- Email: [email protected]
New guanine deaminase inhibito RS
Pharmacological Research Communica~'ons, VoL 16, No. 3, 1984
NEW GUANINE
243
DE~/~INASE INHIBITORS*
A.K.Saxena**, S.Ahmad, K.Shanker and K.Kisbor, Department of Pharmacology & Therapeutics, King George' s Medical College, Lucknow - 226003 (I%~DIA) Received in final form 3 October 1983
2-Aryl/alkyl-3-( 5 '-carboxamido-imidazol-4 ' -yl) -quina zolin4-( 3H) -ones have been reported as Guanine deaminase inhibitors. These compounds ~.~re prepared from 4-amino-5-1midazol-carboxamide and suitable 2-aryl/alkyl-benzoxazin-4-ones.
Compounds were
characterized by their m.ps., elemental analyses and I. P~ spectra. These compounds have shown significant inhibition, aryl substituent was more effective than alkyl group.
This is the first report when
qulnazolones have been reported as Guanine deam~nase inhibitors. Inhibitors of this enzyme can enhance the bioavailability of purina antagonists and in turn are helpful for the chemotherapy of cancer. INTRDDUCTION Guanine deminase ( ~..C.3,5,4,3., quanine-ami~hydrolase, juanase) is an important enzyme of purina catabolism which irreversibly deaminates guanine (I) into Xanthine (II), which is further metabolized to uric acid (III) by Xanthine oxidase (Lehniger, 1975). Role of purina antagonists in the chemotherapy of cancer is well documented.
8-Azagnanine (IV) was the first compound of this
type found to have antineoplastic activity (Kidder a.__ta_._l., 1949) and since than it has been reported to inhibit a number of tumours * Part of Ph.D.Thesis work of A.K.Saxena. ** For correspondence= Present address= Biochemistry Unit, Regional Research Laboratory, Jammu T a w i - 180001, (INDIA). 0031-6989/84/030243-10/$03.00/0
9 1984 The Italian Pharmacological Society
Pharmacological Research Communications, Vol. 16, No. 3, 1984
244
including Leukemia LI210 and Carcinoma 755 (Goldin et a!., 1950; Gellhorn et al., 1950).
6-Thioguanine (V~, mercaptopurine (Vl}
and 6-chloropurine (VIi) are other important purine antagonists in use (Goodman-Gilman, Goodman and Gilman,
1980).
Use of these metabolites is limited in the traahaent of cancer because of degradation of most of these compounds by guanine de~minase and the product so formed is biologically inactive (RDush and Norris, 1950).
Hirschborg et al . (1952) have shown that
turnouts with low guanine deaminase content respond better to 8 -azaguanine. In view of the biotransformation of purine antagonist by the enzYme guanine deaminase into a biologically inactive product, it is reasonable to postulate inhibitors of guanine deminase, if administered alongwith the drug, will enhance the bioavailability of the drug.
4-Amino-5-imidazole carboxamide (VIII), an inhibitor
of guanine deeminase, when administered alongwith 8-azaguanine potentiated antit~nour activity (Carlo and Mandel, 1955).
These
observations have developed interest into guanine de~-ninase inhibitors. Since then different workers have prepared c~npounds having guanine deaminase inhibitory activity (Hoshi et al., 1968 Kanzawa e t a_~l., 1970 and 1971; Baker e___ta_l., 1971, Silipo and Hansel,
1976; Saxena e_t a_~l., 1980). Quinazolones have been reported to possess diverse biological
activities (Ctmlnings and Stokey, 1963; Dubey e_t a___l., 1980, ~ a r w a l e_t a~l., 1981).
4-~nino-5-imidazole carboxamide has been reported
as an inhibitor of guanine deaminase (Mandel e___ta_l., 1957). With an aim to obtain guanine deminase inhibitors, chemotherapy of cancer,
due to t]~ir use in
it was thought worthwhile to prepare new
quinozolones by condensing benzoxain-4-ones with 4-amino-5imidazole carboxamide. report.
