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Design Synthesis and Ion-Transport Properties of a Novel Family of Cyclic Adamantane-Containing Cystine Peptides.

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nisorp 360CX Sorptometer operated under continuous adsorption conditions. "AI
MAS NMR spectra were obtained with a Varian VXR-400 NMR spectrometer
equipped with a Varian MAS probe and SiN rotor. The spectrometer frequency was
104.22 MHz. pulse width 2 ms, and sample spinning rate 6550 Hz
Received: November 17. 1995
Revised version: February 14. 1996 [285631E]
German version: Angew. Chem. 1996, 108. 1180-1 183
Keywords: aluminum compounds
molecular sieves * surfactants
*
mesoporous materials
-
[l] J.S. Beck, L S - A 5057296. 1991.
[2] c'. T. Kresge. M . E. Leonowicz. W J. Roth. J. C. Vartuli, J. S. Beck. Nature
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[3] C.-Y Chen. H.-Y Li, M. E. Davis, Microporous Muter. 1993. 2. 17.
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[6] Q. Huo. D 1. Margolese. U. Ciesla. P. Feng. T. E. Gier, P. Sieger, R. Leon,
P. M Petroff. F Schuth. G. Stucky, Nuture 1994. 368, 317.
171 U. Ciesla. D. Demuth. R Leon, P. Petroff. G. Stucky. K. Unger, F. Schiith.
J C/iiw1. Soi.. C'liern Comn?iin. 1994, 1387.
[8] P. T. Tanev. T. J. Pinnavaia. Science 1995. 267. 865.
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1121 G. Tournier. M. Lecroix-Repellin, G. M. Pajonk, Stud. Surf. Sri. Cuts/. 1987,
31. 333
[13] S. D. Mahanti. personal communication.
[I41 M. R. Porter. Handbook o/Surfuctunr.s. 2nd ed.. Blackie. London, 1994.
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J Cliiwi. Soc Furudur Trons. 1994. 90, 2965.
1181 S J. Gregg. K . S. W. Sing, Adsorption. Surface Areu und Porosity, 2nd ed..
Academic Press. London, 1982.
[19] G Horvath. J. Kawazoe, J. Chem. Eng. Jpn. 1983. 16, 470.
[20] R. W. Cranston. F. A. lnkley, Adv. Coral. 1970, 9, 143.
[21] E. P Barrett. L. G. Joyner, P P. Halender, J Am Chem. SOC. 1951. 73,
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[22] R. Poisson. J.-P. Brunelle, P. Nortier in Cutolysf Supports and Supported Cutu/&vt.i, (Ed : A B. Stiles), Butterworths, Boston. 1987, p. 11
I231 B. C. Gates in Mureridi Chemistry: A n Emerging Discipline, American Chemical Society. Washington, D. C.. 1995, p. 301.
1241 J. W. Akitt, Prii,q. Nucl. Magn. Reson. Specti-ox. 1989, 21, 127.
[25] M. C. Cruickshank, L. S. Dent Glasser. S. A. 1. Barn, I. J. Proplett, J Chem.
Sor. Cliem. Cornman 1986, 23.
[26] H. Adkms. S. H. Watkins, J Am. Cliem. Sor. 1951, 73. 2184.
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I, 547.
[28] R. Sned. Appl. ( b r c r l . 1984. 12, 347.
[29] Introducrfon t o Zcdite Science and Pructice, (Eds.: H. van Bekkum, E. M.
Flanigen, J. C. Jansen) Elsevier, Amsterdam, 1991.
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Design, Synthesis, and Ion-Transport Properties
of a Novel Family of Cyclic, AdamantaneContaining Cystine Peptides**
Darshan Ranganathan,* V. Haridas,
K. P. Madhusudanan, Raja Roy, R. Nagaraj,
G. B. John, and M. B. Sukhaswami
Cyclic peptides have attracted considerable attention in recent years. Apart from acting as templates in the de novo design"' of artificial proteins, they serve as useful models[21for the
study of preferences in protein secondary structure and also play
a pivotal role in ion transport across biological membranes.13]
Recently, a new aspect has developed: the formation of nanotubes from cyclic peptides.l4]
The problem of delineating conformation in cyclic peptides
can be overcome by incorporating rigid units in their framework. The potential of this strategy has recently been shown in
the design of conformationally constrained, high-affinity ligands for GPIIbjIIIb receptor proteinsrs1and in the development
of minimal glucocorticoid receptors models.[61Thus, it was envisaged that when rigid and simultaneously lipophilic units are
incorporated into the cyclic peptide framework, not only would
the peptide have the desired conformational constraint but it
would also interact with lipid bilayers. These cyclic peptides
would thereby effectively and preferentially transport ions
across biological membranes.
