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Conformational Prerequisites for the in vitro Inhibition of Cholate Uptake in Hepatocytes by Cyclic Analogues of Antamanide and Somatostatin.

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Comparative bond length-bond strength calculations1"'
for N b 0 2 and NaNb,05F show that the Nb(2) atoms are
present in the t 4 oxidation state. Thus, a formal charge of
- 12 i s obtained for the [Nb,XxJ unit with Nb(l) in the oxidation state f 2 . In analogy to molecular species, e.g.,
Mo2(OR)(,,["I a &t4
triple bond comes into question for
the Nb-Nb dumbbell.
However, Figure 2, right, indicates that each Nb2 pair in
the structure of NaNb,O,F is "side-on" coordinated by
four Nb" ions. The Nb4+ ions are displaced by about
15 pm from the centers of gravity of the (distorted) coordination octahedra in the direction of an edge X(S)-X(3) toward the Nb2 dumbbell [d(Nb(l)-Nb(2))=309 pm, distance to the center of gravity of the dumbbell 281 pm)].
The d ' ion Nb4+ apparently tends to engage in metal-metal bonding as observed in the structures of the tetrahalides
NbX, ( X = C l , Br,
For N a N b 3 0 5 Fthese bonds can
be regarded as two-electron three-center bonds between
Nb4' (dxz-,2) and n orbitals of the Nb, dumbbell; other
configurations are also conceivable. The diamagnetism
found for N a N b 3 0 5 F is in agreement with the assumption
of a spin pairing of all ten valence electrons in the resulting [ 1.1.1. I]propelIane-Nb, cluster, but is not a proof for
this idea of bonding, since NaNb02F1i31also does not
show the magnetism for a d ' configuration.
It is remarkable that the arrangement M2M4X8(Fig. 2,
right) is also found in the structure of Gd2Cl3,IZ3Ialthough
as part of an infinite chain. The electronic band structure
calculated for the chain can also be interpreted in terms of
the presence of 02n4-bonded Gd, pairs, which form GdGd bonds in the direction of the chain via their TI systern~.l'~'
[I51 C . C . Addison, M. G . Barker, R. M. Lintonbon, R. J. Pulham, Spec. Publ.
Chem. Soc. 22 (1967) 460.
[I61 Space group I m m m (No. 71), a=649.7(1), h=1030.5(1), c=711.8 pm,
2 = 4 , Syntex R3 diffractometer: MoK,; 338 reflections, of which 322
had IFJ >3oIFgJ,R(aniso) =0.0193, R(w) =0.0197: p'.,ie..,
= 5.58 g/cm'.
On account of the similarity of the lattice constants it may be concluded
that the phase Ca,17SNb,06 (orthorhombic, a=711.2, b = 1028.9.
c=656.1 pm), characterized by electron diffraction, is isotypic with
N a N b 3 0 s F (S. J. Hibble, A. K. Cheetham: IIlrd European Conference 017
Solid State Chemistry. Book of Abstracts. Vol. I . Regensburg 1986, p.
136). Further details of the crystal structure investigation may be obtained from the Fachinformationszentrum Energie, Physik, Marhematik
GmbH, D-7514 Eggenstein-Leopoldshafen 2 (FRG), o n quoting the depository number CSD-5 1994, the names of the authors, and the journal
citation.
1171 R. Hoppe, Angew. Chem. 82 (1970) 7; Angew. Chem. Int. Ed. Engl. Y
(1970) 25.
[IS] 1. D. Brown in M. O'Keeffe, A. Navrotsky (Eds.): Struc/ure and Bonding
in Crystals. Vol I / . Academic Press, New York 1981.
1191 A. Broll, H. G. Schnering, H. Schafer, J . Les-Common M e t . 22 (1970)
243.
1201 A. I. Gusev, N. I. Kirillova, Ya. T. Struchkov, Zh. Strukt. Khim. I 1
(1970) 62.
[21] F. A. Cotton, R. A. Walton: Multiple Bonds Between MetalAtoms, Wiley.
New York 1982.
[22] L. F. Dahl, D. L. Wampler, Acta Crystalluyr. I5 (1962) 946; R. E.
