Skip to main content
NCBI home page
ACS Medicinal Chemistry Letters logoLink to ACS Medicinal Chemistry Letters
. 2020 Jul 9;11(8):1605–1610. doi: 10.1021/acsmedchemlett.0c00269

Synthesis and Antitumor Activity of C-7-Alkynylated and Arylated Pyrrolotriazine C-Ribonucleosides

Qingfeng Li †, Elisabetta Groaz †, Leentje Persoons §, Dirk Daelemans §, Piet Herdewijn †,*
PMCID: PMC7429976  PMID: 32832030

Abstract

graphic file with name ml0c00269_0007.jpg

A number of biologically active nucleoside analogues contain the adenine isostere 4-amino-pyrrolo[2,1-f][1,2,4]triazine connected to various sugar moieties through a C–C anomeric linkage. We employed palladium-catalyzed cross-coupling chemistry to promptly functionalize the 7-position of such a heterocyclic scaffold with various alkynyl and aryl groups starting from a common 7-iodo-pyrrolotriazine C-ribonucleoside intermediate. Analogues bearing a 7-cyclopropyl-, 7-propyl-, and 7-butylacetylene moiety displayed potent cytotoxic activity, with the latest being the most selective of this series toward cancer cells. Further insights revealed that such C-nucleosides could exert their antiproliferative action by causing dose-dependent DNA damage.

Keywords: C-nucleosides, palladium-catalyzed cross coupling, antitumor activity, DNA damage, apoptosis

All nucleoside analogues currently licensed for clinical use contain the natural N-glycosidic bond connecting the anomeric carbon of a sugar moiety to the nitrogen atom of a heterocyclic base. In contrast, C-nucleosides are characterized by the presence of a C–C glycosidic linkage,1,2 which makes them more chemically stable and resistant to degradation by cellular enzymes, such as phosphorylases, than N-nucleosides.

Extensive structure–activity relationship (SAR) studies of biologically relevant C-nucleosides initially isolated from natural sources have previously provided several analogues with interesting activities, including antitumoral properties (Figure 1). For example, pyrazofurin was shown to inhibit the growth of some transplantable tumors in mice and rats3 as well as Novikoff rat hepatoma cells.4 Tiazofurin was demonstrated to suppress the growth of several tumors, including Lewis lung carcinoma.5 Significant antitumor activity was found in rats inoculated with hepatoma 3924A50 after treatment with tiazofurin, and its cytotoxic activity was also observed against ovarian carcinoma cells.6 Tiazofurin proceeded to phase II clinical trials in patients with chronic myelogenous leukemia;7 however, the toxic side effects observed during the phase I clinical evaluation limited its further development as an anticancer drug.8

Figure 1.

Figure 1

Open in a new tab

Examples of known C-nucleosides endowed with antitumor activity.

Immucillin-H was found to selectively inhibit the proliferation of human T-lymphocytes,9 which may suggest clinical potential for the treatment of human T-cell leukemia and lymphoma. 9-Deazaadenosine is a C-nucleoside isostere of adenosine possessing nanomolar cytostatic activity against mouse and human leukemia.10

Among the various heterocycles used for the generation of C-nucleosides upon coupling with a suitable glycone moiety, the 4-aza-7,9-dideazaadenine (or pyrrolo[2,1-f][1,2,4]triazine-4-amine) scaffold has led to the discovery of many analogues with interesting biological activities (Figure 2).11,12 For example, 4-aza-7,9-dideazaadenosine (1) has shown cytostatic activity against different mouse and human neoplastic cell lines.13 However, its 1′- and 2′-modified congeners were investigated as antiviral agents due to their lower cytotoxicity. For instance, compounds 2–5 as well as their prodrugs were discovered by scientists at Gilead to exhibit broad spectrum activity against different RNA viruses including Ebola virus (EBOV), respiratory syncytial virus (RSV), and hepatitis C virus (HCV) without significant cytotoxicity.14−16

Figure 2.

Figure 2

Open in a new tab

Previously reported C-nucleoside analogues bearing 4-aza-7,9-dideazaadenine as nucleobase.