The present p a p e r deals with the preliminary
,-4
8 ro~o ! -rl
I
0
! 1--1
,-t
U')
P-I
,;
4
~o~
N
o.O 4J h
L'~
0,-I ~ 0
~8
~'~
il
.u
L~
-M I
L~
GO
9 ['~
0u~
9 LJ')
|
0~
-M -M
t~
0 '
U
,..4 {/1
~o~. ~.o~
0 ,,-t
0 [q
!
ro ~4J ~ ~h
I
~88~d ~ -,-t ..~ ~
0
9-;
d
~
Pharmacological Research Communications, Vol. 16, No. 3, 1984
246
OH
0
HoL # H
I
W
OH
0
H o ~ O H H TE
H2~ ~
E~
N H
gr r
H
0
HaN/~'Xn____ N
E~RIM~TAL The compounds were synthesized as shown in Scheme I and characterized by their melting points, elemental analyses and I. ;hspectra.
The melting IDoints were determined in open capill~ry
tube and reported uncorrected.
The experimental values for C,H
and N elements were within + O.4~ of the theoretical values,
All
the compounds w~re routinely checked for their homogenity by TLC on Silica gel G plates.
De%ails of synthetic methods are as below:
Pharmacological Research Communications, Vol. 16, No. 3, 1984
247
~ Icc%o COOH
NH~
RcocQ.
0
SC.. EM 4 -Amino-5 -imidazole Carboxamide. It was prepared from ethycyanoacetate (Aldrich Chemical Co., bland)
as reported by RDbinson and Shaw (1972) and Cook et el.,
( 1949). 2-Met hyl-bsnzoxazin-4 -o ne. Anthranilic acid (0.05 mole) was refluKed in exCess of freshly distilled acetic anhydride.
Excess of the acetic anhydride was
distilled off and the residue was recrystallized from hexane.
Pharmacological Research Communications, I/ol. 16, No. 3, 1984
248
2-P henyl-benzoxa zin-4 -one. Anthranilic acid (0.I mole) and benzyl chloride in equimolar proportion were taken in pyridine (50 el) and the mixture was stirred below i0 ~ for 1-2 hr.
Residue was washed with ice-cold water and
recrystallized from alcohol. _22-M@thy1-3 -( 5' -ca_rbo_xmn~.i do_imid@zQ1-4 ' -yl) quinazolin-4 -(3H) -one. 2-Methyl-b~nzoxazin-4-one (0.02 mole) was heated with 4-amino-5, imidazole carboxamide in equimolar concentration for 5-10 sin.
The
jelly like mass was obtained which was recrystallized from alcohol. 2-Phenyl-3_-(5 '-carboxamide-imidazol-4 '-yl) quinazolin-4-(3H) -one. 2-Phenyl-benzoxazin-4-one (0.05 mole) and 4-~nino-5-imidazole carboxamide in equimolar concentration w e r e mixed in pyridine (50 el) and water (25 ml); and the reaction mixture was refluxed for 6 hrs. The major portion of pyridine was distilled off at reduced pressure. The residue was digested with N HCI (20 el) for 2 hrs. on water bath.
The solid separated was filtered and recrystallized from
alcohol. BIOLOGICAL
STUDIES
Animal s,: Adult albino rats weighing approximately 100-120 gm %~re used in the present study.
Animals were allowed to access water and
standard laboratory diet a_d libitum. Chemical s: Guanine hydrochloride was obtained from Sigma Chemicals Co., U.S.A.
All the chemicals used were of Analytical grade and solutions
were prepared in glass distilled water. Preparation of homoqenate: Animals were killed by cervical dislocation, testis was immediately removed, cleaned of any adhering tissue and blood, and stored in cold till homogenization.
Homogenate (10Y. w/v) was
Pharmacological Research Communications, Vol. 16, No. 3, 1984
249
prepared in isotonic sucrose solution (0.25 _M) using motor driven Potter-ElvehJem homogenizer consisted of glass tube and Teflon pestle.
