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Metabolic Transformation of Antimalarial Drugs as a Basis for the Development of New Active Substances.

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In the extraction of the lanthanides by TBP, the distribution
coefficient is not a monotonic function of the atomic number,
but deviations occur in the Gd-Dy region. D . G. Karracker
(Aiken, S.C., USA) showed, by spectroscopic investigations,
that this is due to a change in the coordination number of the
extracted complexes Ln(NO3)3(TBP)3 (Ln = lanthanide).
The band shape of the hypersensitive transitions in these
Ln(NO,),(TBP), complexes suggests a coordination number
of 8 for Nd3+, 6 for Er3r, and 6 or 7 for Ho3+. Corresponding
results were obtained with different trialkyl phosphates and
with tri-n-amylphosphine oxide as ligands. 31P- and 1H-NMR
spectra strongly confirm these conclusions, while the Raman
spectra seem to indicate bidentate bonding of the nitrate ions,
also in the case of the heavy lanthanides.
CeIII, like all trivalent lanthanides, is extracted by bis(2ethylhexyl) hydrogen phosphate (HDEHP). As L. A . Bray
(Richmond, Wash., USA) has observed, CelI1 is oxidized to
CeIV during washing of the organic phase with a concentrated
(6 to 7 M) nitrate solution. Likewise, CeIlr is oxidized to
CeIv when it is extracted from concentrated nitrate solutions.
Oxidation is complete within 30 sec and proceeds equally
fast both in air and in a n argon atmosphere. However, if a
nitrite “scavenger” such as sulfamic acid is added, the rate
of oxidation is considerably reduced. Evidently the nitrous
acid (or one of its reaction products) acts as a catalyst in the
oxidation. The above effect is significant in the separation of
cerium from the other lanthanides.
6. Solvent Extraction: Technical Applications
A flow scheme for the isolation of the transplutonium elements americium and curium from highly radioactive Purex
The most important application of liquid-liquid extraction in
waste solutions was developed by G. Koch (Karlsruhe, Gerrecent years has been the processing of spent nuclear fuels in
many). Americium, curium, and the lanthanides are extractwhich uranium and plutonium are separated from fission
ed by HDEHP from the citrate-complexed aqueous phase.
products by extraction with tributyl phosphate (TBP) from
Americium and curium are partitioned away from the rare
nitric acid solution (Purex process). In the processing of fuels
earths by selective back-extraction of the actinides by an
with high plutonium concentrations (in particular those from
aqueous solution, which is 1 M in lactic acid and 0.05 M in
fast breeder reactors), the concentrations of uranium and
sodium diethylenetriaminepentaacetate and is adjusted to a pH
plutonium change in each stage of the multi-stage Purex
of cu. 3. The flow sheet was tested with weakly active synthetic
process, and since each of the two metals influences the exsolutions and gave good decontamination factors for lanthtraction of other, the distribution coefficients are also altered
anides, zirconium, niobium, ruthenium, and iron. Kinetic
in each stage. Consequently, optimization of the process by
experiments showed that in the case of several elements, the
calculation is difficult. W. Ochsenfeld (Karlsruhe, Germany)
extraction kinetics plays a dominant role in the purification
now reported o n the development of empirical functions for
effect. For example, on the basis of equilibrium distribution
the calculation of the distribution coefficients in the system
coefficients iron(m) would be expected to accompany the
P u ( N O & - U O ~ ( N O ~ ) ~ - H N O ~ - T B P - ~ - ~The
O ~equi~ C ~ ~ ~ .actinides, but since the extraction as well as the back-extraction
librium “constants” for the extraction equilibrium
are slow, a good separation from iron is accomplished in the
countercurrent process.
The extraction of lanthanides as tartrate or malonate complexes by long chain primary amines has been studied by D.
Kuiper (Delft, Netherlands). Tartaric and malonic acid (HzL)
are extracted by the amine (A) as (AH)2L at lower acid concentrations and as (AH)HL at higher acid concentrations.
