alexa Rapid Microwave-Assisted Synthesis of Modified Pyrimidine and Purine Pyranonucleosides as Novel Cytotoxic, Antiviral Agents and Glycogen Phosphorylase B Inhibitors | Open Access Journals
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Medicinal chemistry
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Rapid Microwave-Assisted Synthesis of Modified Pyrimidine and Purine Pyranonucleosides as Novel Cytotoxic, Antiviral Agents and Glycogen Phosphorylase B Inhibitors

Manta S1, Dimopoulou A2, Kollatos N2, Kyrkou G2, Spanos S2 and Komiotis D2*

1Department of Chemistry, University of Cyprus, Nicosia, Cyprus

2Department of Biochemistry and Biotechnology, University of Thessaly, Larissa, Greece

*Corresponding Author:
Komiotis D
Laboratory of Bioorganic Chemistry
Department of Biochemistry and Biotechnology
University of Thessaly, Viopolis, 41500 Larissa, Greece
Tel: 302410565290
E-mail:
[email protected]

Received date: April 27, 2017; Accepted date: May 05, 2017; Published date: May 10, 2017

Citation: Manta S, Dimopoulou A, Kollatos N, Kyrkou G, Spanos S, et al. (2017) Rapid Microwave-Assisted Synthesis of Modified Pyrimidine and Purine Pyranonucleosides as Novel Cytotoxic, Antiviral Agents and Glycogen Phosphorylase B Inhibitors. Med Chem (Los Angeles) 7:865-868. doi:10.4172/2161-0444.1000443

Copyright: © 2017 Manta S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Nucleosides take an important place in medicinal chemistry as the structural basis for the development of therapeutic agents. The chemistry of substituted base-modified nucleosides has been an interesting field of study over the last two decades owing to their biological properties. This mini-review summarizes recent efforts on the synthesis of C5- and C8-alkynyl base-modified pyranonucleoside analogues using Sonogashira cross-coupling reaction under microwave irradiation.

Keywords

Sonogashira reaction; Base-modified; Pyranonucleosides; Microwave irradiation; Cytotoxic/antiviral activity

Introduction

Several purine-and pyrimidine-substituted nucleosides exhibit activity in both solid tumors and hematological malignancies, behaving as antimetabolites, competing with physiological nucleosides, and consequently, interacting with a large number of intracellular targets to induce cytotoxicity [1]. Among them, alkynyl-modified uridines exhibited significant antiviral [2-4] and anticancer activities [4]. e.g., the internal aromatic-substituted alkyne p-tolylethynyl-2'-deoxyuridine showed high potency against MCF-7 (IC50 0.9 ± 0.2 μM), comparable to 5-fluorouracil and Cisplatin [5] while 5- ethynyl-2'-deoxyuridine, was the most potent inhibitor against MCF-7 and MDA-MB-231 human breast cancer cells (IC50 0.4 ± 0.3 and 4.4 ± 0.4 μM, respectively), the same compound also inhibited the replication of HSV-1, HSV-2 (herpes simplex virus type 1, 2) and VV (vaccinia virus) at concentrations of 0.1-1 μg/mL [6,7]. Little effort has been made towards the synthesis of C8-modified purine nucleosides, nevertheless, some interesting biological properties have been reported: e.g., selected 8-alkynyl adenosines were selective ligands for the A3 adenosine receptor subtype behaving as adenosine antagonists [8], and various C8-modified 2'-deoxy adenosines induced delayed chain termination in vitro and showed moderate anti HIV-1 activity in cell culture [9]. Considering the progress made in this direction, the present mini review presents an update of recent developments on pyrimidine- and purine-modified pyranonucleosides that possess interesting biological properties. In particular, the molecular design, synthesis and biological activity of C5-alkynyl pyrimidines and C8-alkynyl purine pyranonucleosides is presented. Aiming at a more detailed structure-activity relationship studies, a variety of alkyne substituents R are reported, such as linear alkyl chains and arenes substituted with linear and branched alkyl groups.

