Potential antitumor agents. 24. Synthesis and pharmacological behavior of imidazo[2,1-b]thiazole guanylhydrazones bearing at least one chlorine

Article abstract of DOI:10.1021/jm9509307

In connection with a previous research dealing with the antitumor activity of imidazo[2,1-b]-thiazole guanylhydrazones, this paper reports the synthesis of new derivatives which were tested for antitumor and positive inotropic activity. In most cases the cytotoxic data from the in vitro experiments (HeLa) were in agreement with the antitumor data in vivo (Ehrlich). The active compounds bear a phenyl ring at the 6 position. On the other hand, the most active cardiotonic agents were devoid of the phenyl ring.

Full text of DOI:10.1021/jm9509307

2852
J . Med. Chem. 1996, 39, 2852-2855
Notes
P oten tia l An titu m or Agen ts. 24.1 Syn th esis a n d P h a r m a cologica l Beh a vior of
Im id a zo[2,1-b]th ia zole Gu a n ylh yd r a zon es Bea r in g a t Lea st On e Ch lor in e
Aldo Andreani,*,† Mirella Rambaldi,† Alberto Leoni,† Alessandra Locatelli,† Rosaria Bossa,‡ Alessandra Fraccari,‡
Iraklis Galatulas,‡ and Gaetano Salvatore‡
Dipartimento di Scienze Farmaceutiche, Universita` di Bologna, Via Belmeloro 6, 40126 Bologna, Italy, and Dipartimento di
Farmacologia C.T.M., Universita` di Milano, Via Vanvitelli 32, 20129 Milano, Italy
Received December 20, 1995X
In connection with a previous research dealing with the antitumor activity of imidazo[2,1-b]-
thiazole guanylhydrazones, this paper reports the synthesis of new derivatives which were
tested for antitumor and positive inotropic activity. In most cases the cytotoxic data from the
in vitro experiments (HeLa) were in agreement with the antitumor data in vivo (Ehrlich). The
active compounds bear a phenyl ring at the 6 position. On the other hand, the most active
cardiotonic agents were devoid of the phenyl ring.
Sch em e 1a
In a previous paper of this series,2 we briefly reviewed
the pharmacological behavior of guanylhydrazones (in
the meantime exhaustive reviews on the medicinal
chemistry of amidines/imidates,3 amidinohydrazones,4,5
amidines/guanidines,6 and thiosemicarbazones7 have
been published) and reported synthesis, configuration,
and antitumor activity of a number of imidazo[2,1-b]-
thiazole guanylhydrazones 3 (Scheme 1) where x ) y )
CH or CH2.
Taking into account that some guanylhydrazones
have been reported as cardiotonic agents,8-10 we decided
to test even the positive inotropic activity of our
compounds. We demonstrated that a potent cardiotonic
agent can antagonize11 the cardiotoxicity of doxoru-
bicin,12-16 and we pointed out17 that a molecule endowed
with both antitumor and cardiotonic activity could be
useful to potentiate the antitumor activity of doxorubi-
cin (thus allowing the reduction of its dosage) and to
counteract its harmful effects on the heart. While a
search for such a molecule in the field of phenothiazine
derivatives was unsuccessful,17 we obtained the first
encouraging result with some of the aforementioned2
imidazo[2,1-b]thiazole guanylhydrazones. As a result
of this research, we found that only compounds bearing
a chlorine or a chlorophenyl group at position 6 could
be useful for both the activities.18
In this paper we wish to describe a new series of
compounds 3 with the imidazo[2,1-b]thiazole (x ) CH)
or thiazoline (x ) CH2) moiety bearing two or three
chlorine atoms at the phenyl ring (3a -d , see Table 1)
in order to study the influence of the substituents at
the 6 position while maintaining, at the 2-3 positions,
the same groups present in the previously described
compounds.2 Moreover we prepared a series of com-
pounds 3 bearing different substituents at the 2-3
positions (3e-l) in order to see the influence of these
groups while maintaining, at the 6 position, the same
pharmacophores (Cl and 4-ClC6H4) present in the
aforementioned antitumor agents.2
a
For R, x, and y, see Table 1.
Ch em istr y
The guanylhydrazones 3a -l were prepared by reac-
tion of aminoguanidine with the appropriate aldehydes
2a -l. Some of them are reported in the literature (see
Table 1), and the others are described in the Experi-
mental Section starting from the corresponding imidazo-
[2,1-b]thiazoles 1.
