N-1-Sulfonylated cytosine 5 and 5-halogeno-N-1-sulfonylated cytosine derivatives 1 and 2 were synthesized by condensation of silylated cytosine or 5-halogenocytosine bases with tosylchloride in acetonitrile, or by the reaction of cytosine or 5-halogenocytosine bases with tosylchloride in pyridine. The NMR evidences are presented, showing that 1 and 2 form exclusively rare keto-imino tautomers in DMSO-d(6) solution, while N-1-sulfonylated cytosine 5 appears as a common keto-amino tautomer

Krizmanić, Irena

Vikić-Topić, Dražen

Žinić, Biserka

Žinić, Mladen

N-1-Sulfonylated cytosine 5 and 5-halogeno-N-1-sulfonylated cytosine derivatives 1 and 2 were synthesized by condensation of silylated cytosine or 5-halogenocytosine bases with tosylchloride in acetonitrile, or by the reaction of cytosine or 5-halogenocytosine bases with tosylchloride in pyridine. The NMR evidences are presented, showing that 1 and 2 form exclusively rare keto-imino tautomers in DMSO-d6 solution, while N-1-sulfonylated cytosine 5 appears as a common keto-amino tautomer

Biserka Žinić

Irena Krizmanić

Dražen Vikić-Topić

Mladen Žinić

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ISSN-0011-1643CCA-2629 Original Scientific Paper5-Bromo- and 5–Iodo-N-1-sulfonylated CytosineDerivatives. Exclusive Formation of Keto-IminoTautomersBiserka @ini},a,* Irena Krizmani},b Dra`en Viki}-Topi},aand Mladen @ini} aaRu|er Bo{kovi} Institute, P.O.B.1016, HR–10001 Zagreb, CroatiabHERBOS Chem. Industry, Obrtni~ka 17, 44000 Sisak, CroatiaReceived June 10, 1999; revised October 26, 1999; accepted October 29, 1999N-1-Sulfonylated cytosine 5 and 5-halogeno-N-1-sulfonylated cyto-sine derivatives 1 and 2 were synthesized by condensation of sily-lated cytosine or 5-halogenocytosine bases with tosylchloride inacetonitrile, or by the reaction of cytosine or 5-halogenocytosinebases with tosylchloride in pyridine. The NMR evidences are pre-sented, showing that 1 and 2 form exclusively rare keto-imino tau-tomers in DMSO-d6 solution, while N-1-sulfonylated cytosine 5 ap-pears as a common keto-amino tautomer.Key words: synthesis, N-1-sulfonylated cytosine derivatives, 5-bro-mo and 5-iodocytosine derivatives, NMR study, keto-imino andketo-amino tautomersINTRODUCTIONVarious cytidine derivatives modified at the base or the ribose areknown to exhibit antiviral or antitumor activity.1–4 On the other hand, cyto-sine (C) is a very important nucleic base with respect to DNA structure; inits protonated form (C+) it is involved in formation of C C+ DNA duplexes5,6and C G C + triplexes.7 The keto-imino tautomer of cytosine is a mutagenicbase analogue capable of pairing with adenine.8 Although three tautomersCROATICA CHEMICA ACTA CCACAA 72 (4) 957¿966 (1999)* Author to whom correspondence should be addressed. (E-mail: bzinic@rudjer.irb.hr)Biserka @ini} was previously Biserka Ka{nar.