The introduction of various substituents at the C-7 position of 4-amino-pyrrolo[2,1-f][1,2,4]triazine in combination with a 2′-C-Me sugar moiety led to a series of analogues with potent activity against HCV (Figure 2, 6–9).17 Nonetheless, such potency was accompanied by a concomitant increase in cytotoxicity, as exemplified by compounds 6 (CC50 = 6.5 μM in Huh-7 cells), 8 (CC50 = 0.93 μM in Huh-7 cells), and 9 (CC50 = 0.93 μM in Huh-7 cells).17 Despite limiting the development of these C-nucleosides as antiviral agents, such a strategy can otherwise be exploited for the discovery of potential antitumoral agents.

In a previous study, we reported the cytotoxic activity of compound 1 as well as its 7-cyano analogue 10 (Figure 3) against a panel of different cancer cell lines.18 Herein, we sought to prepare a complementary series of C-7 substituted derivatives of compound 1, bearing either a C-7-alkynyl (Figure 3, 11) or aryl (Figure 3, 12) group. It was anticipated that this set of analogues would reveal key SAR data concerning the presence/influence of rather bulky apolar substituents at the C-7 position of the pharmacophore. These particular molecules were selected for their availability from a common intermediate as well as previous studies on similarly substituted 7-deazapurine ribonucleosides endowed with antileukemic activity.19 Their cytotoxic activity was evaluated against a panel of tumor cell lines, and additional assays were carried out to determine a possible mode of action of these compounds.

Figure 3.

Figure 3

Open in a new tab

7-Alkynyl and aryl substituted 4-amino-pyrrolo[2,1-f][1,2,4]triazine C-nucleosides 11 and 12 investigated in this study.

In order to achieve the rapid generation of analogues of 1, we decided to use 7-iodo-substituted pyrrolo[2,1-f][1,2,4]triazine-4-amine containing C-nucleoside 13 as a highly versatile intermediate for the introduction of a variety of alkynyl and aryl groups at the nucleobase moiety. Compound 13 was obtained from 1 according to a previously described procedure.18 Initially, compound 13 was reacted under palladium-catalyzed Sonogashira cross coupling reaction conditions with a number of terminal alkyl and aryl alkynes (14a–f and 15) to afford unknown 7-alkynyl pyrrolo[2, 1-f][triazin-4-amino]adenine C-nucleosides 11a–f (Scheme 1).

Scheme 1. Synthesis of 7-Alkynylated C-Nucleoside Analogues from 13 via Sonogashira Cross-coupling.

Scheme 1

Open in a new tab

All coupling reactions were performed in the presence of PdCl2(PPh3)2 as catalyst, copper(I) iodide as cocatalyst, and triethylamine as base in anhydrous DMF to afford the desired alkynyl derivatives, albeit in low yields (8–13%). Treatment of 13 with trimethylsilylacetylene, followed by base promoted protodesilylation afforded compound 11g in 11% yield.

The palladium-catalyzed Suzuki–Miyaura cross-coupling reaction has been employed by Bourderioux et al. for the synthesis of a series of 7-aryl and 7-hetaryl-7-deazaadenosines.20 This reaction was also found to be successful in our hands to generate an additional series of 7-modified pyrrolo[2, 1-f][triazin-4-amino]adenine C-nucleosides, starting from 7-iodo-substituted derivative 13 and various aryl boronic acids 15a–k. Specifically, aqueous Suzuki–Miyaura cross-coupling reactions were performed in the presence of Pd(OAc)2, TPPTS as ligand, and Na2CO3 in acetonitrile/water. As a result, different 7-aryl substituted 7-modified C-nucleosides 12a–k were prepared in a single step (Scheme 2) in yields ranging from 7 to 40%.

Scheme 2. Synthesis of 7-Arylated C-Nucleoside Analogues from 13 via Sonogashira Cross-coupling.

