolidines containing uracil or substituted uracil residues 14a-14f, we also noticed that diastereotopic hydrogen atoms in CH 2 -base units which resonate at a lower field (4.05-3.89 ppm) showed significantly smaller vicinal coupling constants to H-C3 (3.3-3.9 Hz) than those associated with higher field signals (3.59-3.32 ppm) when values of 9.1-9. 7 Hz were observed. One may conclude that high-field hydrogens are antiperiplanar to H-C3, while low-field ones are oriented gauche, as depicted by the Newman projection 19 ( Figure 5 ). Although real reasons for the restricted rotation around C3-CH 2 Base bond remain obscure to us at the moment, they may simply reflect repulsive interactions of sterically bulky CH 2 -base groups with Me-N and Hβ-C4-Hα fragments.

Finally, attempts at transformation of isoxazolidine cycloadducts cis-14/trans-14 into γ-lactam derivatives trans-15/cis-15 were made, following the procedure applied previously for transformation of cis-14a into trans-15g [45] . It was expected that since hydrogenation of the N-O bond in the isoxazolidine scaffold releases the amino group, the subsequent intramolecular cyclization to γ-lactams trans-15/cis-15 should occur spontaneously (Scheme 4). Consequently, the isoxazolidine cis-14 would provide trans-15, while isoxazolidine trans-14 should be a substrate for the synthesis of cis-configured γ-lactam cis-15. With that in mind, we concluded that not only can pure diastereoisomers cis-14 and trans-14 be used for the synthesis of trans-15/cis-15, but so can mixtures of the respective isomers cis-14/trans-14, although significantly enriched in one diastereoisomer to maintain control on the stereochemistry of the products formed.

For the either cis or trans isoxazolidines containing uracil or substituted uracil residues 14a-14f, we also noticed that diastereotopic hydrogen atoms in CH2-base units which resonate at a lower field (4.05-3.89 ppm) showed significantly smaller vicinal coupling constants to H-C3 (3.3-3.9 Hz) than those associated with higher field signals (3.59-3.32 ppm) when values of 9.1-9.7 Hz were observed. One may conclude that high-field hydrogens are antiperiplanar to H-C3, while low-field ones are oriented gauche, as depicted by the Newman projection 19 ( Figure 5 ). Although real reasons for the restricted rotation around C3-CH2Base bond remain obscure to us at the moment, they may simply reflect repulsive interactions of sterically bulky CH2-base groups with Me-N and Hβ-C4-Hα fragments.

Finally, attempts at transformation of isoxazolidine cycloadducts cis-14/trans-14 into γ-lactam derivatives trans-15/cis-15 were made, following the procedure applied previously for transformation of cis-14a into trans-15g [45] . It was expected that since hydrogenation of the N-O bond in the isoxazolidine scaffold releases the amino group, the subsequent intramolecular cyclization to γlactams trans-15/cis-15 should occur spontaneously (Scheme 4). Consequently, the isoxazolidine cis-14 would provide trans-15, while isoxazolidine trans-14 should be a substrate for the synthesis of cisconfigured γ-lactam cis-15. With that in mind, we concluded that not only can pure diastereoisomers cis-14 and trans-14 be used for the synthesis of trans-15/cis-15, but so can mixtures of the respective isomers cis-14/trans-14, although significantly enriched in one diastereoisomer to maintain control on the stereochemistry of the products formed. As we recently reported [45] , the hydrogenation of uracil-containing isoxazolidine homonucleoside cis-14a (B = Ura) proceeded smoothly and the intramolecular cyclization of intermediary γ-aminocarboxylic ester to a γ-lactam was accompanied by hydrogenation of the uracil residue to produce the lactam trans-15g (B = diH-Ura) in a good yield (80%) instead of the expected compound trans-15a (B = Ura) ( Table 2 , entry a). Similarly, cis-15g (B = diH-Ura) was obtained from trans-14a (B = Ura) (85%). As we recently reported [45] , the hydrogenation of uracil-containing isoxazolidine homonucleoside cis-14a (B = Ura) proceeded smoothly and the intramolecular cyclization of intermediary γ-aminocarboxylic ester to a γ-lactam was accompanied by hydrogenation of the uracil residue to produce the lactam trans-15g (B = diH-Ura) in a good yield (80%) instead of the expected compound trans-15a (B = Ura) ( Table 2 , entry a). Similarly, cis-15g (B = diH-Ura) was obtained from trans-14a (B = Ura) (85%).