All the operation was carried out in cold (0-5~
Whole
homogenate was centrifuged in ~8frigerated K-24 Centrifuge at 15,000 g for 20 minutes, supernatant collected and used for guanine deaminase assay. Assay of Guanine demina'se actlvity. Guanine demin~se activity was d~termined spectrophotometrically by the disappearance of the substrata (guanine) according to the method of R~ush and Norris (1950) as reported previously (Saxena et al., 1980). Reaction mixture in a final vol~me of 2.0 m l contained Tris-HCl buffer (O.i M, p ~ 8.0, 1.0 ml)
suitable aliquot (0.2 ml)
of the enzyme i.e. 15,000 x g supernatant of rat testis ~mogenate, guanine (1.5 u mole, 0.5 ml of 3ram solution, pH 10.5-11) and water. Reaction was started by the addition of substrata after a preincubation of 5 rain. and stopped by the addition of perchloric acid (i0~ w/v, i.O ml) after an incubation of 15 rain. Tubes were centrifuged at 7~0 g for i0 rain and supernatant was diluted (30 fold) with water. The optical density (.D.) was measured at 245 nm in a Hitachi-Perkin Elmer UV-VXS spectrophotometer.
Simultaneously, suitable controls
were also carried out and the O.D. change w a s taken as an index of enzyme ~ct ivity. -Detenginat_iqon_o_f guanine damina s e
inhibitoi~7 . act_ivi~I
:
To determine the guanine dea~inase inhibitory activity compounds were dissolved in propylene glycol and adaed into the reaction mixture so that t ~
desired concentration was obtained in the final volume.
Simultaneously control e:~q~erlments, without inhibitor, ~ r e carried out which pz~vided total (i00~) activity.
also
On the basis of
Pharmacological Research Communications, Vol. 16, No. 3, 1984
250
optical density change, the percent residual activity in the experiments containing compounds and in turn percent inhibition was cal cul at e d. PuI~ULTS The I. P~ spectra of both the comi~unds showed characteristic bands of -N-C=O (1670 cm -1, quinazoline nucleus), -C=N (1630-1640 cml; imidazole ring) and primary amids group (1750 cm-l~.
When
compared with 4-amino-5-imidazole carboxamids both the coml~oUnds showed disappearance of a broad strong band (650-900 cm -I) for N - H bending. 2 ~4ethyl-3-( 5 ' -carboxamide-imidazol-4 ' -yl ~ quinazolln-4 (3H)-one sho%md 35% inhibition of guanine de agsinase, whereas the 2-ph~nyl-3-( 5 ' -carboxamido-imidazol-4 ' -yli -quinazolin-4 -(3H) -one sho~,~d 50~ inhibition m t a
final concentration of 2 x 10-4_M. At
At the same concentration 4-amino-5-imidazole carboxamide sho%md only 20~ inhibition. These values are the mean value of the three separate experiments done in duplicate. DISCUSSION The I. P~ data are in aga~aement with thQ structure assigned to these compounds.
The inhibition of guanine daaminase by these
compounds is also appreciable.
This study shows that effect of
phenyl gro'~p at position 2 of quinazolone is considerably higher th~n methyl group.
This is the first and preliminary re_port and
the possibility that further substitution may result still in better quanine deaminase in/%ibitors can not be ruled out. Quinazolones are widely used in medicine.
Probably, this is
the first r e p o ~ when quinazolones have been reported as guanine deaminase inhibitors.
Due to their appreciable guanine deaminase
inhibitory activity these compounds deserve further studies to test th~.ir value in combinction chemotherapy.
Pharmacological Research Communications. VoL 16. No. 3, 1984
251
Thar~cs are due to Professor K.P.Bhargava, M.D., Ph.D., F..~.M.So F.N.I., Head of the Department of Pharmacology, K i n g George' s Medical College,Lucknow,
India for his valuable suggestions and encoura~nent.
One of us (A.K.S.) is grateful to Indian Council of Medical Research, Nexz Delhi for providing flnancial assistance.
ERENC ES.
i.
Agarwal, J.C., Gupta, Y.K., Sinha, J.N., Bhargava, K.P. and Shanker, K. Pharmacol. ResoComm. 13, 49 (1981~.
2.
Baker, B.P~ and Siebeneick, H.U.J.Med.Chmn. l_~4, 799 (1971).