(I, II and III, Figure 1) are possible for N-1 substituted cytosine, thelactam-amine structure I has been found to be the dominant tautomer inaqueous and DMSO solutions.9–12 However, some substituted cytosines, forexample, N-4-methoxy (IV)13 or N-4-methoxy-5-methyldeoxycytidine (V),14give the equilibrium with predominant keto-imino tautomer, possessing synarrangement of N-4-methoxy groups (Figure 1). Incorporation of such cyti-dine derivatives in DNA considerably destabilizes the duplex since syn-co-nfiguration is unfavorable for normal Watson-Crick pairing with guanine.15In contrast, derivative VI with its fixed anti-configuration of imino frag-ment forms base pairs with A and G of comparable stabilities.16 These re-sults emphasize the influence of cytosine tautomers on the stability of DNAstructure.Recently, we have described the synthesis and in vitro antitumor activ-ity of a series of novel 1-sulfonyluracil and 1-sulfonylcytosine derivati-ves.17,18 In the next step of our research, we report here on the synthesisand 1H NMR data of 5-bromo-1-p-toluensulfonylcytosine (1) and 5-iodo-1-p-toluensulfonylcytosine (2) derivatives as new candidates for compoundswith antitumor activity. The 1H NMR study revealed that both cytosine de-rivatives in DMSO form exclusively keto-imino tautomers with anti-configu-ration of the imino fragment. This opens a new possibility of preparing N-4--unsubstituted cytidine analogues, which should preferably form keto-imino958 B. @INI] ET AL.Figure 1. Tautomers of cytosine derivatives.tautomers with an anti-configuration favoring efficient pairing with G andA. Such cytidine tautomers, if incorporated in DNA, could exhibit interest-ing effects on the DNA structure and duplex stability.RESULTS AND DISCUSSION5-Halogeno-N-1-sulfonylated cytosine derivatives 1 and 2 have been pre-pared from silylated 5-bromocytosine (3)19 or 5-iodocytosine (4)20 and tosyl-chloride in acetonitrile or by the reaction of cytosine derivatives 3 or 4 withtosylchloride in pyridine (Scheme 1). Both methods gave 1 and 2 in a rela-tively low yield. The C-5 dehalogenation was also observed by the formermethod, giving N-1-sulfonylated cytosine 5 as by-product in 3–5% yield. Incomparison, N-1 sulfonylation of silylated cytosine (6) gave 1-tosylcytosine 5in 80% yield, while the reaction of 6 and tosylchloride in pyridine, besidesthe mono-sulfonylated product 5 (44%), gave also bis-sulfonylated product 7in 24% yield. The sulfonylation of both 5-bromo (3) and 5-iodocytosine (4) isless efficient than that of cytosine (6). Apparently, the electron donating ef-fect of 5-halogeno substituents dominates over the electron withdrawingone, diminishing the acidity of N-1 hydrogen. This may result in a relativelyKETO-IMINO TAUTOMERS OF CYTOSINE DERIVATIVES 959Scheme 1.low effective concentration of N-1 anion and hence low yields of sulfonylatedproducts.1H NMR spectra (all measured in DMSO-d6) of 1 and 2 differ from thatof N-1-sulfonylated cytosine 5, with respect to chemical shifts and multiplic-ity (Figure 2a). The most striking difference refers to N-protons. In the spec-trum of 5, two amino protons at N-4, readily exchangeable for deuterium byaddition of D2O, appear as a singlet at d 7.95 ppm. This is in accord with theexistence of the keto-amino tautomer, known to be the most stable form ofunsubstituted cytosine. In contrast, two slightly broadened one-protonsinglets at d 8.61 and 7.72 ppm and d 9.18 and 8.82 ppm, all exchangeablefor deuterium, can be observed for 1 and 2, respectively. The large chemicalshift difference between these protons, Dd of 0.89 ppm for 1 and of 0.36 ppmfor 2, strongly suggests the formation of the keto-imino tautomer. This largechemical shift difference can hardly be explained by the restricted rotationaround