On the other hand, when a 80:20 mixture of thymine-containing isoxazolidines cis-14b and trans-14b (B = Thy) was subjected to hydrogenation, the respective 80:20 mixture of γ-lactam trans-15b and cis-15b (B = Thy) was obtained. From this mixture pure diastereoisomers were isolated after column chromatography followed by HPLC ( Table 2 , entry b).

During the hydrogenation of 5-halogenated uracil derivatives cis-14/trans-14 (B = X-Ura), we faced the same problem as in case of uracil derivatives. Moreover, halogen atoms were removed from nucleobase skeletons. For example, hydrogenation of a 60:40 mixture of cis-14d and trans-14d isoxazolidines (B = Br-Ura) led to the formation of an inseparable mixture of trans-15a, cis-15a and trans-15g and cis-15g (53:35:8:2) ( Table 2 , entry d). Analogously, a mixture of trans-15a, cis-15a, trans-15g and cis-15g (4:2:74:20) was obtained from the 73:27 mixture of isoxazolidines cis-14e and trans-14e (B = Cl-Ura) ( Table 2 , entry e). Similarly, hydrogenation of a cis-14c (B = F-Ura) gave dihydrouracil-containing γ-lactam trans-15g (B = diH-Ura) ( Table 2 , entry c).

Furthermore, the respective mixtures of isoxazolidines cis-14g/trans-14g, cis-14h/trans-14h and cis-14i/trans-14i were successfully hydrogenated to provide γ-lactams containing dihydrouracil (trans-15g/cis-15g), theophylline (trans-15h/cis-15h) and adenine (trans-15i/cis-15i) as nucleobases ( Table 2 , entry g-i). To supplement a library of designed γ-lactam homonucleosides trans-15/cis-15 with analogues having bromine (trans-15d/cis-15d) and chlorine (trans-15e/cis-15e) atoms, the halogenation of uracil derivatives was proposed [59] [60] [61] . Treatment of the above-mentioned (Table 1 , entry d), inseparable mixture of γ-lactams trans-15a, cis-15a, trans-15g and trans-15g (53:35:8:2) with N-bromosuccinimide (NBS) [59] led to the formation of the mixture of γ-lactams trans-15d, cis-15d, together with unreacted trans-15g and cis-15g (50:37:9:4) (Scheme 5). The purification of this mixture on a silica gel column followed by HPLC allowed us to isolate trans-15d and cis-15d in 30% and 9.3% yields, respectively. Similarly, the reaction of an analogous mixture of trans-15a, cis-15a, trans-15g and cis-15g with N-chlorosuccinimide (NCS) [60] gave the respective mixture of compounds trans-15e, cis-15e, trans-15g and cis-15g (55:34:8:3), from which trans-15e and cis-15e were obtained in 6% and 4.2% yields, respectively (Scheme 5).

All isoxazolidines 14 and γ-lactams 15 obtained were evaluated for their activities against a wide variety of DNA and RNA viruses using the following cell-based assays: (a) human embryonic lung (HEL) cell cultures: herpes simplex virus-1 (KOS strain), herpes simplex virus-2 (G strain), vaccinia virus, thymidine kinase deficient (acyclovir-resistant) herpes simplex virus-1 (TK − KOS ACV r ), adenovirus-2, human coronavirus (229E strain), cytomegalovirus (AD-169 and Davis strains) and varicella-zoster virus (TK + VZV and TK − VZV strains); (b) HeLa cell cultures: vesicular stomatitis virus, Coxsackie virus B4 and respiratory syncytial virus; (c) Vero cell cultures: para-influenza-3 virus, reovirus-1, Sindbis virus, Coxsackie virus B4, Punta Toro virus and yellow fever virus; and (d) MDCK cell cultures: influenza A virus (H1N1 and H3N2 subtypes) and influenza B virus. Ganciclovir, cidofovir, acyclovir, brivudin, zalcitabine, zanamivir, alovudine, mycophenolic acid, amantadine, rimantadine, ribavirin, dextran sulfate (molecular weight 10000, DS-10000) and Urtica dioica agglutinin (UDA) were used as the reference compounds. The antiviral activity was expressed as the EC 50 : the compound concentration required to reduce virus plaque formation (VZV) by 50% or to reduce virus-induced cytopathicity by 50% (other viruses). The cytotoxicity of the compounds tested toward the uninfected host cells was defined as the minimum cytotoxic concentration (MCC) that causes a microscopically detectable alteration of normal cell morphology. The 50% cytotoxic concentration (CC 50 ), causing a 50% decrease in cell viability was determined using a colorimetric MTS assay system. None of the tested compounds showed appreciable antiviral activity toward any of the tested DNA and RNA viruses at the concentration up to 100 µM. At the same time, none of them affected the cell morphologies of used uninfected host cells. Ganciclovir, cidofovir, acyclovir, brivudin, zalcitabine, zanamivir, alovudine, mycophenolic acid, amantadine, rimantadine, ribavirin, dextran sulfate (molecular weight 10000, DS-10000) and Urtica dioica agglutinin (UDA) were used as the reference compounds. The antiviral activity was expressed as the EC50: the compound concentration required to reduce virus plaque formation (VZV) by 50% or to reduce virus-induced cytopathicity by 50% (other viruses). The cytotoxicity of the compounds Scheme 5. Synthesis of γ-lactams trans-15d and cis-15d (X = Br), and trans-15e and cis-15e (X = Cl).