As we demonstrated for analogous guanylhydrazones,
even compounds 3a -l belong to the E configuration
since they show the same spectroscopic features previ-
ously reported2 and, in particular, (1) NOE (useful in
1
the study of configuration) and (2) H-NMR spectra of
the hydrochlorides different from those of the bases
(useful data in the determination of the tautomeric
forms).
P h a r m a cologica l Resu lts
Compounds 3a -l were subjected to a cytotoxic test
in vitro (HeLa cells), to an antitumor test in vivo
(Ehrlich ascites in mice), and to a cardiotonic test on
isolated guinea pig atria. From the results of these
tests, reported in Table 3, it is evident that the phenyl
ring (3a -d ,f,h ,j,l) is essential to the cytotoxic and
antitumor activity since all the 6-chloro derivatives
(3e,g,i,k ) were inactive. The introduction of more than
one chlorine on the phenyl ring (3a -d ) does not bring
an improvement in the antitumor activity compared to
the monochlorophenyl derivatives previously tested.2
Generally speaking, the compounds devoid of cytotoxic
† Universita` di Bologna.
‡ Universita` di Milano.
X Abstract published in Advance ACS Abstracts, J une 15, 1996.
S0022-2623(95)00930-7 CCC: $12.00 © 1996 American Chemical Society

Notes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2853
Ta ble 1. Guanylhydrazones 3a -l
starting compd
compd
x
y
R
1
2
formula (MW)
mp, °C
3a
3b
3c
3d
3e
3f
3g
3h
3i
CH
CH
CH
CH
CH2
CH2
CH
2,4-Cl2C6H3
2,3,4-Cl3C6H2
2,4-Cl2C6H3
2,3,4-Cl3C6H2
Cl
4-ClC6H4
Cl
4-ClC6H4
Cl
1a a
1b
2a a
2b
2ca
2d
2eb
2fb
2g
2h
2i
C13H10Cl2N6S‚2HCl‚H2O (444.2)
C13H9Cl3N6S‚2HCl‚H2O (478.6)
C13H12Cl2N6S‚2HCl‚H2O (446.2)
C13H11Cl3N6S‚2HCl‚H2O (480.6)
C8H9ClN6S‚HCl‚2H2O (329.2)
C14H13ClN6S‚HCl‚2H2O (405.3)
C8H9ClN6S‚2HCl‚H2O (347.6)
C14H13ClN6S‚2HCl‚H2O (423.7)
C9H11ClN6S‚HCl‚H2O (325.2)
C15H15ClN6S‚2HCl‚H2O (437.8)
C7H6Cl2N6S‚HCl‚H2O (331.6)
C13H10Cl2N6S‚2HCl‚H2O (444.2)
298-302 dec
308-310 dec
265-270 dec
215-220 dec
168-170 dec
298-300 dec
205-207 dec
244-246 dec
210-215 dec
258-260
CH2
CH2
CCH3
CCH3
CH
1ca
1d
1eb
1fc
1gd
1h e
1if
1j
CH
CCH3
CCH3
CCH3
CCH3
CH
CH
CCH3
CCH3
CCl
3j
3k
3l
4-ClC6H4
Cl
4-ClC6H4
2j
2k
2l
1k f
1l
195-198 dec
310-313 dec
CCl
CH
a
b
d
Reference 19. Reference 20. c Reference 21. Reference 22. e Reference 23. f Reference 24.
