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Synthesis and Cytotoxic and Antiviral Activity Profiling of All‐Four Full Paper Chemistry—A European Journal doi.org/10.1002/chem.202001124 & DrugDiscovery |Hot Paper| Synthesis and Cytotoxic and Antiviral Activity Profiling of All-Four Isomeric Series of Pyrido-Fused 7-Deazapurine Ribonucleosides Lucia Veselovskµ,[a] Natµlie Kudlovµ,[b, c] SonˇaGurskµ,[b, c] Barbora Lisˇkovµ,[b] Martina Medvedíkovµ,[b] Ondrˇej Hodek,[a] Eva Tlousˇtˇovµ,[a] NemanjaMilisavljevic,[a, d] Michal Tichy´,[a] Pavla Perlíkovµ,[a] HelenaMertlíkovµ-Kaiserovµ,[a] Jana Trylcˇovµ,[a] RadekPohl,[a] Blanka Klepetµrˇovµ,[a] Petr Dzˇubµk,[b, c] MariµnHajdfflch,[b, c] and Michal Hocek*[a, d] Abstract: All four isomeric series of novel 4-substituted The most active werepyrido[4’,3’:4,5]pyrimidine nucleosides pyrido-fused 7-deazapurine ribonucleosides possessing the bearing MeO, NH2,MeS, or CH3 groups at position 4, which pyridine nitrogen atom at different positions were designed showed submicromolar cytotoxic effects and good selectivi- and synthesized. The total synthesis of each isomeric fused ty for cancer cells. The mechanism involved activation by heterocycle through multistep heterocyclizationwas fol- phosphorylation and incorporation to DNA where the pres- lowed by glycosylation and derivatization at position 4by ence of the modified ribonucleosides causes double-strand cross-coupling reactions or nucleophilic substitutions. All breaksand apoptosis. compoundswere tested for cytostatic and antiviral activity. Introduction well as of emerging new viruses,[4] justifiesthe continuous in- terest in the development of other novel nucleoside deriva- Nucleoside derivatives or analogues modified at the heterocy- tives with potential antiviral or cytostatic effects. Particularly in- clic base are an important class of molecules with wide range teresting are modified pyrrolo[2,3-d]pyrimidine(7-deazapurine) of biological activities. Several clinical antiviral[1] and antineo- nucleosides.[5] Long-known natural products tubercidin,[6] toyo- plastic[2] drugs are based on base-modified nucleosides, either camycin[7] and sangivamycin[8] display significant biological ac- with or without additional modifications at the sugar part. The tivitiesand served as inspiration for further structural modifica- need for treatment of drug-resistant leukemia and cancers,[3] as tions at both the heterocyclicand ribose parts. Several types of 7-substituted 7-deazapurine nucleosides bearing 2’-methyl- [a] L. Veselovskµ,Dr. O. Hodek, E. Tlousˇˇtovµ,N.Milisavljevic, Dr.M.Tichy´, or 2’-ethynyl-ribose (or 2’-fluororibose) displayed antiviral activ- Dr.P.Perlíkovµ,Dr. H. Mertlíkovµ-Kaiserovµ,J.Trylcˇovµ,Dr. R. Pohl, ity against HCV or other RNA viruses.[9] Some other modified 7- Dr.B.Klepetµˇrovµ,Prof. Dr.M.Hocek deazapurine nucleosides were potent inhibitors of human or Institute of Organic Chemistry and Biochemistry [10] Czech Academy of Sciences pathogen adenosine kinases or have exerted antiparasitic ac- [11] Flemingovo nam. 2, 16610 Prague 6(Czech Republic) tivities. We have previously reported significant cytostatic ac- E-mail:[email protected] tivitiesof7-hetaryl-7-deazaadenine(e.g.,AB-61)[12] and other 6- Homepage:http://hocekgroup.uochb.cas.cz/ substituted 7-deazapurine ribonucleosides,[13] which act [b] N. Kudlovµ,Dr. S. Gurskµ,Dr. B. Lisˇkovµ,M.Medvedíkovµ,Dr. P. Dzˇubµk, through an unprecedented mechanism based on activation to Prof. Dr.M.Hajdfflch Institute of Molecular and Translational Medicine (ribo)nucleoside triphosphates (NTPs) and incorporation to Faculty of Medicine and Dentistry DNA, where they cause double-strand(ds) breaks and eventu- Palacky University and University HospitalinOlomouc ally apoptosis.[14] Hneˇvotínskµ 5, 775 15 Olomouc(CzechRepublic) More recently,wehave designed and synthesized fused 7- [c] N. Kudlovµ,Dr. S. Gurskµ,Dr. P. Dzˇubµk, Prof. Dr.M.Hajdfflch deazapurine ribonucleosides. Benzo-fused (pyrimidoindole) nu- Cancer Research Czech Republic [15] Hneˇvotínskµ 5, 775 15 Olomouc(CzechRepublic) cleosides were found to be non-cytotoxic, however they ex- [d] N. Milisavljevic, Prof. Dr.M.Hocek erted moderate antiviral activities against HCV or Dengue Department of Organic Chemistry virus, whereas the more bulky naphtho-fused nucleosides[16] Faculty of Science were inactive. On the other hand, the less bulky hetero-ana- CharlesUniversity in Prague logues, that is, thieno-,[17] furo-[18] or methylpyrrolo-fused[18] 7- Hlavova 8, 12843 Prague 2(Czech Republic) deazapurine nucleosides, exerted submicromolar in vitro cyto- Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: toxic effects and some derivatives wereselective against https://doi.org/10.1002/chem.202001124. cancer and leukemiacell lines (Figure 1). Also these com- Chem. Eur.J.2020, 26,13002 –13015 13002 2020 Wiley-VCH GmbH Full Paper Chemistry—A European Journal doi.org/10.1002/chem.202001124 Figure 1. Structures of previouslyreported fused-deazapurine nucleosides. Scheme1.Reagents and conditions: (i) tBuOK, ethyl cyanoacetate, tBuOH, 958C, 6h;(ii)NaH, ethyl cyanoacetate, DMF,rt, 30 min or 6h;(iii)Zndust, AcOH,958C, 75 min or 90 min;(iv) formamide, HCOONH4,1708C, 12 h; [18] pounds were found to be phosphorylated in the cell, got in- (v) N,N-dimethylaniline, BTEACl, POCl3,MeCN, 908C, 1h;(vi)BSA, MeCN, corporated to DNA and induced DNA damage and apoptosis. 