The 50% cytostatic inhibitory concentration (IC 50 ) causing a 50% decrease in cell proliferation was determined for all isolated isoxazolidines 14 and γ-lactams 15 toward nine cancerous cell lines (Capan-1 (pancreatic adenocarcinoma), Hap1 (chronic myeloid leukemia), HCT-116 (colorectal carcinoma), NCI-H460 (lung carcinoma), DND-41 (acute lymphoblastic leukemia), HL-60 (acute myeloid leukemia), K-562 (chronic myeloid leukemia), MM.1S (multiple myeloma) and Z-138 (non-Hodgkin lymphoma)) and normal retina (non-cancerous) cells (hTERT RPE-1). Docetaxel, etoposide and stauroporine were used as the reference compounds.

All of the compounds tested were not toxic to non-cancerous retina cells (hTERT RPE-1) at concentrations up to 100 µM. They were also not active against DND-41, HL-60, K-562, MM.1S or Z-138 cancer cells. All isoxazolidines 14 and γ-lactams 15 we tested, except cis-14c (B = F-Ura), exhibited moderate activity against pancreatic adenocarcinoma cells (Capan-1) (IC 50 = 18.2 to 95 µM), and among them, γ-lactams trans-15e (Cl-Ura) and cis-15h (Theo) were the most active, with IC 50 values of 21.5 and 18.2 µM, respectively (Table 3) . In most cases, both cis-configured isoxazolidines 14 and cis-configured γ-lactams 15 were slightly less active when compared to the respective trans-isomers (e.g., cis-14b-f versus trans-14b-f, cis-14h-i versus trans-14h-I and cis-15b versus trans-15b, cis-15d vs. trans-15d); however, that correlation did to apply for uracil, dihydrouracil and theophiline-derivatives 14a, 15g and 15h. Moreover, several isoxazolidines 14 and γ-lactams 15 inhibited the proliferation of Hap1 (IC 50 = 40.9 to 58.5 µM), HCT-116 (IC 50 = 26.7 to 68,4 µM) and NCI-H460 cells (IC 50 = 28.6 to 62.3 µM) ( Table 3) . 

To a solution of a nitrone (1.00 mmol) in methanol (9 mL), methyl acrylate (10.0 mL) was added. The mixture was stirred at 60 • C for 24 h. The solvent was removed in vacuo and crude products were purified on silica gel columns using chloroform-methanol (100:1, 50:1, 20:1, 10:1, v/v) as eluents. The respective fractions were subjected to HPLC on a X Bridge Prep, C18, 5 µm, OBD, 19 × 100 mm column using water/methanol (90:10, 85:15, v/v) to afford pure isoxazolidines. 