Ta ble 2. IR and 1H-NMR Data of the Guanylhydrazones 3a -l as Hydrochlorides
compd
IR:a
ν
max, cm-1
1H-NMR:b δ, ppm
3a
3b
1680, 1630, 1490, 1165
1680, 1605, 1160, 840
7.59 (1H, d, th, J ) 4.4), 7.60 (2H, s, ar), 7.85 (1H, s, ar), 8.07 (1H, s CH), 8.73 (1H, d, th, J ) 4.4)
7.58 (1H, d, ar, J ) 8.4), 7.59 (1H, d, th, J ) 4.5), 7.80 (1H, d, ar, J ) 8.4), 8.07 (1H, s, CH),
8.73 (1H, d, th, J ) 4.4)
3c
3d
1680, 1610, 1160, 1105
1675, 1620, 1500, 1170
4.04 (2H, t, thn, J ) 7.4), 4.66 (2H, t, thn, J ) 7.4), 7.50 (1H, d, ar, J ) 8),
7.55 (1H, dd, ar, J ) 2, 8), 7.79 (1H, d, ar), 7.88 (1H, s, CH)
4.04 (2H, t, thn, J ) 7.4), 4.66 (2H, t, thn, J ) 7.4), 7.49 (1H, d, ar, J ) 8.4),
7.77 (1H, d, ar, J ) 8.4), 7.90 (1H, s, CH)
2.50 (3H, d, CH3, J ) 1.5), 8.26 (1H, s, CH), 8.43 (1H, q, th, J ) 1.5)
2.50 (3H, d, CH3, J ) 1.5), 7.53 (2H, d, ar, J ) 8), 7.69 (2H, d, ar, J ) 8),
8.43 (1H, q, th, J ) 1.5), 8.46 (1H, s, CH)
2.58 (3H, d, CH3, J ) 1.5), 7.13 (1H, q, th, J ) 1.5), 8.50 (1H, s, CH)
2.57 (3H, d, CH3, J ) 1.5), 7.10 (1H, q, th, J ) 1.5), 7.54 (2H, d, ar, J ) 8),
7.72 (2H, d, ar, J ) 8), 8.50 (1H, s, CH)
3e
3f
1670, 1620, 1245, 1155
1680, 1625, 1600, 1165
3g
3h
1675, 1630, 1500, 1340
1675, 1620, 1515, 1190
3i
3j
3k
3l
1670, 1610, 1265, 1130
1680, 1600, 1510, 1090
1675, 1620, 1240, 1150
1680, 1600, 1490, 1165
2.35 (3H, s, CH3), 2.48 (3H, s, CH3), 8.50 (1H, s, CH)
2.38 (3H, s, CH3), 2.47 (3H, s, CH3), 7.52 (2H, d, ar, J ) 8), 7.71 (2H, d, ar, J ) 8), 8.51 (1H, s, CH)
8.30 (1H, s, CH), 8.90 (1H, s th)
7.56 (2H, d, ar, J ) 8), 7.71 (2H, d, ar, J ) 8), 8.48 (1H, s, CH), 8.90 (1H, s, th)
a
b
The NH group give broad bands in the range 3600-2300 cm-1
.
The NH groups give a broad signal at ∼8 ppm (3H) and a singlet at
∼12 ppm (1H). Abbreviations: th ) thiazole, thn ) thiazoline, ar ) aromatic.
Ta ble 3. Pharmacological Activity of Compounds 3a -l
Emax (mean of 3-4 atria)
Ehrlich
% ∆ from base line
conctn to
obtain Emax (µg)
compd
HeLa IC50 (µg)
% T/C
mg/kg ip
value ) 100a
EC50
∆ rate (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
2.5
2
5
146
180
200
166
106
166
106
133
100
140
120
166
180
200
25
12.5
50
50
50
6.25
50
25
100 ( 0
100 ( 0
119 ( 3
111 ( 4
146 ( 3
106 ( 3
134 ( 3
115 ( 0
137 ( 3
118 ( 2
135 ( 1
100 ( 0
20
20
16
10
16
16
8
6
9
4
0.5
3
4
3
9
3
-30
-13
-21
-11
-26
-29
-20
-17
-34
2.5
>10
1.5
>10
2
>10
50
3j
3k
3l
2
12.5
100
12.5
100
1
20
16
>10
0.6
6
5-fluorouracil
doxorubicin
sulmazole
0.005
163 ( 9
350
15
a
Initial contractile force: 0.4 ( 0.1 g.
and antitumor activity (3e,g,i,k ) were the most active
cardiotonic agents even though a negative chronotropic
effect was observed in all the experiments (see Table
3). The simultaneous presence of both antitumor and
borderline positive inotropic activity was confirmed in
compounds 3c,j.
As far as the substituents at the 2-3 positions are
concerned, it is interesting to point out that, contrary
to the unsubstituted compounds previously described,2,18
in the analogs bearing one or two substituents (3e-l) a
separation between the two activities was observed. The
chlorophenyl derivatives (3f,h ,j,l) showed mainly cyto-
toxic (HeLa) and antitumor (Ehrlich) activity, whereas
the chloro derivatives (3e,g,i,k ) showed cardiotonic
activity only.