Results and Discussion

In 2013, numerous novel C5-alkynyl uracil and cytosine glucopyranonucleosides were first synthesized and biologically evaluated [10]. Analogues 3a,b-9a,b, 11a and 12a were prepared via their iodinated precursors 2a and 2b using Pd(0)-catalyzed Sonogashira cross-coupling reactions under microwave irradiation (Figure 1). When compared to conventional heating [11], the MW technology completed the synthesis much faster, while the yields of the products were slightly increased (by 3-13%). All the newly synthesized compounds were evaluated for their cytostatic activity against human cervix carcinoma (HeLa), human lymphocytes (CEM) as well as murine leukemia (L1210) cells. The 5-substituted uracil pyranonucleosides showed superior antiproliferative activity to their cytosine counterparts. Among the nucleosides tested, the phenylethynyl uracil pyranonucleoside derivative 5a, effectively inhibited tumor cell proliferation (IC50 5.2-6.2 μM) similar to that of 5-fluorouracil (IC50 0.33-18 μM), whereas its cytosine congener showed no appreciable cytostatic action (IC50 201→250 μM). The cyclization of 3a and 4a to the target bicyclic nucleosides 10a and 11a achieved through extended reaction time (irradiation for 8 min) and it was based on a 5-endo-dig electrophilic cyclization via an O-hetero-annulation process. Kinetic studies also showed that 1-(β-D-glucopyranosyl)-5-ethynyluracil 9a was the best glycogen phosphorylase b (GPb) inhibitor (Ki 4.7 μM). Crystallography revealed that inhibitors with a long C5-alkynyl group exploited interactions with the b-pocket of the active site and induced significant conformational changes of the 280s loop compared to GPb complex with compounds hosting a short C5-alkynyl group. The results highlight the importance in the length of the aliphatic groups used to enhance inhibitory potency for the exploitation of the hydrophobic b-pocket. The most active inhibitor also had a moderate effect on glycogenolysis at the cellular lever with an IC50 value of 291.4 μM.

medicinal-chemistry-pyrimidine-glucopyranonucleosides

Figure 1: Synthesis of C5-alkynyl pyrimidine glucopyranonucleosides.

Recently, C5-aryl ethynyl uracil glucopyranonucleosides 13,15 and C5-arylethyl uracil pyranonucleosides 17a,e,i,j,k were also prepared [12] and evaluated for their cytostatic and antiviral activities. The protected analogues 12a,e,i,j (Figure 2) showed better cytostatic activity against human lymphocyte CEM tumor cells (IC50 18-42 μM) compared to their unprotected counterparts 13a,e,i,j which did not enhance growth inhibition of CEM cells (IC50 >250 μM), while derivatives 17a,e,i,j,k were devoid of significant cytostatic activity (IC50 94-250 μM). Their antiviral activities were measured against a large number of DNA and RNA viruses including herpes simplex virus type 1,2 (HSV-1,2), vaccinia virus (VV), adeno-virus 2 (Ad-2) and human coronavirus 229E (HCoV-229E). Only analogue 17i exhibited the best anti-VV activity (EC50 10 μM): 10- and 25-more active than the reference drugs Ganciclovir (CMV) (EC50 100 μM) and Acyclovir (ACV) (EC50 250 μM), respectively, on HEL cell culture. Novel C5- arylalkynyl uracil pyranonucleosides bearing 3΄-C-trifluoromethyl- D-allose as sugar moiety were recently synthesized via microwave assisted Sonogashira coupling and were biologically evaluated [12]. The protected nucleosides 20c,d proved to be cytotoxic against human lymphocyte (CEM) cells (IC50 19-20 μM) similarly to 5-fluorouracil (IC50 0.33-18 μM), contrary to their unprotected analogues 21c,d which proved to be inactive (IC50 >178 μM) (Figure 3).

medicinal-chemistry-Synthesis-arylalkynyl

Figure 2: Synthesis of C5-arylalkynyl uracil glucopyranonucleosides and of 1-(β-D-glucopyranosyl)- 5-[arylethyl]uracil.

medicinal-chemistry-arylethynyl

Figure 3: Synthesis of 1-(3΄-C-trifluoromethyl-β-D-glucopyranosyl)-5-[arylethynyl]uracil.

Finally, the synthesis of the first purine glucopyranonucleosides C8- alkynyl adenines 25, 26 and 8-phenyl-ethynyl-adenine (II) itself were also reported (Figure 4) [13] using the Sonogashira cross-coupling reaction. The cytostatic potential of compounds 25e (IC50 2.9-5.9 μM) and II (IC50 3.0-10.0 μM) was an order of magnitude lower than 5-fluorouracil (IC50 0.33-0.54 μM) on murine leukemia (L1210), and human cervix carcinoma (HeLa) cells, while the same compounds (IC50 1.2-4.2 μM) were more active than 5-fluorouracil (IC50 18 μM) on human lymphocyte (CEM) cells.

medicinal-chemistry-alkynyl-adenine

Figure 4: Synthesis of C8-alkynyl adenine glucopyranonucleosides and 8-phenylethynyl-adenine.

Conclusion

In the present review, we focused our attention on the relatively new literature data, concerning the C5- and C8-alkynyl base-modified glucopyranonucleosides, as well as 8-phenylethynyl-adenine itself, via Sonogashira coupling conditions under microwave irradiation. With chemists becoming increasingly interested in biology, the demand for novel bioactive compounds with improved therapeutic potential is becoming high. Moreover, extensive structure-activity relationship studies of the novel pyranonucleoside analogues concerning different substituents in the aromatic ring as well as more detailed investigations on the molecular drug targets are envisaged.

Acknowledgements

This work was supported in part by the Postgraduate Program "Toxicology", Department of Biochemistry and Biotechnology, University of Thessaly.

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