In this communication we provide the first illustration of this
strategy and report on the design and synthesis of a unique
cystine cyclic peptides with
family of adamantane-~ontaining~'~
the general structure cyclo(Adm-Cyst), (Adm = 1,3-adamantanedicarbonyl; Cyst = L-cystine dimethyl ester; n = 2-5),
which were constructed in a single step by the reaction of Lcystine dimethyl ester with 1,3-adamantanedicarbonyIdichloride. Further, members of this class of cyclic peptides have been
demonstrated to selectively transport sodium and potassium
ions in model membranes.
Treatment of 1,3-adamantane dicarbonyl dichloride with Lcystine dimethyl ester in the presence of triethylamine under
high-dilution conditions afforded a mixture of four products
with similar TLC behavior, which were separated by chromatography on silica gel with ethyl acetatejbenzene (80/20) as
eluent. The products were isolated in yields of 55 ( I ) , 15 (2), 12
(3), and 2 % (4), and were fully characterized by spectroscopic
and analytical data (Scheme 1, Table 1)).
The highly symmetrical nature of 1-4 was evident from
the appearance of only single set of resonances for the cystine
and adamantane units in their 'H and I3C NMK
The chemical shifts of the adamantane and cystine protons in
2-4 were essentially identical to those of 1, suggesting that
these units adopt similar conformations. The ROESY NMR
spectra of 1-3 and the very enhanced ROE e f f e ~ t 1 ~between
~1
the NH and the adamantane methylene protons suggests that
(*I
Dr. D. Ranganathan. V. Haridas
Biomolecular Research Unit, Regional Research Laboratory (CSIR)
Tnvandrum, 695019 (lndiaj
Fax: Int. code +(471)490186
Dr. K. P. Madhusudanan, Dr. R. Roy
Medicinal Chemistry Division, Central Drug Research Institute
Lucknow. 226001 (lndiaj
Dr. R. Nagaraj. G. B. John. Dr. M. B. Sukhaswami
Centre for Cellular and Molecular Biology, Hyderabad (India)
[**I This work was supported financially by the Department o f Science and Technology, New Delhi (India). We are most grateful to Prof. S Ranganathan
(RRL. Trivandrum) and Prof. D. Balasubramanian (CCMB, Hyderabad) for
helpful advice and comments.
Angiw. Clwm. I n / . E d Engl. 1996, 35. No. 10
0 VCH
Verlagsgesellschafi mbH, 0-69481 Weinheim, 1996
0570-0833/96/3510-1105$15.00+ .25/0
1105
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t
R
MeoQ' HN
K
OMe
A
+
4
3
Scheme I . One-step condensation of 1.3-adamantadne dicarbonyl dichloride and cystine dimethyl ester to give macrocycles 1-4
two carbonyl functions are in a syn-anti arrangement. The FABMS resultsl"1 confirmed that 1-4 correspond to the cyclic
1 : M.p 110-112 C ; [?I:'=
-5.99 (c =2.1 in CHCI,): ' H N M R (300MHz.
dimer, trimer, tetramer, and pentamer, respectively, of AdmCDCI,): 6 = 1.59 -2.08 (m. 24 H j , 2 23 (br. s. 4 H). 3.13 (dd, J = 9.0,4.5 Hz. 4 H).
Cyst units.'"
3.30(dd.J=90.4.5Hz,4H),3.78(s.12H),4.81(m,4H).6.59(d,J=7.0Hz.
The formation of 1-4 containing two, three, four, and five
4 H); IR (KBrj: ? = 3365. 2920, 2862, 1748, 1650, 1522cm-', FAB-MS: nil: (%):
913 (95) [ M + HI'
cyclic repeats, respectively, of Adm-Cyst units was rationalized
on the basis of further cyclooligomerizations of the initially
2: M.p 166-~168C: [XI? = -1.92 (c=2.35 in CHCI,): ' H N M R (300MHz.