Exp er im en ta l Section
Ch em istr y. The melting points are uncorrected. Elemen-
tal analyses (C, H, N) were within (0.4% of the theoretical
values. Bakerflex plates (silica gel IB2-F) were used for TLC;
the eluent was a mixture of petroleum ether (60-80 °C)/
acetone in the proportion of 50/50 (containing 0.1% of concen-
trated NH4OH for the guanylhydrazones which were analyzed
as free bases). The IR spectra were recorded in Nujol on a
Perkin-Elmer 298 spectrometer; the 1H-NMR spectra were

2854 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Notes
recorded in DMSO-d6 (CDCl3 for compound 2b only) on a
Varian Gemini spectrometer (300 MHz), and J values are
reported in hertz (Hz).
dec; νmax 1650, 1400, 1340, 1315 cm-1; δ (ppm) 7.58 (2H, d, ar,
J ) 8), 7.91 (2H, d, ar, J ) 8), 8.65 (1H, s, th), 9.89 (1H, s,
CHO).
Syn th esis of th e Im id a zo[2,1-b]th ia zoles 1. The ap-
propriate 2-aminothiazole or thiazoline (20 mmol) was dis-
solved in acetone (100 mL) and treated with the equivalent of
the appropriate 2-bromoacetophenone. The mixture was re-
fluxed for 6-8 h, and the resulting salt was collected by
filtration, washed with acetone, and refluxed for 2 h with 500
mL of 1 N HBr. Before complete cooling, the resulting solution
was cautiously basified with 20% NH4OH, in order to precipi-
tate the crude compound 1 which was crystallized from ethanol
with a yield of 50-60%.
6-(2,3,4-Tr ich lor op h en yl)im id a zo[2,1-b]th ia zole (1b):
C11H5Cl3N2S (303.6); mp 202-205 °C; νmax 1550, 1520, 1200,
640 cm-1; δ (ppm) 7.36 (1H, d, th, J ) 4.4), 7.72 (1H, d, ar, J
) 8.8), 7.98 (1H, d, th, J ) 4.4), 8.14 (1H, d, ar, J ) 8.8), 8.52
(1H, s, H-5).
6-(2,3,4-Tr ich lor oph en yl)-2,3-dih ydr oim idazo[2,1-b]th i-
a zole (1d ): C11H7Cl3N2S (305.6); mp 175-177 °C; νmax 1530,
1355, 1210, 830 cm-1; δ (ppm) 3.93 (2H, t, thn, J ) 7.4), 4.27
(2H, t, thn, J ) 7.4), 7.63 (1H, d, ar, J ) 8.8), 8.02 (1H, d, ar,
J ) 8.8), 8.02 (1H, s, H-5).
6-(4-Ch lor op h e n yl)-2,3-d im e t h ylim id a zo[2,1-b]t h i-
a zole (1j): C13H11ClN2S (262.8); mp 190-194 °C dec; νmax 1535,
1085, 825, 725 cm-1; δ (ppm) 2.32 (3H, s, CH3), 2.33 (3H, s,
CH3), 7.43 (2H, d, ar, J ) 8), 7.83 (2H, d, ar, J ) 8), 8.22 (1H,
s, H-5).
2-Ch lor o-6-(4-ch lor op h en yl)im id a zo[2,1-b]th ia zole (1l):
C11H6Cl2N2S (269.1); mp 220-225 °C dec; νmax 1535, 1185,
1090, 1000, 830, 730 cm-1; δ (ppm) 7.47 (2H, d, ar, J ) 8),
7.87 (2H, d, ar, J ) 8), 8.31 (1H, s, th), 8.34 (1H, s, H-5).
Syn th esis of th e Ald eh yd es 2. The Vilsmeier reagent was
prepared at 0-5 °C by dropping POCl3 (20 mmol) into a stirred
solution of DMF (25 mmol) in CHCl3 (5 mL). Compound 1
(10 mmol) in CHCl3 (60 mL) was added dropwise to the
Vilsmeier reagent while maintaining stirring and cooling. The
reaction mixture was kept for 3 h at room temperature and
under reflux for 8 h. Chloroform was removed under reduced
pressure, and the resulting oil was poured onto ice. The crude
aldehyde 2 thus obtained was collected by filtration and
crystallized from ethanol with a yield of 60-70%.