McCarley, B. A. Torp, Inorg. Chem. 2 (1963) 540.
[23] J. E. Mee, J. D. Corbett, Inorg. Chem. 4 (1965) 85.
[24] P. W. Bullett, Inorg. Chem. 19 (1980) 1780.
Conformational Prerequisites for the in vitro
Inhibition of Cholate Uptake in Hepatocytes by
Cyciic Analogues of Antamanide and
Somatostatin* *
By Horst Kessler, * Mechtild Klein, Arndt Muller,
Klaus Wagner, Jan Willem Bats, Kornelia Ziegler. and
Max Frimmer
Experimental Procedure
Dried NaF (p.A Merck) was ground into a mass with Nb powder (LAB,
Merck) and NbZOs (Merck, Patinale) and placed in a corundum crucible.
This was fused under argon in a quartz ampoule and annealed for 3 d at
800°C. In addition to NbO, NbOz, and oxide fluorides (e.g., NaNb02F),
black. metallic appearing, parallelepiped-shaped single crystals of
N a N b l O i F were formed. By repeated grinding, compression, and annealing
of a tablet containing NaF, Nb, and N b 2 0 5(molar ratio 1.2 ; I : I ; each I d at
750"C), NaNb,O,F in ca. 80% yield was obtained. Such a product, washed
with hydrochloric acid, contained 5.6% F. This value exceeds the calculated
one for NaNbiOsF (4.7%) by only 0.9% and can be explained by the higher F
content for the side products, e.g., NaNbOIF ( I 1.4% F).
Received: June 21, 1986;
revised: August 21, 1986 [Z 1833 IE]
German version: Angew. Chem. 98 (1986) 101I
It is well known1']that liver cells are protected by antamanide 1I2lagainst poisons such as ethanol, dimethyl sulfoxide (DMSO), cysteamine, or p h a l l ~ i d i n , ' ~a ] toxin isolated from the mushroom Amanifa phalloides. In recent
years a similar cytoprotective effect has also been found
for somatostatin 2,14) a naturally occurring peptide horm~ne.[~
Biochemical
I
in vitro investigations of 1 and 2 as
8
9
7
6
II] a ) H. Schafer, H. G. Schnering, Angew. Chem.
[2]
131
141
[S]
161
[7]
76 (1964) 833; b ) A. Simon, ibid. 93 (1981) 2 3 ; Angew. Chem. I n t . Ed. Engl. 20 (1981) I .
R. E. McCarley, K.-H. Lii, P. A. Edwards, L. F. Brough, J. Solid State
Chem. 57 (1985) 17.
a) A. Simon, H. Mattausch. E.-M. Peters, Z . Kristallugr. 174 (1986) 188;
b) H. Mattausch, A. Simon, E.-M. Peters, Inorg. Chem. 25 (1986) 3428;
c) A. Simon, M. Mertin, H. Mattausch, R. Gruehn, Angew. Chem. 98
( 1986) 83 I ; Angew Chem. I n / . Ed. Engl. 25 (1986) 845.
B. 0. Marinder, Chem. Scr. I 1 (1977) 97.
K . Waltersson, Acta Crystallogr. Sect. 8 3 2 (1976) 1485.
N. L. Morrow, L. Katz, Acta Crystallogr. Sect. B24 (1968) 1466.
K.-A. Wilhelm, E. Lagervall, 0 . Muller, Acta Chem. Scand. 24 (1970)
3406.
181 R b. McCarley, private communication, 1985.
19) P. C . Donohue, L. Katz, R. Ward, Inorg. Chem. 4 (1965) 306.
[lo] a ) G. Meyer, R. Hoppe, J . Less-Common Met. 46 (1976) 55: b) 2. Anorg.
Ally. Chein. 424 (1976) 128.
[ I I ] J K. Burdett, T. Hughbanks, Inorg. Chem. 24 (1985) 1741.
1121 H. Schafer, H. G. Schnering, K.-J. Niehaus, H. G . Nieder-Vahrenholz. J .
LewCommon Me! 9 (1965) 95.