C(4)NH2 bond in keto-amino tautomers containing 5-halogeno sub-stituents. Besides, if this were the case, a geminal coupling between twonon-equivalent amino protons of the keto-amino tautomer should exist,which should give an additional doublet at both signals. However, no appar-ent splitting was detected at either of the two signals in 1D spectra of 1 and2. There is a possibility that the magnitude of geminal coupling is smallerthan the signal width. If this happens, the splitting is not observable in 1Dspectrum, but it should be visible in 2D spectra as cross-peaks between thecorresponding signals. However, an inspection of COSY spectrum (Figure2b) showed no cross-peaks between two non-equivalent N-protons, com-pletely ruling out the geminal spin-spin interaction. Therefore, the observedchemical non-equivalency of N-protons is due to their bonding to differentN-atoms, i.e. the existence of keto-imino tautomers of 1 and 2. The configu-ration of the imino fragment in 1 and 2 can be syn- or anti- with respect tolactam NH. In the syn-configuration the free electron pair of imino nitrogenwould be in close proximity to 5-bromo or 5-iodo substituents, as appearsfrom the examination of CPK models. Thus, syn-configuration should beless stable than anti-configuration due to electron repulsion in the former.Consequently, keto-imino tautomers of 1 and 2 with anti-configuration ofthe imino fragment are much more likely to form. This is supported byNOESY spectra, where no cross-peaks between lactam NH and imino NHprotons could be observed, in agreement with the large spatial separation ofthese protons in anti-configuration.CONCLUSIONS5-Bromo-1-p-toluensulfonylcytosine (1) and 5-iodo-1-p-toluensulfonylcyt-osine (2) have been prepared by condensation of the corresponding silylated960 B. @INI] ET AL.KETO-IMINO TAUTOMERS OF CYTOSINE DERIVATIVES 961Figure 2a. 1H NMR Spectra (DMSO-d6) of N-1-sulfonylated cytosine derivatives.5-halocytosine and tosylchloride in acetonitrile or by the reaction of 5-halocytosine and tosylchloride in pyridine. 1H NMR spectra of 1 and 2 takenin DMSO-d6 revealed that in contrast to 1-p-toluensulfonylcytosine (5),which in the same solvent forms keto-amino tautomer, both halogenocyto-sine derivatives form exclusively keto-imino tautomers. It was also foundthat the keto-imino tautomers of 1 and 2 possess anti-configuration of theimino fragment (Figure 3). These results open new possibilities for prepara-tion of rare anti-keto-imino cytosine and cytidine tautomers and the use ofthe latter for incorporation into DNA. Due to favorable pairing of suchtautomers with both G and A, interesting effects on DNA stability andstructure might be expected.962 B. @INI] ET AL.Figure 2b. COSY Spectrum of 5-bromo-N-1-sulfonylated cytosine.EXPERIMENTALGeneral: Solvents were distilled from appropriate drying agents shortly beforeuse. TLC was carried out on Merck precoated glass plates or DC-plastikfolien Kie-selgel 60 F254 and preparative thick layer (2 mm) chromatography on Merck 60 F254.Flash column chromatography was performed on silica gel Merck 0.040–0.063 mm.Melting points were determined on a Kofler hot-stage apparatus and are uncorrect-ed. UV Spectra [lmax / nm, log e / dm3 mol–1 cm–1] were taken on a Philips PU8700UV/VIS spectrophotometer. IR Spectra were obtained for KBr