3.
Carlo, P.E. andMandel,
4.
Cook, A.H., Heilbron, I. and Smith,
5.
Commings, J.P~ and Stokey, E.H. Dru~ Research 1--3,661 (1963).
6.
Dubey, M., Ve~na, V.I<., S h a ~ e r , K., Sinha, J.N., BharTava,I<.P., and Kishor, ~<. PhazTaazie 34, 18 (I97911.
7.
Gellhorn, A., ~ngelman, M., Shapiro, D.,Graff, O.S. and Gillespie, I~ Cancer ~es. 1--0,170 (1950~.
8.
Goldin, A., Greenspan, Inst. II, 319 (195D).
9.
Goo~nan, Gilman, A., Goodman, L.S. and Gilmun, A. (eds.)., "Goodman and Gilman' s. The Pharmacological basis of therapeutics", 6th edn., MacMillan Publ.Co. ,inc. ,New York (1980)
i0.
Hirschber~,
ii.
Hoshi, A., Kt~uagai, K. and Kuratani, K.Ch~n.-Oharrn~. Bull.16 2080 (1968).
12.
Kanzawa, P., Hoshi, A., 1[ishimoto, T. and Kuretani, K. Chem. Pharma. Bull. 18,392 (1970).
13.
Kanza~a, P., Hoshi,A. andKuretani, K.Chem.Pharma.Bull 19. 1737 (1971).
14.
Kidder, G.W., Dewey, V.C., Parker, Science 109, 511 (1949).
I].G.Cancer .Rss. 14,459 (1955). E.J.Chem.Soc. 1440(1949).
S.M. and Schoenbmc]c, E.B.J.Nat.Cancer
E., Kre~u, J. a n d G e l l h o r n , ~ C a n c e r
Res. 12,524(1952).
P~S., Jr.~nd ~;oodsi~,G.L.
252
Pharmacological Research Communications, Vol. 16, No. 3, 1984
15.
Lehnin~er, A.L., Biochemistry, Worth Publishers, 742 (1975)o
16.
Madel, H.G., Way, J.L. and Smith, P.K.Biochem.Biophys.Acta.# 23, 402 (1957).
17.
BDbinson,D.H.
18.
Roush, A. and Nar~-is, E~
and Shaw, C.J.Chem.Soc.1715
Inc.New York,
(1972).
Arch.Biochsm.29,124
(1950).
19.
Saxena, A.K., Abroad, S., shanker, K., Bhargava, K.P. /
20.
Silipo, C. ~nd Hanset, C.J.Med.Chem. 19,62 (1976).
and
NEW GUANINE
243
DE~/~INASE INHIBITORS*
A.K.Saxena**, S.Ahmad, K.Shanker and K.Kisbor, Department of Pharmacology & Therapeutics, King George' s Medical College, Lucknow - 226003 (I%~DIA) Received in final form 3 October 1983
2-Aryl/alkyl-3-( 5 '-carboxamido-imidazol-4 ' -yl) -quina zolin4-( 3H) -ones have been reported as Guanine deaminase inhibitors. These compounds ~.~re prepared from 4-amino-5-1midazol-carboxamide and suitable 2-aryl/alkyl-benzoxazin-4-ones.
Compounds were
characterized by their m.ps., elemental analyses and I. P~ spectra. These compounds have shown significant inhibition, aryl substituent was more effective than alkyl group.
This is the first report when
qulnazolones have been reported as Guanine deam~nase inhibitors. Inhibitors of this enzyme can enhance the bioavailability of purina antagonists and in turn are helpful for the chemotherapy of cancer. INTRDDUCTION Guanine deminase ( ~..C.3,5,4,3., quanine-ami~hydrolase, juanase) is an important enzyme of purina catabolism which irreversibly deaminates guanine (I) into Xanthine (II), which is further metabolized to uric acid (III) by Xanthine oxidase (Lehniger, 1975). Role of purina antagonists in the chemotherapy of cancer is well documented.