CDCI,):6=1.61-2.11(m,36H),2.23(br.s,6H).315(m,12H).3.76(s.18H),
formed linear Adm-Cyst intermediate (Scheme 1). This notion
4.80(m,6H),6.72(d,J=7.0Hz,6Hj,1R(KBr):i.=3417,2930,2861,1748.1651.was supported by the isolation of small amounts (ca. 5 % ) of
1565. 1536cm-'; FAB-MS: ni,'z(%), 1369 (100)[ M + HI'. 913 (44)[Mt - Admlinear polymer of the Adm-Cyst unit.
Cyst + HJ
Molecular modeling and energy minimization[91support the
3: M.p 1 9 0 - 1 9 2 T ; [2]6' = +6.04 (c = 2.50 in CHCI,); ' H N M R (300MHz.
cavitand-like conformation of the 26-, 39-, 52-, and 65-memCDCI,): 6 = 1.59 -2.13 (m, 48 H).2.22 (br. s, 8 H). 3.17 (m, 16 H), 3.76 (s, 24 H).
4.82(m,8H).6.73(d,J=7.0Hz,8H),IR(KBrj:i.=3368.2919.2861,1750,1653, bered macrocycles. The representations of the optimized struc1522cm-': FAB-MS. niir (%). 1825 (86) [ M + HI'. 1369 (43) ( M + - Admtures[' 51 show that while the cavity is hydrophilic, the periphery
Cyst + HJ. 913 (40) [ M i - 2 x Adm-Cyst + H]
consisting of repeating adamantane units is largely hydropho4 : M . p 138-140 C. ' H N M R (300 MHz, CDCI,): rS =1.50-2.16 (m, 60 H). 2.21
bic. This suggests that macrocycles 1-4 may harbor metal ions
(br. s. 10 H). 3 18 (m, 20 Hj. 3.75 (s. 30 H), 4.80 (m. 10 H). 6.71 (br. d. 10 H); IR
and transport them across membranes. This notion has been
(KBr): i'= 3331.2920,2861,1748,1658,1521
cm-':FAB-MS:,ni=(%): 2282(100)
demonstrated experimentally.
[ M + HI', 1825 (35) [ M i - Adm-Cyst + HI. 1369 (40) [M' - 2 x AdmCyst + HI. 913 (47) [ M i - 3 x Adm-Cyst + HI
The capability of compounds 1-3 to transport ions across
model membranes (small unilamellar vesicles) was evaluated by
Polymer: soluble in DMSO and DMF, insoluble in CHCI,, EtOAc. MeOH; m.p
172-173 C; thermogravimetric analysis: T = 250-C; 'H-NMR (90 MHz.
monitoring the decay of a valinomycin-mediated K + diffusion
[DJDMSO): 6 = 1.32-2.37 (m, 14 H). 3.10 (m,4 H). 3.65 (s. 6 H). 4.60 (m. 2 H ) .
potentialr'*. ''1 and with a chlorotetracycline (CTC)/Ca" as7.75 (d, J =7.0 Hz, 2 H): IR (KBrj: 5 = 3349. 2914. 2860. 1750. 1666. 1647. 1562.
say.[t2.1s1The results show that dimer 1 transports Na' in
1536, 1514, 1441 cm-'
preference to K + , trimer 2 is more selective towards K', and
Table 1. Selected data for compounds 1-4.
1106
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AncqepPn..Chem. Inr. E d Engl. 1996. 35. N o . 10
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tetramer 3 shows negligible transport properties for both ions.
None of the compounds were able to transport Cai2 ions across
the lipid bilayers, as judged by the CTC assay. The macrocycles
did not cause the release of entrapped carboxyfluorescein, indicating that the movement of ions across the lipid bilayer was not
due to the formation of large pores or detergentlike
The ion flux may thus be ascribed to a carrier-type of ion-transport mechanism like that of ~ a l i n o m y c i n . ~ ' ~ ~
The cystine cyclic peptides 1-4 described here represent a new
family of adamantane-containing cyclic peptides, which are capable of transporting N a + and K f ions across model membranes. This action and their very simple, short synthesis should
be incentive for the design of related compounds in this novel
class of cyclic peptides
[I 31 Ion transport across membranes can take place either b> carrlers o r by channel
formers. The two mechanisms can be easily distinguished by monitoring the
release of carboxyfluorescein (CF) trapped in lipid vesicles by fluorescence
spectroscopy. Since a channel former leads to the formation of large pores in
membranes. the trapped C F leaks out of the vesicles into the bulk medium,
which causes a sudden enhancement of its fluorescence intensity due to dilution. Carrier molecules. on the other hand. diffuse through the hydrocarbon
region of the membrane and do not cause the escape of CF into the medium.
and hence no change in fluorescence is seen In the present case. the absence of
any fluorescence enhancement in the presence of macrocycles 1 - 3 implies that
trapped C F is not released. and that ion transport occurs by a carrier-type
mechanism, like that of valinomycin.