pellets on a Perkin-Elmer 297 spectrophotometer.The 1H and 13C NMR spectra were recorded on a Varian Gemini 300 spectrome-ter, operating at 75.46 MHz for the 13C nucleus. The samples were dissolved inDMSO-d6 and measured at 20 °C in 5 mm NMR tubes. Concentrations of sampleswere 0.1 M for 1H and 0.2 M for 13C measurements. Chemical shifts (d/ppm) are re-ferred to TMS. Digital resolution was 0.3 Hz per point in 1H and 0.5 Hz per point in13C NMR one-dimensional spectra. The applied techniques were standard 1H and 13Cwith broadband proton decoupling, 13C gated decoupling, COSY, NOESY and HET-COR. For proton decoupling, the Waltz-16 modulation was used. The COSY spectrawere recorded in the magnitude mode with 1024 points in F2 dimension and 256 in-crements in F1 dimension, zero-filled to 1024 points. Increments were measuredwith 16 scans, 4500 Hz spectral width and a relaxation delay of 0.8 s. The corre-sponding digital resolution was 8.9 Hz per point and 17.6 Hz per point in F2 and F1dimensions, respectively. The NOESY spectra were recorded in a phase-sensitivemode and mixing times 0.45–0.80 s. All other measurement parameters were as forCOSY spectra. The HETCOR spectra were recorded with 2048 points in F2 dimen-sion and 256 increments in F1 dimension, zero-filled to 512 points. Each incrementwas recorded by 96 scans with a relaxation delay of 1.0 s. Spectral widths were19000 Hz in F2 and 4500 Hz in F1 dimensions, and the corresponding digital resolu-tions were 18.6 Hz per point and 17.6 Hz per point, respectively.1-p-Toluenesulfonylcytosine (5)A) A mixture of cytosine (6) (222 mg, 2.00 mmol) and bis(trimethylsilyl)aceta-mide (BSA) (1.48 mL, 6.00 mmol) was heated under reflux in dry acetonitrile (7 mL)for 30 minutes. The obtained colorless solution was cooled to 0 °C and p-toluenesu-KETO-IMINO TAUTOMERS OF CYTOSINE DERIVATIVES 963Figure 3. Tautomers of N-1-sulfonylated cytosine derivatives.lfonylchloride (TsCl) (457 mg, 2.40 mmol) was added. After heating under reflux for45 minutes, the solvent was evaporated. Ethanol was added into the residue and theobtained solid was filtered off and recrystallized from hot ethanol, yielding product 5as white crystals: 421 mg (80%); m.p. = 216 C; Rf = 0.66 (CH2Cl2/MeOH 3:1); UV(MeOH) lmax = 234.5 and 248.0, log e = 3.18 and 3.57; IR (KBr) nmax/cm–1: 3360 (s),3100 (s), 1660 (s, br), 1520 (s), 1490 (s), 1380 (s), 1375 (s), 1350 (s), 1285 (s), 1185 (s),1175 (s); 1H NMR (DMSO-d6) d/ppm: 8.14 (d, 1H, H-6, J6,5=7.8 Hz), 7.95 (s, 2H, NH2),7.87 (d, 2H, Ph, J=8.1 Hz), 7.46 (d, 2H, Ph, J=8.1 Hz), 5.98 (d, 1H, H-5, J5,6=7.8 Hz),2.42 (s, 3H, CH3); 13C NMR (DMSO-d6) d/ppm: 166.27 (s, C-4), 151.22 (s, C-2), 145.61(s, Ph), 139.73 (d, C-6), 134.47 (s, Ph), 129.80 (d, Ph), 129.02 (d, Ph), 97.50 (d, C-5),21.20 (q, CH3).Anal. Calcd. for C11H11N3O3S (Mr = 265.30): C 49.80, H 4.18, N 15.84%; found: C50.09, H 4.02, N 15.89%.B) TsCl (343 mg, 1.8 mmol) was added to a suspension of cytosine (6) (100 mg,0.9 mmol) in dry pyridine (9.5 mL). After stirring at room temperature for 48 hours,the solvent was evaporated under pressure. The remaining oil contained two com-pounds that were separated by chromatography on silica gel (CH2Cl2/MeOH 15:1).Fractions containing the individual products were pooled and concentrated to dry-ness to give 106 mg (44%) of 