8-Azagnanine (IV) was the first compound of this
type found to have antineoplastic activity (Kidder a.__ta_._l., 1949) and since than it has been reported to inhibit a number of tumours * Part of Ph.D.Thesis work of A.K.Saxena. ** For correspondence= Present address= Biochemistry Unit, Regional Research Laboratory, Jammu T a w i - 180001, (INDIA). 0031-6989/84/030243-10/$03.00/0
9 1984 The Italian Pharmacological Society
Pharmacological Research Communications, Vol. 16, No. 3, 1984
244
including Leukemia LI210 and Carcinoma 755 (Goldin et a!., 1950; Gellhorn et al., 1950).
6-Thioguanine (V~, mercaptopurine (Vl}
and 6-chloropurine (VIi) are other important purine antagonists in use (Goodman-Gilman, Goodman and Gilman,
1980).
Use of these metabolites is limited in the traahaent of cancer because of degradation of most of these compounds by guanine de~minase and the product so formed is biologically inactive (RDush and Norris, 1950).
Hirschborg et al . (1952) have shown that
turnouts with low guanine deaminase content respond better to 8 -azaguanine. In view of the biotransformation of purine antagonist by the enzYme guanine deaminase into a biologically inactive product, it is reasonable to postulate inhibitors of guanine deminase, if administered alongwith the drug, will enhance the bioavailability of the drug.
4-Amino-5-imidazole carboxamide (VIII), an inhibitor
of guanine deeminase, when administered alongwith 8-azaguanine potentiated antit~nour activity (Carlo and Mandel, 1955).
These
observations have developed interest into guanine de~-ninase inhibitors. Since then different workers have prepared c~npounds having guanine deaminase inhibitory activity (Hoshi et al., 1968 Kanzawa e t a_~l., 1970 and 1971; Baker e___ta_l., 1971, Silipo and Hansel,
1976; Saxena e_t a_~l., 1980). Quinazolones have been reported to possess diverse biological
activities (Ctmlnings and Stokey, 1963; Dubey e_t a___l., 1980, ~ a r w a l e_t a~l., 1981).
4-~nino-5-imidazole carboxamide has been reported
as an inhibitor of guanine deaminase (Mandel e___ta_l., 1957). With an aim to obtain guanine deminase inhibitors, chemotherapy of cancer,
due to t]~ir use in
it was thought worthwhile to prepare new
quinozolones by condensing benzoxain-4-ones with 4-amino-5imidazole carboxamide. report.
The present p a p e r deals with the preliminary
,-4
8 ro~o ! -rl
I
0
! 1--1
,-t
U')
P-I
,;
4
~o~
N
o.O 4J h
L'~
0,-I ~ 0
~8
~'~
il
.u
L~
-M I
L~
GO
9 ['~
0u~
9 LJ')
|
0~
-M -M
t~
0 '
U
,..4 {/1
~o~. ~.o~
0 ,,-t
0 [q
!
ro ~4J ~ ~h
I
~88~d ~ -,-t ..~ ~
0
9-;
d
~
Pharmacological Research Communications, Vol. 16, No. 3, 1984
246
OH
0
HoL # H
I
W
OH
0
H o ~ O H H TE
H2~ ~
E~
N H
gr r
H
0
HaN/~'Xn____ N
E~RIM~TAL The compounds were synthesized as shown in Scheme I and characterized by their melting points, elemental analyses and I. ;hspectra.
The melting IDoints were determined in open capill~ry
tube and reported uncorrected.
The experimental values for C,H
and N elements were within + O.4~ of the theoretical values,
All
the compounds w~re routinely checked for their homogenity by TLC on Silica gel G plates.
De%ails of synthetic methods are as below:
Pharmacological Research Communications, Vol. 16, No. 3, 1984
247
~ Icc%o COOH
NH~
RcocQ.
0
SC.. EM 4 -Amino-5 -imidazole Carboxamide. It was prepared from ethycyanoacetate (Aldrich Chemical Co., bland)
as reported by RDbinson and Shaw (1972) and Cook et el.,
( 1949). 2-Met hyl-bsnzoxazin-4 -o ne. Anthranilic acid (0.05 mole) was refluKed in exCess of freshly distilled acetic anhydride.