Scheme 2

Open in a new tab

In order to explore the SAR of 7-alkynyl and aryl substituted C-nucleosides as potential anticancer agents, all synthesized compounds were tested against a panel of eight different human cancer lines, representing both solid tumor types, including glioblastoma (LN-229), pancreatic adenocarcinoma (Capan-1), colorectal carcinoma (HCT-116), and lung carcinoma (NCI-H460), and hematological tumors, such as acute lymphoblastic leukemia (DND-41), acute myeloid leukemia (HL-60), chronic myeloid leukemia (K-562), and non-Hodgkin lymphoma (Z-138). The inhibition of cell proliferation of these different cancer cell lines was monitored in real-time over a period of 3 days using an IncuCyte live-cell imager that uses automated imaging to determine cellular confluence as a measure of cellular viability. The calculated compound concentrations required to inhibit tumor cell viability by 50% (IC50 values) after 72 h of incubation are shown in Table 1.

Table 1. Cytotoxic Activity of C-Nucleoside Analogues 11a–f and 12a–k against a Range of Tumor Cell Linesa.

  IC50 (μM)a
Compound LN-229 Capan-1 HCT-116 NCI-H460 DND-41 HL-60 K-562 Z-138
11a 0.04 0.02 0.2 0.4 0.08 0.2 1.1 0.02
11b 1.0 1.0 2.9 1.7 0.4 0.4 2.4 0.2
11c 0.03 0.02 0.05 0.08 0.04 0.04 0.04 0.02
11d >100 55.4 >100 79.4 >100 >100 >100 89.0
11e >100 32.0 65.5 26.6 33.4 >100 >100 50.1
11f 88.0 37.7 46.9 38.5 62.6 >100 >100 41.4
12a 75.1 65.2 82.6 >100 >100 >100 >100 >100
12b 65.6 65.6 42.5 55.5 39.3 68.3 >100 >100
12c 32.6 56.7 59.3 45.9 35.1 37.9 47.8 40.2
12d >100 >100 >100 >100 >100 >100 >100 95.3
12e 43.5 50.9 59.5 93.3 68.2 99.3 69.7 59.1
12f 40.3 43.9 47.1 69.3 41.7 >100 76.4 62.6
12g >100 97.5 >100 >100 94.1 48.4 >100 66.0
12h 1.0 0.9 1.4 1.5 0.1 0.5 2.1 0.3
12i 3.9 2.6 4.8 3.7 1.7 2.0 3.1 1.3
12j 57.7 56.2 45.2 35.6 85.4 37.3 66.4 43.5
12k >100 54.9 >100 >100 78.5 >100 >100 76.1
Docetaxel 0.002 0.025 0.007 0.004 0.005 0.05 0.009 0.004
Staurosporine 0.003 0.03 0.04 0.06 0.03 0.04 0.04 0.02
Open in a new tab
a

IC50 is the compound concentration required to inhibit tumor cell viability by 50%.

Among all 7-substituted analogues, 7-cyclopropylacetylene derivative 11c emerged as the most active of this series with IC50 values ranging from 0.02 to 0.08 μM. Such 7-alkynyl compound exhibited a similar profile as the alkaloid staurosporine. Moreover, it was found to have comparable activities as docetaxel against Capan-1 and HL-60 cell lines. The 7-propylacetylene derivative 11a displayed similar antitumoral activity as 11c against LN-229, Capan-1, DND-41, and Z-138; however, it was slightly less active against the remaining cancer cell lines (HCT-116, NCI-H460, HL-60, and K-562). 7-Butylacetylene derivative 11b displayed a somewhat lower antiproliferative effect compared to structurally related compounds 11a and 11c but nonetheless retained a good potency with IC50 values in the 0.2–1.7 μM range against six out of the eight cancer cell lines tested. In contrast, the 7-thienyl and 7-phenylacetylene derivatives (11d–f) completely lacked activity against all tumor cell lines tested, displaying IC50 values higher than 10 μM.

In the case of 7-aryl substituted C-nucleosides, the 7-furanyl and 7-vinyl substituted compounds 12i and 12h showed good to moderate cytotoxic activity against different cancer cell lines with IC50 ranging from 0.2 to 2.1 μM and 1.3 to 4.8 μM, respectively. In contrast, other 7-aryl substituted derivatives 12a–g and 12j–k were found to be devoid of antitumoral activity against all cancer cell lines.