A solution of the respective isoxazolidines cis-14 and trans-14 (1.00 mmol) in methanol (3 mL) was stirred under atmospheric pressure of hydrogen over Pd/C (0.05 mmol) with Pd(OH) 2 /C (0.05 mmol) at room temperature for 1-2 days. The suspension was filtered through a layer of Celite. The solvent was removed in vacuo and crude products were chromatographed on silica gel columns with chloroform:methanol mixtures (50:1, 20:1 and 10:1, v/v) and then on HPLC using a X Bridge Prep, C8, 5 µm, OBD, 19 × 100 mm column and a water:methanol mixture (98:2, v/v) as an eluent to give γ-lactams trans-15 and cis-15. 3 .84 (dd, 1H, 2 J (HCH) = 13.4Hz, 3 J (HCC-H2) = 6.5 Hz, HCH-ClUra), 2.92 (s, 3H, CH 3 N), 2.48 (ddd, 1H, 2 J (H3α-H3β) = 13.6 Hz, 3 J = 7.8 Hz, 3 J = 7. 6 Hz, H α C3), 1.75 (ddd, 1H, 2 J (H3β-H3α) = 13.6 Hz, 3 J = 5. 6 Hz, 3 J = 5. 3 Hz, H β C3). 13 

The compounds were evaluated against different herpesviruses, including herpes simplex virus type 1 (HSV-1) strain KOS, thymidine kinase-deficient (TK − ) HSV-1 KOS strain resistant to ACV (ACV r ), herpes simplex virus type 2 (HSV-2) strain G, adeno virus-2, human coronavirus, varicella-zoster virus (VZV) TK + strain Oka, TK -VZV strains 07-1, human cytomegalovirus (HCMV) strains AD-169 and Davis; para-influenza-3 virus, reovirus-1, Sindbis virus, Coxsackie virus B4, Punta Toro virus, respiratory syncytial virus (RSV), vesicular stomatitis virus, yellow fever virus, influenza A virus subtypes H1N1 (A/PR/8) and H3N2 (A/HK/7/87); and influenza B virus (B/HK/5/72). The antiviral assays were based on inhibition of virus-induced cytopathicity or plaque formation (for VZV) in human embryonic lung (HEL) fibroblasts, African green monkey kidney cells (Vero), human epithelial cervix carcinoma cells (HeLa), or Madin Darby canine kidney cells (MDCK) . Confluent cell cultures in microtiter 96-well plates were inoculated with 100 CCID 50 of virus (1 CCID 50 being the virus dose to infect 50% of the cell cultures) or with 20 plaque forming units (PFU) (for VZV) and the cell cultures were incubated in the presence of varying concentrations of the test compounds. Viral cytopathicity or plaque formation (VZV) was recorded as soon as it reached completion in the control virus-infected cell cultures that were not treated with the test compounds. Antiviral activity was expressed as the EC 50 or compound concentration required to reduce virus-induced cytopathicity or viral plaque formation by 50%. Cytotoxicity of the test compounds was expressed as the minimum cytotoxic concentration (MCC) or the compound concentration that caused a microscopically detectable alteration of cell morphology.

All assays were performed in 96-well microtiter plates. To each well was added (5−7.5) × 10 4 tumor cells and a given amount of the test compound. The cells were allowed to proliferate at 37 • C in a humidified, CO 2 -controlled atmosphere. At the end of the incubation period, the cells were counted in a Coulter counter. The IC 50 (50% inhibitory concentration) was defined as the concentration of the compound that inhibited cell proliferation by 50%.

A series of isoxazolidine analogues of homonucleosides cis-14 and trans-14 was synthesized by 1,3-dipolar cycloaddition of nucleobase-derived nitrones 13 and methyl acrylate. Based on 1 H-NMR vicinal coupling constants the preferred 2 E conformations were established for the isoxazolidine ring in both cis-14 and trans-14. Hydrogenolytic transformation of isoxazolidines cis-14 and trans-14 into γ-lactams trans-15 and cis-15 was then performed to produce the respective γ-lactams containing thymine (trans-15b/cis-15b), dihydrouracil (trans-15g/cis-15g), theophylline (trans-15h/cis-15h) and adenine (trans-15i/cis-15i) as nucleobases by the application of the established protocol.

Since, during the hydrogenation of 5-halogenated uracil-containing isoxazolidine homonucleosides, the halogen atom was removed from a nucleobase skeleton, 5-bromouracil and 5-chlorouracil derivatives trans-15d/cis-15d (Br-Ura) and trans-15e/cis-15e (Cl-Ura) were obtained via the treatment of uracil-containing γ-lactams with NBS and NCS, respectively.

All obtained isoxazolidine and γ-lactam homonucleosides were evaluated against a broad-spectrum of DNA and RNA viruses and appeared inactive at concentrations up to 100 µM.

Antiproliferative properties of the obtained isoxazolidines and γ-lactams were evaluated on nine cancerous cell lines and several of them exhibited moderate inhibitory activity, and at the same time they were inactive toward normal retina cells.