Excess of the acetic anhydride was
distilled off and the residue was recrystallized from hexane.
Pharmacological Research Communications, I/ol. 16, No. 3, 1984
248
2-P henyl-benzoxa zin-4 -one. Anthranilic acid (0.I mole) and benzyl chloride in equimolar proportion were taken in pyridine (50 el) and the mixture was stirred below i0 ~ for 1-2 hr.
Residue was washed with ice-cold water and
recrystallized from alcohol. _22-M@thy1-3 -( 5' -ca_rbo_xmn~.i do_imid@zQ1-4 ' -yl) quinazolin-4 -(3H) -one. 2-Methyl-b~nzoxazin-4-one (0.02 mole) was heated with 4-amino-5, imidazole carboxamide in equimolar concentration for 5-10 sin.
The
jelly like mass was obtained which was recrystallized from alcohol. 2-Phenyl-3_-(5 '-carboxamide-imidazol-4 '-yl) quinazolin-4-(3H) -one. 2-Phenyl-benzoxazin-4-one (0.05 mole) and 4-~nino-5-imidazole carboxamide in equimolar concentration w e r e mixed in pyridine (50 el) and water (25 ml); and the reaction mixture was refluxed for 6 hrs. The major portion of pyridine was distilled off at reduced pressure. The residue was digested with N HCI (20 el) for 2 hrs. on water bath.
The solid separated was filtered and recrystallized from
alcohol. BIOLOGICAL
STUDIES
Animal s,: Adult albino rats weighing approximately 100-120 gm %~re used in the present study.
Animals were allowed to access water and
standard laboratory diet a_d libitum. Chemical s: Guanine hydrochloride was obtained from Sigma Chemicals Co., U.S.A.
All the chemicals used were of Analytical grade and solutions
were prepared in glass distilled water. Preparation of homoqenate: Animals were killed by cervical dislocation, testis was immediately removed, cleaned of any adhering tissue and blood, and stored in cold till homogenization.
Homogenate (10Y. w/v) was
Pharmacological Research Communications, Vol. 16, No. 3, 1984
249
prepared in isotonic sucrose solution (0.25 _M) using motor driven Potter-ElvehJem homogenizer consisted of glass tube and Teflon pestle.
All the operation was carried out in cold (0-5~
Whole
homogenate was centrifuged in ~8frigerated K-24 Centrifuge at 15,000 g for 20 minutes, supernatant collected and used for guanine deaminase assay. Assay of Guanine demina'se actlvity. Guanine demin~se activity was d~termined spectrophotometrically by the disappearance of the substrata (guanine) according to the method of R~ush and Norris (1950) as reported previously (Saxena et al., 1980). Reaction mixture in a final vol~me of 2.0 m l contained Tris-HCl buffer (O.i M, p ~ 8.0, 1.0 ml)
suitable aliquot (0.2 ml)
of the enzyme i.e. 15,000 x g supernatant of rat testis ~mogenate, guanine (1.5 u mole, 0.5 ml of 3ram solution, pH 10.5-11) and water. Reaction was started by the addition of substrata after a preincubation of 5 rain. and stopped by the addition of perchloric acid (i0~ w/v, i.O ml) after an incubation of 15 rain. Tubes were centrifuged at 7~0 g for i0 rain and supernatant was diluted (30 fold) with water. The optical density (.D.) was measured at 245 nm in a Hitachi-Perkin Elmer UV-VXS spectrophotometer.
Simultaneously, suitable controls
were also carried out and the O.D. change w a s taken as an index of enzyme ~ct ivity. -Detenginat_iqon_o_f guanine damina s e
inhibitoi~7 . act_ivi~I
:
To determine the guanine dea~inase inhibitory activity compounds were dissolved in propylene glycol and adaed into the reaction mixture so that t ~
desired concentration was obtained in the final volume.
Simultaneously control e:~q~erlments, without inhibitor, ~ r e carried out which pz~vided total (i00~) activity.
also
On the basis of
Pharmacological Research Communications, Vol. 16, No. 3, 1984
250
optical density change, the percent residual activity in the experiments containing compounds and in turn percent inhibition was cal cul at e d. PuI~ULTS The I. P~ spectra of both the comi~unds showed characteristic bands of -N-C=O (1670 cm -1, quinazoline nucleus), -C=N (1630-1640 cml; imidazole ring) and primary amids group (1750 cm-l~.