Subsequently, the mechanism of action of the most active compounds 11a–c and 12h–i was elucidated in further detail. Generally, anticancer drugs can exert their cytotoxic activity by acting on different molecular targets (e.g., tubulin, DNA, etc.). In an initial stage, compounds 11a–c and 12h,i were evaluated for their ability to interfere with microtubule polymerization or undergo intercalation into DNA. However, in vitro assays ruled out that the cytotoxicity caused by these compounds could be related to polymerization or depolymerization inhibition as well as DNA intercalation (Figure S1 and S2, Supporting Information).

Therefore, we decided to investigate other possible mechanisms involved in their antiproliferative activity. It is known that N-linked nucleoside analogues such as gemcitabine and fludarabine can interfere with DNA synthesis by either being incorporated into DNA with consequent termination of chain elongation or inhibiting specific enzymes.21 The resulting DNA damage may ultimately induce programmed cancer cell death or apoptosis, thus leading to an overall inhibition of cell growth.

The H2A histone family variant X (H2AX) has been identified as a key player in DNA repair processes. When severe double stranded breaks occur, H2AX undergoes phosphorylation at its 139 serine residue.22 The resulting phosphorylated protein γ-H2AX can be used as a sensitive marker for detecting DNA damage in cells. Here, we performed an in vitro immunofluorescence staining assay to determine the levels of γ-H2AX after treatment of human cervix carcinoma HEp-2 cells with compounds 11a–c and 12h,i.

As can be seen in Table 2 and Figure S3 (Supporting Information), at a 100 μM concentration, C-nucleosides 11a–c and 12h produced only a moderate increase of the percentage of γ-H2AX positive cells compared to the reference compound etoposide, while the effect of (E)-2-phenylvinyl substituted compound 12i on HEp-2 cells was negligible. A similar trend for compounds 11a–c and 12h was observed at a 10 μM concentration. However, when the concentration was further lowered at 1 μM, C-nucleosides 11a and 11c featuring a 7-propyl and cyclopropyl group, respectively, not only retained the ability to induce γ-H2AX but also surpassed etoposide in the case of compound 11c.

Table 2. Dose Dependent Effect of Compounds 11a–c and 12h,i on γ-H2AX Levels in HEp-2 Cells.

  γ-H2AX positive cells (%)
Compound 100 μM 10 μM 1 μM
11a 9.38 0.82 1.14
11b 1.57 0.35 0.31
11c 16.22 5.20 3.22
12h 3.74 1.54 0.13
12i 0.22 0.00 0.05
Etoposide 89.31 89.89 1.66
DMSO 0.51
Open in a new tab

A particular feature of early stage apoptosis is the activation of caspase enzymes, which are cysteine aspartyl-specific proteases that promote the cleavage of numerous target proteins required for normal cellular function.23 As a result, apoptotic cells undergo morphological changes that induce the macrophage response. Caspases are divided into two groups according to their roles in the apoptotic pathway, namely initiator (including caspase-2, -8, -9, and -10) and executioner caspases (caspase-3, -6, and -7); the latest cleave the cellular cytoskeletal and nuclear proteins eventually inducing cell death.

In order to establish whether the observed cytotoxicity is selective toward cancer cell lines, an apoptosis induction assay was performed in peripheral blood mononuclear cells (PBMCs). Thus, PBMCs from two healthy donors were treated with compounds 11a–c and 12h–i, followed by the addition of an IncuCyte Caspase 3/7 Green Reagent. This reagent contains a four-amino acid peptide (DEVD) conjugated to a nucleic acid binding dye and allows for the detection of apoptotic cells following the caspase-promoted cleavage of the DEVD peptide sequence and binding of the released dye to DNA with consequent generation of a fluorescence signal.

As can be seen in Table S1 (Supporting Information), compounds 11a and 11c emerged as the most toxic analogues of this series in PBMCs with IC50 values in the 0.05–11.0 and 0.1–0.4 μM range, respectively. On the other hand, compounds 11b and 12h–i did not induce significant cytotoxicity in PBMCs at concentrations ranging from 100 to 6.4 × 10–3 μM in the case of both donors. Figure 4(A) shows a graphical representation of the different levels of apoptosis induced in PMBCs by the most selective compounds of this series, 11b and 12h, as compared with 11c, which was identified as the most potent compound in the antiproliferative assay.