44 (C5), 65.29 (C3), 52.74 (C(O)OCH 3 ), 50.73 (CH 2 -BrUra)

Calcd for C 11 H 14 BrN 3 O 5 : C, 37

Yield: 15%; a colorless amorphous solid; m.p. = 185-186 • C (crystallized from chloroform-methanol). IR (KBr, cm −1 ) ν max : 3416

83 (s, 3H, C(O)OCH 3 ), 3.50 (dddd

70 (s, 3H, CH 3 N), 2.38 (ddd, 1H, 2 J (H4β-H4α) = 13.5 Hz, 3 J (H4β-H5) = 9

Calcd for C 11 H 14 BrN 3 O 5 : C, 37

Yield: 5.7%; a colorless amorphous solid; m.p. = 129-131 • C (crystallized from chloroform-methanol). IR (KBr, cm −1 ) ν max : 3473

82 (s, 3H, C(O)OCH 3 ), 3.58 (dd, 1H, 2 J (HCH) = 13.9 Hz

48 (dddd, 1H, 3 J (H3-CCH) = 9

J (H3-H4β) = 2.2 Hz, HC3), 2.88 (ddd, 1H, 2 J (H4α-H4β) = 13.5 Hz, 3 J (H4α-H5) = 9.9 Hz, 3 J (H4α-H3) =

65 (s, 3H, CH 3 N)

CDCl 3 ) δ: 171.37 (C(O)OCH 3 ), 159.55 (C4 )

Yield: 5.0%; a colorless amorphous solid; m.p. = 165-167 • C (crystallized from chloroform-methanol). IR (KBr, cm −1 ) ν max : 3453

Hz, 3 J (H3-H4α) = 7.5 Hz, 3 J (H3-CCH) = 3.7 Hz, 3 J (H3-H4β)

Hz, 3 J (HCC-H3) = 9.7 Hz, HCH-ClUra), 2.87 (ddd, 1H, 2 J (H4α-H4β) = 13.5 Hz, 3 J (H4α-H5) = 7.5 Hz

70 (s, 3H

CDCl 3 ) δ: 172.26 (C(O)OCH 3 )

Yield: 2.7%; a colorless amorphous solid; m.p. = 189-191 • C (crystallized from ethyl acetate-hexane). IR (KBr, cm −1 ) ν max : 3407

Hz, 3 J (H5-H4β) = 5.3 Hz, HC5), 3.92 (dd, 1H, 2 J (HCH) = 13.9 Hz, 3 J (HCC-H3) = 3.8 Hz, HCH-IUra)

87 (ddd, 1H, 2 J (H4α-H4β) = 13.6 Hz, 3 J (H4α-H5) = 9.8 Hz, 3 J (H4α-H3) = 8.4 Hz, H α C4), 2.64 (s, 3H, CH 3 N), 2.19 (ddd, 1H, 2 J (H4β-H4α) = 13.6 Hz, 3 J (H4β-H5) = 5.3 Hz, 3 J (H4β-H3) = 2.2 Hz, H β C4); 13 C-NMR (150 MHz, trans-1-[(4-Hydroxy-1-methyl-5-oxopyrrolidin-2-yl)methyl]-5-methylpyrimidine-2,4(1H,3H)-dione (trans-15b)

Hz, 3 J (H4-H3α) = 8.1 Hz, HC4), 4.01 (dd, 1H, 2 J (HCH) = 13.9 Hz, 3 J (HCC-H2) = 4.6 Hz, HCH-Thy), 3.92 (dddd, 1H, 3 J (H2-H3β) = 9.0 Hz, 3 J (H2-CCH) = 5.9 Hz, 3 J (H2-CCH)

J (H3α-H3β) = 13.2 Hz, 3 J (H3α-H4) = 8.1 Hz, 3 J (H3α-H2) = 1.0 Hz, H α C3)

Hz, 3 J (H3β-H4) = 9.0 Hz, 3 J (H3β-H2) = 9.0 Hz, H β C3)

55 (C2 ), 142.71 (C5 ), 111.53 (C6 ), 68.26 (C4)

3H)-dione (cis-15b). Yield: 6.0%; a colorless amorphous solid; m.p. > 230 • C (crystallized from methanol-chloroform). IR (KBr, cm −1 ) ν max : 3552

O) δ: 7.36 (q, 1H, 4 J = 1.1 Hz

J (H2-CCH) = 5.9 Hz, 3 J (H2-H3β) = 5.8 Hz, 3 J (H2-CCH)

