Organomercury(II) Complexes of 6-Thioguanine: Synthesis, Characterization, and Biological Studies Vinod IL Ahluwalia, Jasjeet Kaur, Balbir S. Ahuja, and Gurvinder S. Sodhi VKA, JK. Department of Chemistry, University of Delhi, Delhi, India.-BSA. Department of Biotechnology, Punjabi University, Patiala, India.-GSS. Department of Chemistry, S. G. T.B. Khalsa College, University of Delhi, Delhi, India

ABSTRACT Organomercury(I1) complexes involving 6-thioguanine, of the type p-XCsH,HgL (Fig. 1) [LH = 6thioguanine; X = Me, MeO, NO,], have been synthesized and characterized. Conductance measurements indicate that the complexes are nonelectrolytes. From IR and UV studies, it is concluded that 6-thio?uanine acts as a bidentate ligand, coordinating through the 6-thione group and deprotonation of N-7. H and 13C NMR support the stoichiometry of the complexes. From thermal studies (TG and DSC) various kinetic and thermodynamic parameters for thermal degradation have been enumerated. In addition, the fragmentation pattern of the complexes have been analyzed on the basis of mass spectra. The p-MeCsH,HgL and p-MeOC6H,HgL complexes display significant activity against L1210 leukemia cells.


6-Thioguanine belongs to the class of purine bases and is known to act as an antimetabolite drug [l]. Interest in its metal complexes has arisen because of the following reasons. First, as a result of antitumor activity of some metal complexes, considerable interest has been shown in the design of model complexes involving purines which could mimic the interaction of metal ions with DNA [2, 31. Second, the investigation of mercury-purine complexes is of particular value because the known toxic effects of organomercury compounds, which are often attributed to the

Address reprint requests to: Professor V. K. Ahluwalia, Department of Chemistry, University of Delhi, Delhi-l 10007, India. Journal of Inorganic Biochembtry, 42, 147-151 (1991) 0

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IR Spectra The evidence for the involvement of exocyclic sulphur at C-6 in complexation is provided by the absorption frequency of the thione group. Whereas in the free ligand, the v(C = S) stretching frequency absorbs at 1220 cm-‘, it is shifted to - 1180 cm-’ on complexation. The bands at 1660 and 1530 cm-’ which are assigned, respectively, to the v(C = C) and v(C = N) stretching modes in 6&oguanine are shifted to - 1570 and - 1490 cm-’ in the complexes. This shows the involvement of N-7 in complexation. Thus, the 6-thioguanine ligand acts as a bidentam group, being coordinated to the mercury(I1) ion through exocyclic sulphur at C-6 and deprotonation of N-7. In structurally related theophylline ligand, where exocyclic sulphur at C-6 is replaced by oxygen, complexation involves deprotonation of N-7 alone [6]. The absence of chelate formation in theophylline is explained by the fact that exocyclic oxygen participates in strong intramolecular interligand hydrogen bonding [7]. This possibility is ruled out in 6-thioguanine. Moreover, the “soft” sulphur atom has a greater tendency as compared to the “hard” oxygen atom to coordinate to “soft” mercury(II) ion. The v(N - H) stretching frequency in the complexes absorbs at - 3200 cm-‘. In the far IR region, a weak band at - 375 cm- ’ is attributed to v(Hg-S) vibrational frequency.

W Spectra The UV spectrum of 6-thioguanine shows a broad band at 310 the ?r - K* transitions of the 6-thione group. On complexation, 320 nm (log E - 3.2). The shift is attributed to the involvement complexation, thus supporting the conclusions drawn from IR

run (log E 2.0) due to this band is shifted to of the C = S group in studies.

NMR Spectra In the ‘H NMR spectrum of 6-thioguanine, the signal at 6 8.22 is attributed to the absorption of H-8. In the complexes, this signal is observed at ca. 68.40. The downfield shift indicates the involvement of N-9 in complexation. In the 13C NMR spectrum of 6-thioguanine, the signal at 170 ppm is attributedto the C-6 thione. In the complexes this signal shifts downfield, to ca. 174.5 ppm. The C-8 absorption at 138.5 ppm in the free ligand is observed at 143.5 ppm in the complexes. These results further confirm that the 6-thioguanine moiety chelates to the mercury(n) ion through 6-thione and deprotonation of N-7. The resonance signals due to C-2, C-4, and C-5 which appear at 160.12, 148.80, and 105.42, respectively, in 6-thioguanine are unaltered on complexation. Thermal

Studies Thermogravimetric (TG) studies of the complexes reveal that the weight loss in each case, corresponds to the formation of HgO, which subsequently volatilizes, leaving the crucible of the thermobalance empty. The order (n) and activation energy (E,) of the thermal decomposition reaction have been elucidated by the method of Coats and Redfem [81. The order of reaction in each case is one. A comparison of the activation energy data reveals that the p-NO,C,H,HgL has the lowest value of E,. This may be explained on the basis of electron withdrawing effect of the nitro group, which leads



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ion, which may be liberated as a product o f drug metabolism, is expected to chelate with the constituents of D N A and R N A , thus interfering with their synthesis and thereby supplementing the activity of antimetabolite 6-thioguanine ligand. The authors are thankful to Dr. R. J. Bernacki, Grace Cancer Drug Center, New York, U.S., for screening samples against leukemia cells.

REFERENCES 1. A. Grollman and E. F. Grollman, Pharmacology and Therapeutics, Lea and Febiger, Philadelphia, 1970. 2. D. M. L. Goodgame, I. Jeeves, F. L. Phillips, and A. C. Skapski, Biochem. Biophys. Acta 378, 153 (1975). 3. D. J. Hodgson, Prog. Inorg. Chem. 23, 211 (1977). 4. J. J. Mulvihill, Science 176, 132 (1972). 5. A. N. Nesmeyanov, L. G. Makarova, and I. V. Polovyanyuk, J. Gen. Chem. 35, 682 (1965). 6. S. Bhatia, N. K. Kaushik, and G. S. Sodhi, J. Chem. Res. (S), 186 (1987); J. Chem. Res. (M), 1519 (1987). 7. E. Sletten, J. Chem. Soc. Chem. Commun., 558 (1971). 8. A. W. Coats and J. P. Redfern, Nature (London) 201, 68 (1964). 9. W. F. Bryant and T. H. Kinstle, J. Organomet. Chem. 24, 573 (1970). Received June 29, 1990; accepted October 16, 1990

Organomercury(II) complexes of 6-thioguanine: synthesis, characterization, and biological studies.

Organomercury(II) complexes involving 6-thioguanine, of the type p-XC6H4HgL (Fig. 1) [LH = 6-thioguanine; X = Me, MeO, NO2], have been synthesized and...
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