Figure 4.

Figure 4

Open in a new tab

Proportion of apoptotic cells upon treatment with compounds 11b, 11c, and 12h and reference compound staurosporine (STS) in (A) PBMC and (B) Capan-1 cells.

Finally, the same assay was repeated for compounds 11b, 11c, and 12h using Capan 1 cells, as shown in Figure 4(B). An increase in the percentage of apoptotic cells could be observed especially in the case of the most potent compound 11c, suggesting that these compounds could exert their antiproliferative activity through a combination of mechanisms.

In summary, the synthesis and antitumor properties of two series of 4-amino-pyrrolo[2,1-f][1,2,4]triazine C-nucleoside analogues functionalized at the 7 position via palladium-catalyzed cross-coupling reactions were described. Among all compounds obtained, analogues bearing a 7-alkylacetylene group exhibited potent cytotoxic activity against a panel of human hematological and solid cancer cell lines with the following order 7-cyclopropyl- > 7-propyl- > 7-butylacetylene. An opposite trend was observed with regard to their selectivity profile toward cancer cells. In comparison, for analogues bearing an aryl group on the nucleobase, only 7-furanyl and 7-vinyl substituted compounds exhibited medium cytotoxic activity. Mechanism of action studies indicated that such compounds cause DNA damage in a dose dependent manner.

Acknowledgments

Q.L. thanks the China Scholarship Council (CSC) for funding (grant 201506890014). The authors wish to thank Chantal Biernaux for editorial help.

Glossary

Abbreviations

DMF

N,N-dimethylformamide

EBOV

Ebola virus

HCV

hepatitis C virus

PBMCs

peripheral blood mononuclear cells

RSV

respiratory syncytial virus

SAR

structure–activity relationship

TPPTS

3,3′,3″-phosphanetriyltris(benzenesulfonic acid) trisodium salt

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00269.

  • General synthetic procedures and spectral data; 1H and 13C NMR spectra of intermediates and final compounds; biological materials and assays (PDF)

Author Contributions

All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Supplementary Material

ml0c00269_si_001.pdf (3MB, pdf)