[I41 L. A. R. Pioda, V. Stdnkova, W. Simon, A n d . Lerr. 1969. 2. 665; H. B. Jenny,
C. Riess. D. Ammann. B. Mayyar. R. Asper, W. Simon, Mikrochirn. Actu 1980
(2). 309.
(151 Further details may be obtained from the author on request.
E . i p r iiiwut d Procedure
A solutioii o f frchhly prepared 1.3-adamantane dicarbonyl dichloride (2 mmol) in
dry CH,CI, 1 I00 mL) was added dropwise over 0.5 h to a well-stirred solution of
i-cystine diinethyl ebter hydrochloride ( 2 mmol) and triethylamine (9 mmol) in dry
CH,CI, (1 50 mL) a t 0 C. The reaction mixture was stirred at room temperature for
4 6 h and monitored by TLC. The reaction mixture was washed sequentially with
ice-cold 1 N H,SO,. H,O, and 5% NaHC0,3 (ca. 20 mL each). The organic layer
was dried over MgSO, and concentrated in vacuo. The residue was chroinatogi-aphed on silica gel with ethyl acerateibenzene (80/20)as eluent to afford
inacrocycles I ( S S % ) . 2(15%)3(12%). a n d 4 ( 2 % ) , a n d a smallamount(ca. 5 % )
of ii lineur Adm-<'yst polymer.
Received: November 2, 1995
Revised version: February 12. 1996 [Z8522IE]
German version: A n g i w Clinn. 1996. 108, 1193--1195
Keywords: adamantanes . cyclopeptides
*
l i i ~ .E d
Engl. 1996, 35. KO. 10
('
,
Nikolaus Korber,* Jorg Daniels, and
Hans Georg von Schnering*
Dedicated to Projessor Marianne Baudler
on the occasion of her 75ih birthday
ion transport
[ I ] A. Grove. M. Mutter, 1. E. Rivier, M Montal. J A m Chrni.Soc. 1993, 115.
5919 5934.
[2] J Ri70, L M. Gierasch. Annu Rev. Biuci7en2. 1992,61,387-418. and references
therein.
(31 Y. A Ovchinnikob. V Yivanov, A. M. Shkrob. Menibrune Acriw Conip/e.ror. Amsterdam. 1974: B. C. Pressman, Annu. Ria, Blochen?. 1976.45.
501: T J. Marrone. K. M. Merz. Jr.. J. Aiii Cheui. Soc. 1992, 114. 7542 -7549.
pi] M . R Ghadiri. J. R. Granja. R. A. Miiiigan, D. E. McRee, N. Khazanovich.
.Nurim, 1993. 366. 324 - 327: M R. Ghadiri. J. R. Granja. L. K. Buehler. ihid.
1994. .tW. 301 304; N Kharanovich. J. R. Granja. D. E. McRee. R. A. Milligan. M. R. Chndii-I.J. Am. Choii. Soi. 1994. 116. 601 1-6012: M. R. Ghadiri.
K. Kobayash~.R. K. Chadha, D. E. McRee. Angeh-. Chcw. 1995. 107. 76-78:
A ~ i p i c~' l i o i i / n r . Ed. Engl. 1995. 34. 93-95; K. Kobayashi. J. R. Granja.
M R. Ghadiri. ihid 1995. 107. 79-81 and 1995. 34, 91-98.
[51 A. C. kich. 11. C. J Eyermdnn, J. D. Gross, M. J. Bower. R L. Harlow. P. C .
Weber. W F. Detirado. J. A m . Clirnr. So<. 1994. /16. 3207- 3219: S. Jackson,
W. F. DeGrado. A. Dwivedi. A. Parthasarathy, A. Hig. J. Krywko. A. Rockwell. J. Markwalder. G . Wells. R. Wexler. S. Mousa, R. Harlow. &id. 1994, 116,
3220 3230.
[6] S. Ranpinathati. N Jaydraman. R. Roy. K. P. Madhusudanan. Terruhi~i/run
Lei/. 1993. 34. 7x01 -7804.
[71 The I .i-adomancnnediyl unit appeared particularly attriictive as a low molecular waght. rigid. lipophilic component for fixing the macrocycle in membranes.