The distribution coefficients of the lanthanides increase with
increasing (AH)2L concentration and decrease in the presence
was expressed as a function of the total ionic strength p.:
of (AH)HL. By a series of different experiments the composition of the extracted complexes was found to be (AH)5LnL4.
Kpu = 12.163 - 9.033 p. + 2.230 11’ - 0.163 p.3
F. Baurngartner (Karlsruhe, Germany) reported o n the
kinetics of extraction and back-extraction of uranium(v1)
and plutonium(1v) by tributyl phosphate (TBP). Contrary to
the older view that the kinetics of extraction is controlled by
diffusion, measurements on drops showed the participation
of one or more “interfacial complexes” in the rate-determining
step. The formation of such a complex at the interface between the two liquid phases can be described by the Langmuir
adsorption-desorption theory if one considers that adsorption and desorption may take place from both sides of the
interface. From the kinetic data the following picture o f the
extraction mechanism may be drawn: As soon as the metal
enters the interface in ionic or neutral form it belongs to the
interfacial complex; the latter successively adds TBP molecules from the organic phase and NO3- ions from the aqueous phase, there being no indication of the sequence of this
addition. When the coordination shell of the complex is complete, the complex can be desorbed into the organic phase.
However, since all the steps taking place at the interface are
reversible, it is also possible that the interfacial complex is
re-desorbed into the aqueous phase. Furthermore, exchange
reactions can take place between the interfacial complexes.
Back-extraction from the organic into the aqueous phase can
be described in an analogous fashion.
-
E“
=
8.791
+ 6.071 p - 6.176 p2 + 1.579 p.3
These functions describe the extraction in the concentration
range 20-30 vol-% TBP, 0.1-0.6 molejl UVI, 0.01-0.2
mole:l PuIv, 0.6-3.0 molejl H N 0 3 with good accuracy.
The extractant TBP suffers considerable radiation damage,
particularly in the processing of highly burnt fuels. Zirconium
is particularly well extracted by the degradation products of
the TBP, so that the decontamination factors for this fission
product are strongly reduced. As P . Faugeras (Fontenay-auxRoses, France) pointed out, the coextraction of zirconium
can be suppressed by addition of small amounts (10-3 to 10-2
molell) of fluoride ions. The separation of the fission product
ruthenium was also improved a t the same time. In this way,
decontamination factors of > lo5 for Zr and > lo4 for Ru
could be demonstrated with solutions containing up to lo3
Cijl fission product activity.
Angew. Chem. internar. Edit. J VoI. 8 (1969) 1 No. 4
German version: Angew. Chem. 81, 262 (1969)
[VB 187 IE]
Metabolic Transformation of Antimalarial Drugs
as a Basis for the Development of
New Active Substances
By P . Nickel *I
The last 20 years have seen considerable progress in malaria
therapy; nevertheless, the disease still presents a very serious
problem in many tropical countries. The increasing occurrence of cases of therapy-resistant malaria in South America,
and above all in Southeast Asia, in recent years has provided
new impetus to the search for effective antimalarials.
During metabolism, the chinchona alkaloids are hydroxylated
at C-2 of the quinoline ring, thereby losing their antimalarial
285
activity. This hydroxylation is hindered and the activity of
the alkaloids increased by the presence of substituents,
especially phenyl. Owing to toxic side-effects, however, no
representative of this much-investigated class of compounds
has yet found application in therapy.
The activity of Plasmochin@' [8-(4-diethylamino-l-methylbutylamino)-6-methoxyquinoline] must be due to a metabIt = Ii, CH3, C6H,
n = I: (5). 2,2';(6), 2,4'; (7j, 4,4';
olite since the substance itself is inactive in vitro. As long
ago as 1942, Schonhofer suspected that quinoid forms were
responsible for the activity, which was later confirmed by the
discovery of the highly effective metabolite 8-(4-diethylamino1 -methylbutylamino)-5.6-dihydroquinoline-5,6-dione.