608C, 30 min;then 1-O-acetyl-2,3,5-tri-O-benzoyl-b-d-ribofuranose,TMSOTf, 608C, 12 h. As acontinuation of the systematic SAR study of this new in- teresting class of biologically active nucleosides,and to estab- lish whether the activity of the hetero-analogues is based on mide afforded the tricyclicheterocycles 8A–D (86, 67, 79 and their reducedstericbulk or on the presence of the hetero- 92%).[20] The next step was the conversion of the pyrimidone atoms, we designedand presenthere the synthesis of all four derivatives 8A–D to fused chloropyrimidines 9A–D.However, novel isomeric series of pyrido-fused 7-deazapurine ribonucleo- the reportedprocedure using POCl3 with Et3Ndescribed for sides and their biological profiling. the preparation of relatedchloropyrimidine nucleobases[20] did not give the desired chloropyrimidine, but diethylamino nucle- obase 9Ax (see the Supporting Information). Therefore, these Results and Discussion tricyclicpyrimidone derivativeswere convertedinto chloropyri- midine using POCl in the presence of dimethylaniline and Chemistry 3 benzyltriethylammonium chloride (BTEACl) (in analogytopro- There are four possible isomers of pyrido-fused 7-deazapur- ceduredeveloped previously in our group[13]). The desired key ines:pyrido[2’,3’:4,5]- (series A), pyrido[3’,4’:4,5]- (series B), intermediates 9A–D were isolated in yields of 65, 13, 52 and pyrido[4’,3’:4,5]- (series C)and pyrido[3’,2’:4,5]pyrrolo[2,3-d]pyri- 59%, respectively.The synthesis of pyrido[3’,4’:4,5]pyrimidine midine (series D)(Scheme 1) and we aimed at the synthesis of 9B was more problematic in each step due to lower stability, all of them. Each individual heterocycle requiredindependent partial decomposition of the intermediates and due to partial total synthesis. In all four cases, the synthesiswas designed in hydrolysis back to 8B in the last step. The total yield of synthe- analogy to the previous syntheses of pyrimidoindoles sis of 9B was only 4.5 %and only ca. 400 mg of the material (Scheme 1), but every step needed to be optimized for each was prepared even after repeated attempts.The other isomers isomer. 9A,C,D were prepared in reasonable overall yields of 52, 29 The key isomeric 4-chloropyridopyrrolopyrimidine intermedi- and 44%, respectively. ates 9A–D were synthesized in four steps (Scheme 1), starting The pyridopyrrolopyrimidine nucleobases 9A–D were then from the corresponding isomeric chloronitropyridines 5A–D. subjected to Vorbrüggen glycosylationwith 1-O-acetyl-2,3,5-tri- The synthesis started with anucleophilic substitution of chlor- O-benzoyl-b-d-ribofuranose.[15] Nucleobaseswere dissolved in ine with ethyl cyanoacetate, which,inthe case of electron- anhydrous MeCN and stirred with N,O-bis(trimethylsilyl)aceta- poor chloronitropyridines, proceeded smoothly.Incase of 5A mide (BSA) for 30 minutes at 608Cand then trimethylsilyl tri- and 5C,potassium tert-butoxide in tert-butyl alcohol was used flate (TMSOTf)and 1-O-acetyl-2,3,4-tri-O-benzoyl-b-d-ribofura- as abase according to areported procedure.[19] In case of com- nose were added and the mixture wasstirred overnight at pounds 5B and 5D,astronger base NaH in DMF was used to 608C. This procedureproduced the key intermediates,protect- reach good conversions.[20] In each of the four series, formation ed 4-chloropyridopyrrolopyrimidine nucleosides 10 A--D (yields of adifferent tautomer or mixture of tautomers of the arylcya- 72, 12, 58 and 57 %, respectively). In case of the B-series,we noacetate 6A–D was observed (see Figure S1 in Supporting In- also observedformation of bis-ribosylated by-products 10Bx formation).Compounds 6A–D weresubsequently reduced and 10 By bearing another sugar linked to the pyridine nitro- with zinc dust in acetic acid followed by spontaneouscycliza- gen (see Figure S2 in Supporting Information). These inter- tion to obtain isomeric pyrrolopyridine products 7A–D (94, 53, mediates were characterized by NMR and MS and by-product 73 and 81%). The next cyclocondensation step with forma- 10Bx was easily converted backinto the desired 10 B by in- Chem.Eur.J.2020, 26,13002 –13015 www.chemeurj.org 13003 2020 Wiley-VCH GmbH Full Paper Chemistry—A European Journal doi.org/10.1002/chem.202001124
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