Journal of Medicinal Chemistry, 1979, Vol 22, No 1 111
Notes
G. D. Birnie, H. Kroeger, and C. Heidelberger, Biochemistry, 2, 566 (1963). G. H. Jones and J . G. Moffatt, J . Am. Chem. Soc., 90, 5337 (1968). M. R. Harris, D. A. Usher, H. P. Albrecht, G. H. Jones, and J. G. Moffatt, Proc. Natl. Acad. Sci. C.S.A., 63, 246 (1969). R. K. Johnson, T. Inouye, A. Goldin, and G. R. Stark, Cancer Res., 36, 2720 (1976). K. 0. Collins and G. R. Stark, J . Riol. Chem., 246, 6599 (1971). H. J. Thomas and J. A. Montgomery, J . Med. Pharm. Chem., 5 , 24 (1962). J . A. Montgomery, A. G. Laseter. and K. Hewson, J . Heterocycl. Chem., 11, 211 (1974). G. H. Jones, K. K. Hamamura, and J. G. Moffatt, Tetrahedron Lett., 5731 (1968). B. A. Otter, E. A. Falco, and J . J . Fox, J . Org. Chem., 34, 1390, 2636 (1969). A. J. Wahba and M. Friedkin, J . Riol.Chem., 237, 3794 (1962). R. P. Leary and R. L. Kisliuk, Prep. Biochem., 1 , 4 7 (1971). J. Galivan, G. F. Maley, and F. Maley, Biochemistry, 13, 2282 (1974). L. L. Bennett, Jr., M. H. Vail. P. W. Allan, and S. C. Shaddix, Biochem. Pharmacol., 22, 1221 (1973).
barium hydroxide solution, which was then filtered, and the filtrate diluted with 20 mL of ethanol to give the product as a white precipitate. It was collected by filtration, washed with absolute ethanol, and dried 4 h at 100 O C (0.07 mm): yield 308 mg (15%); UV (0.1 N HCl) 268 nm (log c 8.63), (pH 7) 268 (8.78), (0.1 N NaOH) 268 (7.20); NMR (D20)6 1.3-2.1 (m, 2H6 and 2Hs), 2.3 (m, 2H2), 3.96 (m, H 4 ) ,6.26 (t, H l ) , 7.5 (d, JHF = 6 Hz, He); LC, CIBcolumn (Waters), 0.1 M NH,H,PO, (pH 3.51, retention time C, H, N. 7.8 min. Anal. (CloH11FN207P~l.5Ba~l.5H,0) Acknowledgment. This investigation was supported by t h e National Cancer Institute, National Institutes of Health, Department of Health, Education a n d Welfare, under Contract N01-CM-43'762 and Grant CA 10914. The authors are indebted t o Dr. W. C. Coburn, Jr., and M. C. Thorpe, who interpreted NMR data, and to other members of t h e Molecular Spectroscopy Section of Southern Research Institute, who performed most of t h e microanalytical a n d spectral determinations reported.
References and Notes ( 1 ) C. Heidelberger in "Antineoplastic and Immunosuppressive Agents", Part 11, A. C. Sartorelli and D. G. Johns, Eds., Springer-Verlag, Berlin, 1975, p 193. (2) R. R. Brockman in ref 1, Part I, 1974, p 325.