(131 W. Rudorff, D. Krug, 2. Anorg. Allg. Chem. 329 (1964J 21 I .
[I41 0. Ruff, E. Schiller, Z . Anorg. Chem. 72 (191 I ) 329; P Ehrlich, F. Pflogcr. G. Pietzka, 2. Anorg. Allg. Chem 282 (1955) 19.
Anyew. Chem.
Int.
Ed. Engl. 25 (1986) No. 11
1
0
5
1
1
2
3
antarnanrde 1
1
2
3
11
L
5
6
1
8
13
12
11
10
9
somatostatin 2
well as of their derivatives have shown that the cause of
this biological effect is the inhibition of a transport system.[,] This system is responsible for the transport of cholate from blood into the bile and also for the detoxification
of the blood via the bile.@l Searching for a common structural feature for the activity of antamanide and somatostatin, we found that cyclic peptides containing the modified
[*] Prof. Dr. H. Kessler, M. Klein, Dr. A. Muller, K. Wagner, J. W. Bats
lnstitut fur Organische Chemie der Universitat
Niederurseler Hang, D-6000 Frankfurt am Main 50 (FRG)
Dr. K. Ziegler, Prof. Dr. M. Frimmer
lnstitut fur Pharmakologie und Toxikologie
Mehrzweckinstitut der Universitat
Frankfurter Strasse, D-6300 Giessen (FRG)
[**I
This work was supported by the Fonds der Chemischen lndustrie and
the Deutsche Forschungsgemeinschaft.
0 VCH Verlagsgesellschafr mhH. 0-6940 Weinheim. 1986
0570-0833/86/111l-0997 $ 02.50/0
997
Fig. I . Conformation of cycle(-Phe-Thr-Lys(Z)-Trp-Phe-D-Pro-) 3 in DMSO (left) and cycle(-Phe-Phe-Pro-Phe-Phe-o-Pro-) 5
in the crystal (right).
retro-sequence 6- 11 of somatostatin[61exhibit high cytoprotective activity. Figure 1 (left) shows the preferred conformation of the most effective peptide found so far
cycle(- Phe-Thr-Lys(Z)-Trp-Phe-D- Pro-) 3
(Z = benzyloxycarbonyl). The conformation was determined by means of 2D N M R methods17’ in DMSO solution.
The comparison of a number of cyclic peptides demonstrates that cytoprotective activity requires two adjacent
aromatic amino acid residues. Activity is increased when
an L-proline residue precedes this sequence or a o-proline
residue follows (Table 1). Therefore, it was not surprising
that cyclolinopeptide A 4[*](Table I), which was isolated
from linseed oil, also inhibits the uptake of cholate into
hepatocytes. As far as we know, this is the first biological
activity that has been found for this natural product.
Table I . 50% Inhibition of cholate uptake in isolated hepatocytes by CyClOpeptides [6].
No. Peptide
Name
Concentration [ ~ M J
2
220
I
Somatostatin
I
“Veber.
peptide”
100
H-Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp
I
HO- Cys- Ser - Thr- Phe -Thr-
Lys
Pro-Phe-0-Trp
I
phe- Thr-Lys
1
Antamanide
8
Pro-Pro-Phe-Phe
cyclolino.
3
Leu - ile -Ile -LLu
peptide A
Phe-Pro-Pro-Phe-Phe
1
Phe -Ala-Pro
4
5
Val<
-Pro
0-Pro-Phe
r
I
- Val
-Phe
Phe-Phe-Pro
3
I
0-Pro-Phe-Thr
t
I
..p~r
3
..oo8’.