When
compared with 4-amino-5-imidazole carboxamids both the coml~oUnds showed disappearance of a broad strong band (650-900 cm -I) for N - H bending. 2 ~4ethyl-3-( 5 ' -carboxamide-imidazol-4 ' -yl ~ quinazolln-4 (3H)-one sho%md 35% inhibition of guanine de agsinase, whereas the 2-ph~nyl-3-( 5 ' -carboxamido-imidazol-4 ' -yli -quinazolin-4 -(3H) -one sho~,~d 50~ inhibition m t a
final concentration of 2 x 10-4_M. At
At the same concentration 4-amino-5-imidazole carboxamide sho%md only 20~ inhibition. These values are the mean value of the three separate experiments done in duplicate. DISCUSSION The I. P~ data are in aga~aement with thQ structure assigned to these compounds.
The inhibition of guanine daaminase by these
compounds is also appreciable.
This study shows that effect of
phenyl gro'~p at position 2 of quinazolone is considerably higher th~n methyl group.
This is the first and preliminary re_port and
the possibility that further substitution may result still in better quanine deaminase in/%ibitors can not be ruled out. Quinazolones are widely used in medicine.
Probably, this is
the first r e p o ~ when quinazolones have been reported as guanine deaminase inhibitors.
Due to their appreciable guanine deaminase
inhibitory activity these compounds deserve further studies to test th~.ir value in combinction chemotherapy.
Pharmacological Research Communications. VoL 16. No. 3, 1984
251
Thar~cs are due to Professor K.P.Bhargava, M.D., Ph.D., F..~.M.So F.N.I., Head of the Department of Pharmacology, K i n g George' s Medical College,Lucknow,
India for his valuable suggestions and encoura~nent.
One of us (A.K.S.) is grateful to Indian Council of Medical Research, Nexz Delhi for providing flnancial assistance.
ERENC ES.
i.
Agarwal, J.C., Gupta, Y.K., Sinha, J.N., Bhargava, K.P. and Shanker, K. Pharmacol. ResoComm. 13, 49 (1981~.
2.
Baker, B.P~ and Siebeneick, H.U.J.Med.Chmn. l_~4, 799 (1971).
3.
Carlo, P.E. andMandel,
4.
Cook, A.H., Heilbron, I. and Smith,
5.
Commings, J.P~ and Stokey, E.H. Dru~ Research 1--3,661 (1963).
6.
Dubey, M., Ve~na, V.I<., S h a ~ e r , K., Sinha, J.N., BharTava,I<.P., and Kishor, ~<. PhazTaazie 34, 18 (I97911.
7.
Gellhorn, A., ~ngelman, M., Shapiro, D.,Graff, O.S. and Gillespie, I~ Cancer ~es. 1--0,170 (1950~.
8.
Goldin, A., Greenspan, Inst. II, 319 (195D).
9.
Goo~nan, Gilman, A., Goodman, L.S. and Gilmun, A. (eds.)., "Goodman and Gilman' s. The Pharmacological basis of therapeutics", 6th edn., MacMillan Publ.Co. ,inc. ,New York (1980)
i0.
Hirschber~,
ii.
Hoshi, A., Kt~uagai, K. and Kuratani, K.Ch~n.-Oharrn~. Bull.16 2080 (1968).
12.
Kanzawa, P., Hoshi, A., 1[ishimoto, T. and Kuretani, K. Chem. Pharma. Bull. 18,392 (1970).
13.
Kanza~a, P., Hoshi,A. andKuretani, K.Chem.Pharma.Bull 19. 1737 (1971).
14.
Kidder, G.W., Dewey, V.C., Parker, Science 109, 511 (1949).
I].G.Cancer .Rss. 14,459 (1955). E.J.Chem.Soc. 1440(1949).
S.M. and Schoenbmc]c, E.B.J.Nat.Cancer
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