[S] Iiiterescitigly. metiil ]on doping experiments with cyclic peptides I - 3 indicated
ii strong tendenq t'or the uptake of alkali metal ions (FAB-MS). The signal
intensity lor ( 1 + M ) ' and of (2 + M ) ' appeared in the order of
L i ' > R h ' > C \ ' > K + > N a + and for ( 3 + M ) ' in the order of
Rb' > <'hi > K ' > Na' > L i t .
[9] The inodek for ~nacrocycles1-3were generated with the Biosym program
package. veriioii 3.3 5 . a Silicon Graphics IRIS Crimson Elan Work Station.
The energy minimtrntion was done with INSIGHT and DISCOVER program
packages (Biosgrn Technologies. San Diego, CA). using a consistent valence
force field
I101 P. J. Sinih. A S Waggoner, C. H Wang. J F. Hoffman, Bioc/ir~iii.~ii-~
1974, 13.
3315 3330.
[I I ] I-. M l.ocu. I. Rwenberg. M . Bridse, C. Gitter. Biocheinf.mi~1983, 22. 837844. L M. Loew. L. Benson. P. Lazarovici. I. Rosenberg. ;hid. 1985.?4.2101-2104; Y. Shai. D. Bach, A. Yanovsky. J. B i d C/iim. 1990.265.20202-20209;
. G. Cumsky, [bid 1990.265.8808 -8816; D. Roise, Proc. Nut/
1992.89.608--612: R. M. Epand. Y. Shdl, J. P Segrest, G . M
Anantharamalah. Biopoii.nio..\ 1995. 37. 319- 338
1121 R. Nagaral. M K Mathew. P. Balaram. F&BS Lerr. 1980. / I / . 365- 368.
A i i , q ~ i i .Choii
Directed Synthesis of Stable Hydrogen
Polyphosphides: Preparation and Structural
Characterization of HPT 1 in (NBnMe,),HP,
and (PBnPh,),HP,, as Well as Its Comparison
with the First "Naked" P:; Ion
in (NEtMe,),P,
Recently, the surprisingly stable tetraphenylphosphonium
salt of the dihydrogen heptaphosphide H,P; was isolated and
characterized by single-crystal X-ray structure analysis.['] Even
today, very little is known about hydrogen polyphosphides,
which are situated between polyphosphanes[2.31 and polyphosp h i d e ~ . ' ~Phosphides
]
and phosphanes with identical phosphorus frameworks (for example, P:-[41 and heptaphosphane(3)
P,H, ,[51 both with the nortricyclane cage) are formally related
by the Brnnsted acid-base concept;[61however, this formal relationship is difficult to prove experimentally, because the deprotonation of polyphosphanes as well as the protonation of the
corresponding polyphosphides both lead to rapid decomposition. Therefore, partially protonated polyphosphides (or partially deprotonated polyphosphanes) are highly reactive species
that have rarely been observed in practice. An exception has
been a detailed study of the reaction between diphosphane(4)
and n-butyllithium by Baudler et al., during which several partially lithiated polyphosphanes were detected as highly reactive
intermediates by 31P N M R s p e c t r ~ s c o p y . ~ ' ~
In solution, (PPh,)H,P, decomposes as well, yielding undetined higher polyphosphanes; as a crystalline solid. however, it
is stable at room temperature and even in air, probably because
of the spatial separation of the H,P; ions by the large cations.
(PPh,)H,P, forms in small yields during the reaction of K,P,
with (PPh,)CI in liquid NH, . [ l l
["I
[**I
Dr. N. Korber. DipLChem. J. Daniels
Institut fur Anorganische Chemie der Universitit
Gerhard-Domagk-Strasse I , D-53121 Bonn (Germany)
Fax: Int. code +(228)735660
e-mail: korber(a plumbumxhemie uni-bonn.de
Prof. Dr. H. G. von Schnering
Max-Planck-Institut fur Festkorperforschung
Heisenbergstrasse 1, D-70506 Stuttgart (Germany)
Fax: Int. code +(711)689-1562
The authors are grateful to Dr. W. Hoffbauer for the recording of the solidstate NMR spectra. Bn = benzyl.
VCH ~,rlugsjieselisc.liufrmhH, 0-69451 Weinheirn,1996
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synthesis, properties, containing, design, ion, cyclic, cystine, transport, family, novem, peptide, adamantane
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