1-p-toluenesulfonylcytosine (5) and 92 mg (24%) of lesspolar product, bis(p-toluenesulfonyl)cytosine 7.4-N-p-Toluenesulfonyl-1-p-toluenesulfonylcytosine (7) white crystals:m.p. = 182 C; Rf = 0.80 (CH2Cl2/MeOH 9:1); UV (MeOH) lmax = 227.2 and 283.0,log e = 4.39 and 4.45; IR (KBr) nmax/cm–1: 3200 (w), 3090 (w), 3030 (w), 2920 (w),2850 (w), 1730–1715 (s, doublet), 1630 (s), 1570 (s, doublet), 1450 (m, doublet), 1400(s, doublet), 1370 (m), 1290 (s), 1260 (m), 1175 (s), 1155 (s); 1H NMR (DMSO-d6)d/ppm: 12.10 (s, br, 1H, NH-4), 8.26 (d, 1H, H-6, J6,5=8.4 Hz), 7.93 (d, 2H, Ph, J=8.1Hz), 7.73 (d, 2H, Ph, J=8.1 Hz), 7.49 (d, 2H, Ph, J=8.1 Hz), 7.37 (d, 2H, Ph, J=8.1Hz), 6.76 (d, 1H, H-5, J5,6=8.4 Hz), 2.43 (s, 3H, CH3), 2.38 (s, 3H, CH3); 13C NMR(DMSO-d6) d/ppm: 159.79 (s, C-4), 146.79 (s, Ph), 146.42 (s, C-2), 142.94 (s, Ph),139.52 (d, C-6), 132.91 (s, Ph), 132.90 (s, Ph), 130.06 (d, Ph), 129.63 (d, Ph), 129.38(d, Ph), 126.47 (d, Ph), 98.78 (d, C-5), 21.21 (q, CH3), 20.95 (q, CH3).Anal. Calcd. for C18H17N3O5S2 (Mr = 419.48): C 51.54, H 4.09, N 10.02%; found:C 51.26, H 4.20, N 10.00%.5-Bromo-1-p-toluenesulfonylcytosine (1)A) A mixture of 5-bromocytosine (3) (110 mg, 0.58 mmol) and BSA (0.43 mL, 1.74mmol) in dry acetonitrile (2 mL) was heated under reflux for 45 minutes. The color-less solution was cooled to 0 °C and TsCl (133 mg, 0.70 mmol) was added. After heat-ing under reflux for 30 minutes, the solvent was evaporated under pressure. Ethanolwas added into the residue and the obtained solid of 5-bromocytosine was filteredoff. The filtrate was evaporated, and the residue was separated by preparative chro-matography (CH2Cl2/MeOH 9:1) yielding product 1, 48 mg (24%) and 1-p-toluenesu-lfonylcytosine (5), 8 mg (5%).B) TsCl (300 mg, 1.58 mmol) was added to a suspension of 5-bromocytosine (3)(150 mg, 0.79 mmol) in dry pyridine (8 mL). After stirring at room temperature over-964 B. @INI] ET AL.night, the solvent was evaporated under pressure. Ethanol was added and the ob-tained solid of 5-bromocytosine was filtered off. The filtrate was evaporated and theresidue was purified by preparative chromatography (CH2Cl2/MeOH 9:1). After re-crystallization from methanol, product 1, 50 mg (18%) was obtained: m.p. = 213 C; Rf= 0.44 (CH2Cl2/MeOH 9:1); UV (MeOH) lmax = 234.7 and 254.0; log e = 3.98 and 3.95;IR (KBr) nmax/cm–1: 3450 (s), 3070 (m), 2960 (w), 2920 (w), 1680 (s), 1640 (s), 1605(m), 1490–1475 (s, dublet), 1370 (s), 1170 (s); 1H NMR (DMSO-d6) d/ppm: 8.61 (s, 1H,NH), 8.35 (s, 1H, H-6), 7.95 (d, 2H, Ph, J=8.1 Hz), 7.72 (s, 1H, NH), 7.46 (d, 2H, Ph,J=8.1 Hz), 2.42 (s, 3H, CH3); 13C NMR (DMSO-d6) d/ppm: 159.10 (s, C-4), 149.00 (s,C-2), 148.08 (d, C-6), 145.19 (s, Ph), 138.73 (s, Ph), 128.70 (d, Ph), 125.91 (d, Ph),85.27 (s, C-5), 21.03 (q, CH3).Anal. Calcd. for C11H10N3O3SBr (Mr = 344.19): C 38.39, H 2.93, N 12.21%; found:C 38.19, H 2.94, N 12.44%.5-Iodo-1-p-toluenesulfonylcytosine (2)A) A mixture of 5-iodocytosine (4) (250 mg, 1.06 mmol) and BSA (0.78 mL, 3.17mmol) in dry acetonitrile (4 mL) was heated under reflux for 45 minutes. TsCl (242mg, 1.27 mmol) was added into the obtained red solution, cooled to 0 °C. After heat-ing under reflux for 45 minutes, the solvent was evaporated under pressure. Ethanolwas added into the residue and the obtained solid of product 2 was filtered off andrecrystallized