1.5
Phe-Trp -Lys IZI
998
0 VCH Verlagsgesellschafi mbH. 0-6940 Weinheim. 1986
However, in addition to the sequence homology the spatial structure is also crucial for the biological effect.‘’] To
determine the conformational requirements cycle(-Pro-ProPhe-Phe-Gly-) was synthesized. The conformation of this
homologue of antamanide and cyclolinopeptide A was
studied in
The spatial arrangement of the
backbone and the side chains of the two phenylalanine residues strongly differs from the conformations of the
bioactive cyclopeptides mentioned above.” ‘’I As expected, this cyclopentapeptide does not exhibit cytoprotective activity. In contrast, the crystal conformation of the
sequence analogue of antamanide, cycfo(-Phe-Phe-ProPhe-Phe-D-Pro-) 5,[’31agrees to a large extent with the conformation of 3 in solution (Fig. I, right). Thus, in this peptide the constitutional and conformational requirements
for biological activity are excellently fulfilled. Indeed, this
compound strongly inhibits the uptake of cholate into hepatocytes (Table 1). Therefore, there is good reason to localize the hatched regions of the molecules 3 and 5, shown
in Figure 1, as that part of the peptide which is responsible
for the biological activity. Computer-assisted molecular
modeling will show whether other compounds affecting
the cholate transport system will have the same spatial
structure.
’,
Received: June 27, 1986;
revised: July 10, 1986 [Z1835 IE]
German version: Angew. Chem. 98 (1986) 1030
111 M. Frimmer, E. Petzinger, Arzneim.-Forsch. 25 (1975) 1423.
[2] T. Wieland, G . Liiben, H. Ottenheym, J. Faesel, J. X. d e Vries, W. Konz,
A. Prox, J. Schmid, Angew. Chem. 80 (1968) 209: Angew. Chem. I n t . Ed.
Engl. 7 (1968) 204.
131 T. Wieland, Inr. J. Pept. Protein Res. 22 (1983) 257.
141 S. Raptis, J. Rosenthal, J. E. Gerich (Eds.): Proc. 2nd Znt. Symp. Somalosrutin (June 1-3, 1981, Athen (Greece)), Attempto Verlag, Tiibingen 1984.
[5] S. Szabo, K. H. Usadel, Experientia 38 (1982) 254.
161 K. Ziegler, M. Frimmer, H. Kessler, 1. Damm, V. Eiermann, S . Koll, J.
Zarbock, Biochim. Biophys. Acru 845 (1985) 86.
171 H. Kessler, C. Griesinger, S. Koll, K. Wagner, unpublished results.
[8] H. P. Kaufmann, A. Tobschirbel, Chem. Ber. 92 (1959) 2805; A. Prox, F.
Weygand, Peprides, Proc. 8th Eur. Pepr. Symp.. Noordwijle, Niederlande
1966, p. 158.
0570-0833/86/1 111-0998 $ 02.50/0
Angew. Chem. Int. Ed. Engl. 25 (1986) No. I 1
[9] H. Kessler, Angew. Chem. 94 (1982) 509; Angew. Chem. I n f . Ed. Engl. 21
(1982) 512.
(101 H Kessler, A. Muller, Liebigs Ann. Chem., in press.
[ I I] A. Muller, Disserfafion.Un~versitatFrankfurt am Main 1986.
[ 121 M. Gehrke, Diplomarbeil, Universitat Frankfurt am Main 1986.
[ I 3 1 Crystal structure analysis of 5.2 C H 3 0 H . H 2 0 ; triclinic, space group
P I ; a=7.370(1), b = 13.092(?), c = 13.544(3) A, a=66.85(2), 0=75.05(2),
1.253 g/cm'; Enraf-Nony=76.07(2)"; V = 1146.6(3) A'; Z = 1, pCdICd=
ius CAD4 diffractometer; Mo,, radiation, half-sphere up to 2 8 = 54",
4941 unique reflections with f > c ( f ) ;structure determination by direct
methods; positions of hydrogens on the carbon framework calculated,
a11 others determined from difference Fourier synthesis; structure refinement to R(F)=0.047; S D P program. Further details of the crystal
slructure investigation may be obtained from the Fachinformationszentrum Energie, Physik, Mathematik GmbH, D-7514 Eggenstein-Leopoldshafen 2 (FRG), on quoting the depository number CSD-51982, the
names of the authors, and the journal citation.