References

  1. De Clercq E. C-Nucleosides To Be Revisited. J. Med. Chem. 2016, 59, 2301–2311. 10.1021/acs.jmedchem.5b01157. [DOI] [PubMed] [Google Scholar]
  2. Temburnikar K.; Seley-Radtke K. L. Recent Advances in Synthetic Approaches for Medicinal Chemistry of C-Nucleosides. Beilstein J. Org. Chem. 2018, 14, 772–785. 10.3762/bjoc.14.65. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Sweeney M. J.; Davis F. A.; Gutowski G. E.; Hamill R. L.; Hoffman D. H.; Poore G. A. Experimental Antitumor Activity of Pyrazomycin. Cancer Res. 1973, 33, 2619–2623. [Google Scholar]
  4. Plagemann P. G. W.; Behrens M. Inhibition of Denovo Pyrimidine Nucleotide and DNA-Synthesis and Growth of Cultured Novikoff Rat Hepatoma-Cells and Other Cell Lines by Pyrazofurin (Nsc 143095). Cancer Res. 1976, 36, 3807–3812. [PubMed] [Google Scholar]
  5. Robins R. K.; Srivastava P. C.; Narayanan V. L.; Plowman J.; Paull K. D. 2-Beta-D-Ribofuranosylthiazole-4-Carboxamide, a Novel Potential Anti-Tumor Agent for Lung-Tumors and Metastases. J. Med. Chem. 1982, 25, 107–108. 10.1021/jm00344a002. [DOI] [PubMed] [Google Scholar]
  6. Shen F.; Herenyiova M.; Weber G. Synergistic down-regulation of signal transduction and cytotoxicity by tiazofurin and quercetin in human ovarian carcinoma cells. Life Sci. 1999, 64, 1869–1876. 10.1016/S0024-3205(99)00133-2. [DOI] [PubMed] [Google Scholar]
  7. Tricot G. J.; Jayaram H. N.; Lapis E.; Natsumeda Y.; Nichols C. R.; Kneebone P.; Heerema N.; Weber G.; Hoffman R. Biochemically Directed Therapy of Leukemia with Tiazofurin, a Selective Blocker of Inosine 5′-Phosphate Dehydrogenase-Activity. Cancer Res. 1989, 49, 3696–3701. [PubMed] [Google Scholar]
  8. Melink T. J.; Vonhoff D. D.; Kuhn J. G.; Hersh M. R.; Sternson L. A.; Patton T. F.; Siegler R.; Boldt D. H.; Clark G. M. Phase-I Evaluation and Pharmacokinetics of Tiazofurin (2-Beta-D-Ribofuranosylthiazole-4-Carboxamide, Nsc-286193). Cancer Res. 1985, 45, 2859–2865. [PubMed] [Google Scholar]
  9. Kicska G. A.; Long L.; Horig H.; Fairchild C.; Tyler P. C.; Furneaux R. H.; Schramm V. L.; Kaufman H. L. Immucillin H, a powerful transition-state analog inhibitor of purine nucleoside phosphorylase, selectively inhibits human T lymphocytes. Proc. Natl. Acad. Sci. U. S. A. 2001, 98, 4593–4598. 10.1073/pnas.071050798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Lim M. I.; Klein R. S. Synthesis of 9-Deazaadenosine - a New Cyto-Toxic C-Nucleoside Isostere of Adenosine. Tetrahedron Lett. 1981, 22, 25–28. 10.1016/0040-4039(81)80031-7. [DOI] [Google Scholar]
  11. Draffan A. G.; Frey B.; Pool B.; Gannon C.; Tyndall E. M.; Lilly M.; Francom P.; Hufton R.; Halim R.; Jahangiri S.; Bond S.; Nguyen V. T. T.; Jeynes T. P.; Wirth V.; Luttick A.; Tilmanis D.; Thomas J. D.; Pryor M.; Porter K.; Morton C. J.; Lin B.; Duan J. M.; Kukolj G.; Simoneau B.; McKercher G.; Lagace L.; Amad M.; Bethell R. C.; Tucker S. P. Discovery and Synthesis of C-Nucleosides as Potential New Anti-HCV Agents. ACS Med. Chem. Lett. 2014, 5, 679–684. 10.1021/ml500077j. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Clarke M. O.; Mackman R.; Byun D.; Hui H.; Barauskas O.; Birkus G.; Chun B. K.; Doerffler E.; Feng J.; Karki K.; Lee G.; Perron M.; Siegel D.; Swaminathan S.; Lee W. Discovery of beta-D-2 ‘-deoxy-2 ‘-alpha-fluoro-4 ‘-alpha-cyano-5-aza-7,9-dideaza adenosine as a potent nucleoside inhibitor of respiratory syncytial virus with excellent selectivity over mitochondrial RNA and DNA polymerases. Bioorg. Med. Chem. Lett. 2015, 25, 2484–2487. 10.1016/j.bmcl.2015.04.073. [DOI] [PubMed] [Google Scholar]