Correlation of Carbonic Anhydrase Inhibitory Activities of Benzenesulfonamides with the Data Obtained by Use of Nitrogen-14 Nuclear Quadrupole Resonance S. N. Subbarao a n d P. J. Bray* Department of Physics, Broun Uniuersity, Proridence, Rhode Island 02912. Received July 12, 1978 Nitrogen-14 nuclear quadrupole resonance (NQR) spectra of several benzenesulfonamides in their solid state are reported and analyzed in the framework of the Townes and Dailey theory. Satisfactory correlations between the (0" - uNs) electron densities at the sulfamyl nitrogen and the in vitro carbonic anhydrase inhibitory activities of the sulfonamides have been found. The correlations are in accord with the results of other studies that show the carbonic anhydrase inhibitory activities to be largely influenced by the electronic property of the sulfamyl group. I t has been well established's2 t h a t sulfonamides are active as inhibitors of carbonic anhydrase, t h e enzyme responsible for the conversion of carbon dioxide and water t o hydrogen ion a n d bicarbonate ion. Since the original observation by M a n n and Keilin,3 other reports4 have confirmed the fact that high carbonic anhydrase inhibition was obtained in these compounds where the unsubstituted sulfamyl group (-SO2",) was attached directly t o an aromatic group (phenyl. naphthyl, or heterocyclic) and that N-sulfamyl substitution abolished activity for practical purposes. Kakeya e t a1.j have shown t h a t carbonic anhydrase inhibitory activity of t h e sulfonamides depends largely on t h e electronic property of t h e sulfamyl group. These authors correlate the in vitro inhibitory activity of t h e sulfonamides with various parameters such as t h e H a m m e t t u value, N M R chemical shift of the sulfamyl protons, a n d pK,. In the present work, several benzenesulfonamides have been investigated by nitrogen-14 nuclear quadrupole resonance (NQR) spectroscopy. NQR techniques are well suited t o probe t h e electronic environment of a nucleus a n d , thus, can be employed t o determine t h e electron distribution a t t h e site of t h e atom containing t h e nu~ l e u s . ~ , 'Correlations of NQR d a t a with t h e in vitro carbonic anhydrase inhibitory activities of t h e benzenesulfonamides are considered.
Experimental Section The NQR signals were detected by using the spin-echo t e c h n i q ~ e . Two ~ , ~ radio-frequency (rf) pulses of height about 4 0022-2623/79/1822-0111$01.00/0
kV peak to peak were applied to a coil containing the sample, one pulse (90") at t = 0 and the second pulse (180') at t = 7 , and an echo was observed at t = 27. The 90 and 180' pulses were of widths about 20 and 40 ps, respectively, and the interval between the pulses was on the order of 2-3 ms. The experiments were performed on polycrystalline samples obtained from commercial sources and used as such. All the measurements were made at liquid nitrogen temperature (77 K). Very weak resonances were detected with the aid of a signal averager."
Experimental Results For nitrogen-14 ( I = l), the NQR spectrum consists, in general, of three lines6,'
and 'd
= u+
- 1'
(2)
where eQ is t h e quadrupole moment of the nucleus; e2qQ a n d are, respectively, the quadrupole coupling constant a n d asymmetry parameter. T h e quantities qxx, q?,, a n d q = q,, are the diagonalized components of the electric-field gradient (EFG) tensor at t h e site of t h e nitrogen in t h e principal axis system chosen such t h a t l q * z l 2 Iq,,l 2 l q x x l
In this notation
(3) C 1978 American Chemical Society
112 JoiirnnI of .\f(adi(ina/ ( ' h c ) r n c \ t r i 197.9 L'o/ 22 Z ~ J/
Notes
Table I. Nitrogen-14 NQR Spectra of Sulfamyl Nitrogen in Several Sulfonamides at 7 7 K
compound
K
SUI fanilamitie
p-NH
o-toluenesulfonamide metanilamide
0-CH 171-NH
be ii L e nesu I f onam i de p - toluenesulfonamide p chlorobenzenesulfonamide
H P-CH I
p-nitrobenzenesulfonamide tn-nitrobenzenesulfonamide p-methoxybenzenesulfonamide
p-KO:
p-CI
m-NOp-OCH
p-carboxybenLenesulfonamide p-COOH Values for the nitrogen in the R substituent Table I lists the frequencies and related parameters of t h e compounds investigated in this work. T h e presence of' nonequivalent nitrogens in some molecules (e.g.. sulfanilamide) poses the question of' pairing in su1f'the frequencies. T h e difference frequency. anilamide was detected (930 kHzi. T h i s facilitates the pairing of i ~ +with the appropriate lines. A s can be seen from Table I. the various substituents tend t o increase the coupling constant of t h e sulfamyl nitrogen compared to benzenesulfonamide. Therefore. it is reasonable t o assign t h e larger of the two coupling constants in sulfanilaniide to t h e sulfamyl nitrogen. I n the case ot' t h e nitrobenzenesulfonamides. only two lines have been detected. These lines have been assigned t o the sulfani>-l nitrogen because it i b k n o w n : ' that the coupling constant of' t h e nitrogen of the nitro group is much smaller ion the order of 1 AZHzl.
Hz 3478 312Ya 3690 3430 3340O 3363 342