88 (s, 3H

Hz, 3 J (H3α-H2) = 7.6 Hz, H α C3)

H3β-H4) = 6.1 Hz, 3 J (H3β-H2) = 5.8 Hz, H β C3); 13 C-NMR (150 MHz, D 2 O) δ: 176

11 (C4)

-Hydroxy-1-methyl-5-oxopyrrolidin-2-yl)metyl]dihydropyrimidine-2,4(1H,3H)-dione (trans-15g). Yield: 4.0%; a colorless amorphous solid; m.p. > 230 • C with decomposition (crystallized from methanol-chloroform). IR (KBr, cm −1 ) ν max : 3226

J (HCH) = 14.1 Hz, 3 J (HCC-H2) = 4.8 Hz, HCH-dihydroUra), 3.58-3.49 (m, 2H), 3.46 (dd, 1H, 2 J (HCH) = 14.1 Hz, 3 J (HCC-H2) = 6.5 Hz, HCH-dihydroUra

02 (ddd, 1H, 2 J (H3β-H3α) = 13.1 Hz

CD 3 OD) δ: 175.44 (C(O)), 171.24 (C4 ), 154.34 (C2 ), 68.17 (C4), 56.28 (CH 2 -dihydroUra), 48.60 (C2)

Yield: 23%; a colorless amorphous solid; m.p. > 230 • C with decomposition (crystallized from methanol-chloroform). IR (KBr, cm −1 ) ν max : 3298

HCH-dihydroUra), 3.79-3.75 (m, 1H, HC2), 3.56-3.53 (m, 2H), 3.45 (dd, 1H, 2 J (HCH) = 14.3 Hz, 3 J (HCC-H2) = 5.9 Hz, HCH-dihydroUra

Hz, 3 J (H3α-H2) = 7.5 Hz, H α C3), 1.73 (ddd, 1H, 2 J (H3β-H3α) = 13.4 Hz, 3 J (H3β-H4) = 7.0 Hz

C(O)), 171.29 (C4 ), 154.26 (C2 ), 68.99 (C4), 55.97 (CH 2 -dihydroUra)

Yield: 34%; a colorless amorphous solid; m.p. > 230 • C (crystallized from methanol-chloroform). IR (KBr, cm −1 ) ν max : 3345, 3103

HCH-The), 4.16 (dd, 1H, 3 J (H4-H3α) = 8.6 Hz, 3 J (H4-H3β) = 8.6 Hz, HC4

14 (ddd, 1H, 2 J (H3β-H3α) = 13.4 Hz, 3 J (H3β-H2) = 9.0 Hz, 3 J (H3β-H4) = 8.6 Hz

CDCl 3 ) δ: 174.89 (C(O)), 155.35 (C2 ), 151.48 (C6 ), 149.23 (C4 ), 141.20 (C8 ), 106.92 (C5 ), 67.79 (C4)

Yield: 26%; a colorless amorphous solid; m.p. > 230 • C (crystallized from methanol-chloroform). IR (KBr, cm −1 ) ν max : 3284

J (HCC-H2) = 4.8 Hz, HCH-The), 4.31 (dd, 1H, 3 J (H4-H3α) = 7.6 Hz, 3 J (H4-H3β) = 4.0 Hz, HC4), 4.23 (dd, 1H, 2 J (HCH) = 13.4 Hz, 3 J (HCC-H2) = 7.9 Hz, HCH-The)

62 (s, 3H, CH 3 ), 3.44 (s, 3H, CH 3 ), 2.96 (s, 3H

36 (C4 ), 141.63 (C8 ), 106.83 (C5 ), 69.26 (C4), 57.75 (CH 2 -The)

Yield: 28%; a colorless amorphous solid; m.p. > 230 • C with decomposition (crystallized from water). IR (KBr, cm −1 ) ν max : 3319

82 (ddd, 1H, 2 J (H3β-H3α) = 13.1 Hz, 3 J = 9.1 Hz, 3 J = 9.0 Hz, H β C3)

Amino-9H-purin-9-yl)methyl]-3-hydroxy-1-methylpyrrolidin-2-one (cis-15i). A colorless oil. IR (KBr, cm −1 ) ν max : 3469