Syn th esis of th e Gu a n ylh yd r a zon es 3. The appropriate
aldehyde 2 (5 mmol) was dissolved in 150 mL of ethanol and
treated with 5 mmol of aminoguanidine hydrochloride, pre-
pared in turn from an ethanol suspension of aminoguanidine
bicarbonate and excess of 37% hydrochloric acid. The reaction
mixture was refluxed for 30 min, and the resulting precipitate
was collected by filtration with a yield of 80-90% (see Tables
1 and 2).
P h a r m a cology. (a ) In Vitr o An titu m or Activity. Stock
cultures of HeLa cells were plated on Falcon plastic dishes
(150 cells/plate) in MEM (minimum essential medium; Whit-
taker-M.A. Bioproducts) and incubated at 37 °C in 5% CO2.
The compounds under test, dissolved in DMSO (1-10 µL/mL),
were added directly to the growth medium after 48 h; the
amount of DMSO, previously used in analogous experiments,
did not affect cell growth. At the end of the drug exposure
period (48 h), the growth medium was removed and a new
medium was added. Colonies that contained more than 50
cells were counted after 7 days of incubation, and IC50 values
were calculated. Compounds displaying IC50 < 4 µg/mL are
considered significantly active.
(b) In Vivo An titu m or Activity. One group of animals
included 10 female Swiss mice (average weight 24 ( 1 g) which
were implanted with 106 Ehrlich ascites tumor cells from donor
mice. After 24 h each group was treated ip with a single dose
(100 mg/kg) of the test compound dissolved in DMSO (0.05
mL/mouse); the amount of DMSO, previously used in analo-
gous experiments, did not affect tumor growth. If the dose
was toxic or active, the test was repeated at halved doses
(range 100-3.125 mg/kg). Deaths were recorded for a period
of 40 days. The activity was measured as the ratio of the mean
survival time of the test animals to that of the control (10 mice
receiving vehicle only) expressed as a percentage (% T/C).
Significant activity is achieved as 25% increase in the life span
(T/C g 125).
(c) P ositive In otr op ic Activity. The experiments were
carried out on spontaneously beating guinea pig (300-450 g
of body weight) atria. The preparation was suspended at 37
°C in a 20 mL bath of Tyrode solution (composition in g/L:
NaCl, 8.0; NaHCO3, 1.0; KCl, 0.2; NaH2PO4, 0.005; MgCl2, 0.1;
CaCl2, 0.2; glucose, 1.0). An initial tension of 1 g was applied
to the preparation. Isometric contractions were recorded by
a strain gauge transducer connected to a recording micrody-
namometer. After taking basal responses, the test compounds
were added to the preparation at 5-800 µmol on a cumulative
basis, and the responses were recorded. The contact time for
each dose was 5 min. Concentrations producing 50% of the
maximal effect (EC50) were calculated from concentration-
response curves.25
6-(2,3,4-Tr ich lor op h en yl)im id a zo[2,1-b]th ia zole-5-ca r -
boxa ld eh yd e (2b): C12H5Cl3N2OS (331.6); mp 255-258 °C;
ν
max 1655, 1320, 1265, 1180 cm-1; δ (ppm) 7.15 (1H, d, th, J )
4.4), 7.45 (1H, d, ar, J ) 8.4), 7.55 (1H, d, ar, J ) 8.4), 8.39
(1H, d, th, J ) 4.4), 9.64 (1H, s, CHO).
6-(2,3,4-Tr ich lor oph en yl)-2,3-dih ydr oim idazo[2,1-b]th i-
a zole-5-ca r boxa ld eh yd e (2d ): C12H7Cl3N2OS (333.6); mp
209-212 °C dec; νmax 1650, 1310, 1295, 1180 cm-1; δ (ppm)
4.06 (2H, t, thn, J ) 7.4), 4.52 (2H, t, thn, J ) 7.4), 7.58 (1H,
d, ar, J ) 8.4), 7.77 (1H, d, ar, J ) 8.4), 9.39 (1H, s, CHO).
6-Ch lor o-3-m et h ylim id a zo[2,1-b]t h ia zole-5-ca r b oxa l-
d eh yd e (2g): C7H5ClN2OS (200.6); mp 153-155 °C dec; νmax
1660, 1350, 1315, 1270 cm-1; δ (ppm) 2.68 (3H, s, CH3), 7.21
(1H, s, th), 9.73 (1H, s, CHO).