Vicinal Pentaketones**
By Rolf Gleiter,* Gerhard Krennrich, and Michael Langer
Dedicated to Professor Mordecai B . Rubin
on the occasion of his 60th birthday
The kinetic stability decreases with increasing number of
carbonyl groups in going from vicinal dicarbonyl to tricarbony1 to tetracarbonyl compounds. Vicinal tri- and tetraketones".2J react readily with water and rearrange in the presence of base, undergoing decarbonylation. Vicinal pentaketones have not yet been prepared. We report here o n the
synthesis (Scheme 1) and some properties of tBu(CO),tBu
6a and Ph(CO),Ph 6b, the first vicinal pentaketones.
H-COzEt
1
+
b)
a)
HsC-CO-CHs
2
--t
R-CO-CH2-CO-CHz-CO-R
65%
65%
3
Table 1. Spectroscopic data of 4-7 [6]. 'H-NMR: 300 MHz, CDCI';
"C-NMR: 75.46 MHz, CDCI,; UV: CH2C12. DMSO=dimethyl sulfoxide.
~~
~~
4 a : m.p.=60-6IoC, yellow; IR (KBr): I=2105, 1650 c m - ' ; 'H-NMR:
6 = 1.28; "C-NMR: 6= 195.9 (s), 177.5 (s), 78.9 (s), 44.8 (s), 26.3 (4);UV:
A,,,(&)=381 (186, sh), 290 (7900, sh), 238 nm (23600)
5 a : m.p.=64-65"C, yellow; IR (KBr): I=3455, 1725, 1700 c m - ' ; 'H-NMR:
d=1.31 ( s, 18H),4.76(br. s , 2 H ) ; "C-NMR(DMSO):6=205.8(s), 187.8(s),
93.6 (s), 42.3 ( s ) , 25.7 (q); UV: &,,,,(&)=402 nm (114)
5b: m.p.=llO-II3"C, yellow; IR (KBr): 5=3460, 1730, 1718, 1665 cm";
'H-NMR: 6=5.0 (2H, H/D, br.), 7.50-7.56 (4H. m), 7.67-7.73 (2H, m),
8.17-8.2 (4H, m); "C-NMR (DMSO): 6= 192.2 ( s ) , 191.5 ( s ) , 135.6 (d), 132.4
( s ) , 130.1 (d), 129.5 (d), 95.5 (s); UV: A,,,(&)=403 (125). 284 nm (18900)
6 a : IR (film): I=
1734, 1710, 1700 c m - ' ; "C-NMR: 6=204.9 ( s ) , 190.7 ( s ) ,
182.2 (s), 42.8 (s), 25.1 (4); UV: d,,,(&)=559 (96), 436 ( I O I ) , 352 nm (sh,
196)
6b: I3C-NMR: 6 = 190.1 (s), 188.4 ( s ) , 182.4 ( s ) , 136.0 (d), 13 1.3 (s), 130.7 (d),
129.2 (d); UV/VIS:A2,,,(&)=547 (130),437 n m (154)
7a: m.p.=64-65"C, yellow; IR(KBr): I=
1710, 1695, 1670 c m - ' ; 'H-NMR:
6=1.41 ( s , 9H), 1.47 (s, 9H), 7.86-7.98 (m, 2H), 8.18-8.23 (m, 2 H ) ; UV:
&,,,(&)=425 (loo), 315 nm (7300)
7b: m.p.=125-126"C, yellow; IR (KBr): I=1710, 1665, 1650 c m - ' ; 'HNMR:6=7.45-7.6 (m, 4H), 7.6-7.7 (m, 2H), 7.87-8.02 (m. 2H), 8.05-8.2 (m,
4H), 8.2-8.3 (m. 2 H ) ; UV: A,.,,(&)=402 (sh, 124), 320 (sh, 9100), 261 n m
(43 600)
shown in Table 2 by comparison of the ionization energies
of the lone pairs, the first reduction potentials, and the energies of the first bands of the UV/VIS spectra of the diphenylketones Ph(CO),Ph with x = 1-5. The first reduction
potential decreases linearly with increasing x, while the
first ionization energy and the energy of the first absorption band increase and level off to a final value.
+
d)
R-(cO)~-R
6
a , R = I-CqHg;
b, R
C6H5
Scheme I. a) NaH, monoglyme; b) p-CH3-C6H4-SO2N,/Et3N,
C f f-CqH,-OCI/HCOOH;
d ) P205, CHCI,.