DMSO-d6) δ: 8.14 (s, 1H, HC2 ), 8.11 (s, 1H, HC8 )

m, 1H), 2.77 (s, 3H, CH 3 N), 2.27-2.23 (m, 1H, H α C3), 1.45 (dt, 1H 2 J = 14.2 Hz, 3 J = 7.0 Hz, H β C3

Synthesis of γ-Lactams cis-15d and trans-15d A solution of a 53:35:8:2 mixture of γ-lactams trans-15a, cis-15a

594 mmol) in DMF (4 mL) was stirred at room temperature for 24 h. The solvent was removed in vacuo and the crude product was purified on a silica gel column using chloroform-methanol (100:1, v/v) as an eluent. The respective fractions were subjected to chromatography on a X Bridge Prep, C8, 5 µm, OBD, 19 × 100 mm column using water/methanol (98:2, v/v) to give pure γ-lactams trans

Yield: 30%; a colorless amorphous solid; m.p. = 199-200 • C with decomposition (crystallized from methanol-chloroform). IR (KBr, cm −1 ) ν max : 3381

Hz, 3 J (H4-H3α) = 8.7 Hz, HC4), 4.03 (dd, 1H, 2 J (HCH) = 13.4 Hz, 3 J (HCC-H2) = 4.9 Hz, HCH-BrUra

Hz, 3 J (HCC-H2) = 5.0 Hz, HCH-BrUra)

J (H3α-H4) = 8.7 Hz, 3 J (H3α-H2) = 5.7 Hz, H α C3), 2.07 (ddd, 1H, 2 J (H3β-H3α) = 13.5 Hz, 3 J (H3β-H4) =

Hz, 3 J (H3β-H2) = 8.9 Hz, H β C3); 13 C-NMR (150 MHz, CD 3 OD) δ: 175.66 (C(O)), 160.46 (C4 ), 151.08 (C2 ), 145.19 (C5 ), 95.73 (C6 ), 68.04 (C4)

Calcd for C 10 H 12 BrN 3 O 4 : C, 37

yl)methyl]pyrimidine-2,4(1H,3H)-dione (cis-15d). Yield: 9.3%; a colorless amorphous solid; m.p. = 209-210 • C with decomposition (crystallized from methanol-chloroform). IR (KBr, cm −1 ) ν max : 3550

-H3α) = 7.8 Hz, 3 J (H2-H3β) = 7.1 Hz, 3 J (H2-CCH) = 4.9 Hz, HC2), 3.87 (dd, 1H, 2 J (HCH) = 14.3 Hz, 3 J (HCC-H2) = 9.8 Hz, HCH-BrUra)

Hz, 3 J (H3α-H4) = 8.1 Hz, 3 J (H3α-H2) = 7.8 Hz, H α C3), 1.68 (ddd, 1H, 2 J (H3β-H3α) = 13.7 Hz

H β C3). 13 C-NMR signals of cis-15d were extracted from the spectra of a 53:47 mixture of cis-15d and trans-15d 13 C-NMR (150 MHz

cis-15a, trans-15g and trans-15g (0.136 g, 0.61 mmol) and N-chlorosuccinimide (0.163 g, 1.22 mmol) in freshly distilled pyridine (12 mL) was stirred at 100 • C for 1 h. The solvent was removed in vacuo and the crude product was purified on a silica gel column using chloroform-methanol (100:1, v/v) as an eluent. The respective fractions were subjected to chromatography on an X Bridge Prep

Yield: 4.2%; a colorless amorphous solid; m.p. > 230 • C with decomposition (crystallized from methanol-chloroform). IR (KBr, cm −1 ) ν max : 3404

HCH-ClUra), 4.00 (dddd, 1H, 3 J (H2-H3β) = 8.9 Hz, 3 J (H2-CCH) = 6.2 Hz, 3 J (H2-CCH)

J (H3α-H3β) = 13.3 Hz, 3 J (H3α-H4) = 8.1 Hz, 3 J (H3α-H2) = 0.8 Hz, H α C3)

Hz, 3 J (H3β-H4) = 8.9 Hz, 3 J (H3β-H2) = 8.9 Hz, H β C3). 13 C-NMR (150 MHz, CD 3 OD) δ: 175.47 (C(O)), 163.12 (C4 ), 153.08 (C2 ), 142.11 (C5 ), 108.39 (C6 ), 67.83 (C4)

-hydroxy-1-methyl-5-oxopyrrolidin-2-yl)methyl]pyrimidine-2,4(1H,3H)-dione (cis-15e)

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The authors declare no conflict of interest.