  13. Patil S. A.; Otter B. A.; Klein R. S. 4-Aza-7,9-Dideazaadenosine, a New Cytotoxic Synthetic C-Nucleoside Analog of Adenosine. Tetrahedron Lett. 1994, 35, 5339–5342. 10.1016/S0040-4039(00)73494-0. [DOI] [Google Scholar]
  14. Cho A.; Zhang L. J.; Xu J.; Lee R.; Butler T.; Metobo S.; Aktoudianakis V.; Lew W.; Ye H.; Clarke M.; Doerffler E.; Byun D.; Wang T.; Babusis D.; Carey A. C.; German P.; Sauer D.; Zhong W. D.; Rossi S.; Fenaux M.; McHutchison J. G.; Perry J.; Feng J.; Ray A. S.; Kim C. U. Discovery of the First C-Nucleoside HCV Polymerase Inhibitor (GS-6620) with Demonstrated Antiviral Response in HCV Infected Patients. J. Med. Chem. 2014, 57, 1812–1825. 10.1021/jm400201a. [DOI] [PubMed] [Google Scholar]
  15. Siegel D.; Hui H. C.; Doerffler E.; Clarke M. O.; Chun K.; Zhang L.; Neville S.; Carra E.; Lew W.; Ross B.; Wang Q.; Wolfe L.; Jordan R.; Soloveva V.; Knox J.; Perry J.; Perron M.; Stray K. M.; Barauskas O.; Feng J. Y.; Xu Y. L.; Lee G.; Rheingold A. L.; Ray A. S.; Bannister R.; Strickley R.; Swaminathan S.; Lee W. A.; Bavari S.; Cihlar T.; Lo M. K.; Warren T. K.; Mackman R. L. Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo(2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses. J. Med. Chem. 2017, 60, 1648–1661. 10.1021/acs.jmedchem.6b01594. [DOI] [PubMed] [Google Scholar]
  16. Cho A.; Saunders O. L.; Butler T.; Zhang L. J.; Xu J.; Vela J. E.; Feng J. Y.; Ray A. S.; Kim C. U. Synthesis and antiviral activity of a series of 1 ‘-substituted 4-aza-7,9-dideazaadenosine C-nucleosides. Bioorg. Med. Chem. Lett. 2012, 22, 2705–2707. 10.1016/j.bmcl.2012.02.105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Draffan A. G.; Frey B.; Fraser B. H.; Pool B.; Gannon C.; Tyndall E. M.; Cianci J.; Harding M.; Lilly M.; Hufton R.; Halim R.; Jahangiri S.; Bond S.; Jeynes T. P.; Nguyen V. T. T.; Wirth V.; Luttick A.; Tilmanis D.; Pryor M.; Porter K.; Morton C. J.; Lin B.; Duan J. M.; Bethell R. C.; Kukolj G.; Simoneau B.; Tucker S. P. Derivatives of imidazotriazine and pyrrolotriazine C-nucleosides as potential new anti-HCV agents. Bioorg. Med. Chem. Lett. 2014, 24, 4984–4988. 10.1016/j.bmcl.2014.09.030. [DOI] [PubMed] [Google Scholar]
  18. Li Q. F.; Lescrinier E.; Groaz E.; Persoons L.; Daelemans D.; Herdewijn P.; De Jonghe S. Synthesis and Biological Evaluation of Pyrrolo[2,1-f][1,2,4]triazine C-Nucleosides with a Ribose, 2-Deoxyribose, and 2,3-Dideoxyribose Sugar Moiety. ChemMedChem 2018, 13, 97–104. 10.1002/cmdc.201700657. [DOI] [PubMed] [Google Scholar]
  19. Schram K. H.; Townsend L. B. Pyrrolopyrimidine Nucleosides. 8. Synthesis Of Sangivamycin Derivatives Possessing Exocyclic Heterocycles At C5. J. Carbohydr., Nucleosides, Nucleotides 1974, 1, 39–54. [Google Scholar]
  20. Bourderioux A.; Naus P.; Perlikova P.; Pohl R.; Pichova I.; Votruba I.; Dzubak P.; Konecny P.; Hajduch M.; Stray K. M.; Wang T.; Ray A. S.; Feng J. Y.; Birkus G.; Cihlar T.; Hocek M. Synthesis and Significant Cytostatic Activity of 7-Hetaryl-7-deazaadenosines. J. Med. Chem. 2011, 54, 5498–5507. 10.1021/jm2005173. [DOI] [PubMed] [Google Scholar]
  21. Ewald B.; Sampath D.; Plunkett W. Nucleoside analogs: molecular mechanisms signaling cell death. Oncogene 2008, 27, 6522–6537. 10.1038/onc.2008.316. [DOI] [PubMed] [Google Scholar]
  22. Rogakou E. P.; Pilch D. R.; Orr A. H.; Ivanova V. S.; Bonner W. M. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem. 1998, 273, 5858–5868. 10.1074/jbc.273.10.5858. [DOI] [PubMed] [Google Scholar]
  23. Pfeffer C. M.; Singh A. T. K. Apoptosis: A Target for Anticancer Therapy. Int. J. Mol. Sci. 2018, 19. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ml0c00269_si_001.pdf (3MB, pdf)

Articles from ACS Medicinal Chemistry Letters are provided here courtesy of American Chemical Society

RESOURCES