CH,CN;
The readily available compounds 2,2,8,8-tetramethyl3,5,7-nonanetrione 3a and 1,5-diphenyl- 1,3,5-pentanetrione 3bI3]can be converted into the bisdiazo compounds
4a and 4b, respectively.[41Reaction of these products with
tert-butyl hypochlorite in formic acid1*]leads directly to the
hydrates of the pentaketones 5a and 5b, respectively,
which can be dehydrated to the deeply colored pentaketones 6a and 6b, respectively. Both pentaketones react
smoothly with o-phenylenediamine to give the corresponding quinoxaline derivatives 7a and b.
The most important spectroscopic data of 4-7 are given
in Table 1. The electronic properties of the pentaketones
f i t in with their congeners having fewer C O groups. This is
['I
["I
Prof. Dr. R. Gleiter, DipLChem. G. Krennrich,
DipLChem. M. Langer
lnstitut fur Organische Chemie der Universitat
Im Neuenheimer Feld 270, D-6900 Heidelberg (FRG)
This work was supported by the Deutsche Forschungsgerneinschaft, the
Fonds der Chemischen Industrie, and BASF AG. We are grateful to Dr.
P. Kunzelmann. M . Rimmler, and G . Rissmann for recording the spectra.
Angew. Chem. f n t . Ed. Engl. 25 (1986)
No. I !
Table 2. Comparison between the ionization energies of the lone pairs, the
first reduction potentials, and the energies of the first UV/VIS bands of the
diphenyl ketones Ph(CO),Ph with x = 1-5.
Compound
PhCOPh
Ph(CO),Ph
Ph(CO)]Ph
Ph(CO),Ph
Ph(CO)sPh
I , , Ievl
n,
n,
n2
9.4
9.1
8.9
8.9
8.9
-
-
11.1
10.2
10.2
9.9
-
11.6
11.2
10.9
E1'* IVl
n4
ns
la1
-
-
< -2.0
-
-
- 0.52
12.0
-0.27
11.8
11.6
- 1.25
-0.88
Am.,x Inml
(G
337 (150) [2a]
380 (75) [2a]
450 (45) [2a]
5 15 (200) [2a]
547 (130)
[a] I n CH2C12with 0.1 M n B u , N @ P e under argon atmosphere, using a glassy-carbon electrode, Ag/AgCI in LiCl/ethanol as reference electrode, and Pt
as counter electrode. Scan rate, 15 mV/s; Fe(Cp)2[Fe(Cp)210, f 0 . 4 eV
Received: July 2, 1986 [Z 1842 IEJ
German version: Angew. Chem 98 (1986) 1019
CAS Registry numbers:
3a, 104779-75-1 ; 3b, 1467-40-9; 4a, 104779-76-2; 4b, 22760-83-4; Sa, 10477977-3; 5b, 104779-78-4,6a, 104779-79-5; 6b, 104779-80-8; 7a, 104779-81-9. 7b,
104779-82-0; o-phenylenediamine, 95-54-5.
[I] M. B. Rubin, Chem. Reu. 75 (1975) 177.
[2] a) L. Horner, F. Maurer, Chem. Ber. I01 (1968) 1783; b) R. Gleiter, W.
Dobler, ibid. 118 (1985) 1917; c) R. Gleiter, G. Krennrich, Angew. Chem.
98 (1986) 452; Angew. Chem. f n f . Ed. Engl. 25 (1986) 449.
131 M. L. Mites, T. M. Harris, C. R. Hauser, J . Org. Chem. 30 (1965) 1007.
141 M. Regitz, H. J. Geelhaar, Chem. Ber. 102 (1969) 1743.
151 H. M. Teeter, E. W. Bell, Org. Synfh. 32 (1952) 20.
161 For 4, 5, and 7 , correct elemental analyses have been obtained.
0 VCH Verlag.rgesellsehafi mbH. 0-6940 Weinherm. 1986
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999
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conformational, cholate, somatostatin, cyclic, prerequisite, inhibition, hepatocyte, uptake, vitro, antamanide, analogues
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