The assumption that a similar mode of action could apply to
the 6-aminoquinolines led to the discovery of the extremely
'meta'-derivatives (8)-(10) the second reduction step is
effective, yet highly toxic, 6-(4-diethylamino-l-methylbutyl- irreversible. Prolongation of the vinylene chain as in ( I I )
amino)-5,8-dimethoxyquinoline (Schiinhiifr and Schulerapidly reduces K , but the vinylene bridges in (12) and (13)
mann, 1961). Our investigations of the effects of substituents
have hardly any influence. The methine groups in ( I ) can be
o n the antimalarial activity of this compound indicate a
partly or wholly replaced by phenylene groups or N atoms;
certain similarity to the state of affairs with 8-aminoquinolines.
is
Proguanil [N1-(p-~hlorophenyl)-N~-isopropylbiguanide]
also inactive in vitro; 2,4-diamino-5-(p-chlorophenyl)-6,6dimethyl-5,6-dihydro-1,3,5-triazine
(known as cycloguanil)
was isolated as active metabolite in this case. Since this compound is rapidly excreted, it is not very effective in humans.
However, an intramuscular injection of a difficultly soluble
salt of the metabolite does provide protection against infection for a period of several months. Its activity is attributed
to inhibition of dihydrofolic acid reductase.
[VB 189 IE]
Lecture at Erlangen on January 17, 1969
German version: Angew. Chem. 81, 295 (1969)
~~
[*] Dr. P. Nickel
Institut fur Angewandte Chemie der Universitat
Erlangen-Numberg
852 Erlangen, Schuhstrasse 19 (Germany)
for example, the species (14) that is known [31 in the reduced
and the oxidized form, comproportionates to the stable green
radical ion (14)sem.The system (IS),which can also be iso-
Reversible Redox Systems with Stable Radical
Cations
By S. Hunig[*l
In principle, compounds of the general formula ( I ) can exist
in three oxidation states that are related by two one-electron
transfersfll. Whether the radical ion (I)sem can be detected
lated in all three oxidation states, forms a very stable radical
ion, which disappears reversibly on addition of acid owing to
and (I-Tjred . 2 He.
disproportionation to
or isolated depends both on its thermodynamic stability,
which can be expressed as K = [sem@]z,"red] [oxze], and on
the reactivity of each of the three components towards the
medium.
red
+
ox2@
1 2 OH@
2 sem@
t-
structure
I
K is determined polarographically from the redox potentials
dependingon
and in the cases studied amounts to -103-109,
the structure of the compound ( I ) . This Iecture was confined
to compounds of the Weitz type (2) (X = N-CH3)Lzl and
variations thereof. For example, introduction of 0 ( 3 ) or S
( 4 ) both lead to stable radical ions which have fully resolved
EPR spectra and dimerize reversibly at higher concentrations in CHzClz. Nucleophiles remove 0x28 irreversibly, so
that complete disproportionation occurs. The systems ( 5 ) to
(7) show the same value -103 for K . However, with the
286
Lecture at Miinster (Germany) on January 13, 1969
German version: Angew. Chem. 81,295 (1969) [VB 186 IEI
[*I Prof. Dr.
S. Hunig
Institut fur organische Chemie der Universitat
87 Wurzburg, Rontgenring 11 (Germany)
[I] S . Hunig, Liebigs Ann. Chem. 676, 32 (1964); Pure appl.
Chem. I S , 109 (1967).
[Z] Only the formula of the compound introduced in the experiment is reproduced.
131 A. J. Kiprianov and M. Yu. Kornilov, 2. obSE. Chim. 31, 1699
(1961).
Physical and Chemical Probes €or Enzyme
Conformation
By G. K . Radda
The response of bovine liver glutamate dehydrogenase (GDH)
to allosteric inhibitors has been examined by a variety of
methods.
Angew. Chem. internal. Edit. / VoI. 8 (1969) / No. 4
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