6-(4-Ch lor op h en yl)-3-m eth ylim id a zo[2,1-b]th ia zole-5-
ca r boxa ld eh yd e (2h ): C13H9ClN2OS (276.7); mp 197-200 °C;
νmax 1665, 1400, 1340, 830 cm-1; δ (ppm) 2.72 (3H, s, CH3),
7.15 (1H, s, th), 7.57 (2H, d, ar, J ) 8), 7.84 (2H, d, ar, J ) 8),
9.73 (1H, s, CHO).
6-Ch lor o-2,3-d im eth ylim id a zo[2,1-b]th ia zole-5-ca r box-
a ld eh yd e (2i): C8H7ClN2OS (214.7); mp 130-134 °C; νmax
1670, 1300, 1270, 855 cm-1; δ (ppm) 2.37 (3H, s, CH3), 2.60
(3H, s, CH3), 9.72 (1H, s, CHO).
6-(4-Ch lor oph en yl)-2,3-dim eth ylim idazo[2,1-b]th iazole-
5-ca r boxa ld eh yd e (2j): C14H11ClN2OS (290.8); mp 210-214
°C; νmax 1665, 1340, 1320, 1090 cm-1; δ (ppm) 2.40 (3H, s, CH3),
2.65 (3H, s, CH3), 7.57 (2H, d, ar, J ) 8), 7.83 (2H, d, ar, J )
8), 9.71 (1H, s, CHO).
Ack n ow led gm en t. This work was supported by a
grant from Ministero dell’Universita` e della Ricerca
Scientifica e Tecnologica (MURST).
Refer en ces
(1) For part 23, see: Andreani, A.; Rambaldi, M.; Locatelli, A.;
Andreani, F.; Lollini, P. L.; Nanni, P.; Bossa, R.; Galatulas, I.
Cytotoxic and Differentiating Activity of Compounds Related to
Hexamethylenebisacetamide. Farmaco 1993, 48, 1503-1513.
(2) Andreani, A.; Rambaldi, M.; Locatelli, A.; Bossa, R.; Fraccari,
A.; Galatulas, I. Potential Antitumor Agents. 21. Structure
Determination and Antitumor Activity of Imidazo[2,1-b]thiazole
Guanylhydrazones. J . Med. Chem. 1992, 35, 4634-4637.
(3) Patai, S.; Rappoport, Z. The Chemistry of Amidines and Imidates;
Wiley: Chichester, U.K., 1991; Vol. 2.
(4) Richter, P. H.; Wunderlich, I.; Schleuder, M.; Keckeis, A.
Amidinohydrazone als Gegenstand der Arzneistofforschung
(Amidinohydrazones as Target Compounds in Drug Research).
Pharmazie 1993, 48, 83-94.
(5) Richter, P. H.; Wunderlich, I.; Schleuder, M.; Keckeis, A.
Amidinohydrazone als Gegenstand der Arzneistofforschung.
2,6-D ic h lo r o im id a zo [2,1-b ]t h ia zo le -5-c a r b o x a ld e -
h yd e (2k ): C6H2Cl2N2OS (221.1); mp 180-183 °C; νmax 1650,
1500, 1295, 1255 cm-1; δ (ppm) 8.64 (1H, s, th), 9.75 (1H, s,
CHO).
2-Ch lor o-6-(4-ch lor op h en yl)im id a zo[2,1-b]t h ia zole-5-
ca r boxa ld eh yd e (2l): C12H6Cl2N2OS (297.2); mp 178-180 °C
Teil
2 (Amidinohydrazones as Target Compounds in Drug
Research. Part 2). Pharmazie 1993, 48, 163-184.
(6) Greenhill, J . V.; Lue, P. Amidines and Guanidines in Medicinal
Chemistry. Prog. Med. Chem. 1993, 30, 203-326.

Notes
(7) Liu, M. C.; Lin, T. S.; Sartorelli, A. C. Chemical and Biological
Properties of Cytotoxic R-(N)-Heterocyclic Carboxaldehyde Thio-
semicarbazones. Prog. Med. Chem. 1995, 32, 1-35.
(8) Mutschler, E.; Scherf, H.; Voss, P.; Wassermann, O. Relations
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