from ethanol. The filtrate was evaporated and the residue was sepa-rated by preparative chromatography (CH2Cl2/MeOH 9:1), yielding 10 mg of product2 (overall yield 5%) and 1-p-toluenesulfonylcytosine (5), 8 mg (3%).B) TsCl (322 mg, 1.69 mmol) was added to a suspension of 5-iodocytosine (4)(200 mg, 0.84 mmol) in dry pyridine (9 mL). After stirring at room temperature over-night, the solvent was evaporated under pressure. Ethanol was added and the ob-tained solid of product 2 was filtered off. After recrystallization from ethanol, prod-uct 2 was obtained: 171 mg (52%); m.p. = 210 C; Rf = 0.80 (CH2Cl2/MeOH 9:1); UVlmax = 228.9 and 289.4, log e = 4.15 and 3.67; IR (KBr) nmax/cm–1: 3480 (m), 3310 (m),3200 (w), 2920 (vw), 2850 (vw), 1640 (s), 1560 (s), 1525 (m), 1390 (s), 1370 (s), 1190(s), 1170 (s); 1H NMR (DMSO d6) d/ppm: 9.18 (s, 1H, NH), 8.82 (s, 1H, NH), 8.25 (s,1H, H-6), 7.53 (d, 2H, Ph, J=8.0 Hz), 7.16 (d, 2H, Ph, J=8.0 Hz), 2.31 (s, 3H, CH3);13C NMR (DMSO d6) d/ppm: 160.46 (s, C-4), 153.49 (d, C-6), 147.38 (s, C-2), 145.32(s, Ph), 138.36 (s, Ph), 128.48 (d, Ph), 125.76 (d, Ph), 55.08 (s, C-5), 20.88 (q, CH3).Anal. Calcd. for C11H10N3O3SI (Mr = 391.19): C 33.77, H 2.58, N 10.74%; found:C 33.94, H 2.75, N 10.71%Acknowledgement. – Funding from the Croatian Ministry of Science and Tech-nology is gratefully acknowledged.REFERENCES1. S. S. Cohen, Prog. Nucleic Acid Res. Mol. Biol. 5 (1966) 1–88.2. R. J. Suhadolnik, Nucleoside Antibiotics, Wiley-Interscience, New York, 1970.3. K. A. Watanabe, U. Reichman, K. Hirota, C. Lopez, and J. J. Fox, J. Med. Chem.22 (1979) 21–24.KETO-IMINO TAUTOMERS OF CYTOSINE DERIVATIVES 9654. S. Hayashi, S. Phadtare, J. Zemlicka, M. Matsukura, H. Mitsuya and S. R. Bro-der, Proc. Natl. Acad. Sci. U.S.A. 85 (1988) 6127–6131.5. K. A. Hartman and A. Rich, J. Am. Chem. Soc. 87 (1965) 2033–2039.6. R. B. Inman, J. Mol. Biol. 9 (1964) 624–637.7. P. Rajagopal and J. Feigon, Nature 339 (1989) 637–640.8. L. C. Sowers, G. V. Fazakerley, R. Eritja, B. E. Kaplan, and M. F. Goodman, Proc.Natl. Acad. Sci. U.S.A. 83 (1986) 5434–5438.9. D. T. Edmonds and P. A. Speight, J. Magn. Reson. 6 (1972) 265–273;W. Saenger in: Principes of Nucleic Acid Structure, Springer Verlag, New York,1982.10. R. Blinc, M. Mali, R. Osredkar, A. Prelesnik, J. Seliger, I. Zupan~i~, and L. Ehren-berg, J. Chem. Phys. 57 (1972) 5087–5093.11. R. A. Katritzky and A. J. Waring, J. Chem. Soc. 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Tipson(Eds.), John Wiley & Sons, New York, 1978, pp. 779–782.SA@ETAK5-Brom- i 5–jod-N-1-sulfonilirani derivati citozina.Isklju~ivo nastajanje keto-imino-tautomeraBiserka @ini}, Irena Krizmani}, Dra`en Viki}-Topi} i Mladen @ini}Sintetizirani su N-1-sulfonilirani derivat citozina 5 i 5-halogen-N-1-sulfoniliraniderivati citozina 1 i 2 i to kondenzacijom sililiranog citozina ili 5-halogencitozina stosil-kloridom u acetonitrilu, ili reakcijom citozina ili 5-halogen citozina s tosil-klo-ridom u piridinu. NMR eksperimenti pokazuju isklju~ivo nastajanje keto-imino-tau-tomera 1 i 2 u DMSO-d6 otopinama, dok se N-1-sulfonilirani derivat citozina 5 po-javljuje u uobi~ajenom keto-amino-obliku.966 B. @INI] ET AL.

5-bromo- and 5-iodo-N-1-sulfonylated cytosine derivatives. Exclusive formation of keto-imino tautomers

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