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Development of Tailor-Made Cytostatics Activable by Acid-Catalyzed Hydrolysis for Selective Tumor Therapy.

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(1 1J T D. Newbound, M. R. Colsman, M. M. Miller, G. P. Wulfsberg, 0. P.
Anderson, S . H. Strauss, J Am. Chem. Suc. 111 (1989) 3762.
[12] No species containing ethylene coordinated prior to insertion into the
Ti-C CI bond (1-11) was detected. i n the absence of d electrons, group IV
metal centers are unable to stabilize x complexes through back-donation,
and species of type I are unlikely to have significant lifetimes. For a theoretical treatment of the ethylene insertion step, see [Id]. Occupancy of d
orbitals in early transition metals leads to energetically highly favorable
back-bonding as a barrier against insertion: 0. Eisenstein, R. Hoffmann,
J Am. Chem. Sue. 102 (1980) 6148; ibid. 103 (1981) 4308.
b]
HO
HO
CHzOH
HO
HO
R e
I
[;.Ti
OH
+ R'R~C-O
3
HO
+
R~OH
4
1
+ [Cp,Ti-CH,CH,RIe
11
[13] This observation is in agreement with earlier results on a Cp,TiMeCI/
AIMeCl, catalytic system where only a fraction of the available Ti-Me
bonds were shown to participate in chain-growth reactions: G. Fink, W
Fenzl, R. Mynott, Z. Narurfursch. 40B (1985) 158.
[I41 J. Haslam, H. A. Willis, D. C. M. Squirrel: IdentifiL.atiun and Analysis of
P[asrics, 2nd ed., Heyden, London 1980.
[lS] W. Kaminsky, Angew. Makrumol. Chem. 1451146 (1986) 149. By contrast,
the thermally unstable Cp,TiPh,/methylaIumoxane system at temperaI
Am.
tures below -4S"C gives isotactic polypropylene: J. A. Ewen, .
Chem. Suc. 106 (1984) 6385.
Development of Tailor-Made Cytostatics
Activable by Acid-Catalyzed Hydrolysis
for Selective Tumor Therapy **
By Lutz E: Tietze,* Matthias Beller, Roland Fischer,
Michael Logers, Eckhard Jahde, KarLHeinz Glusenkamp,
and Manfred E: Rajewsky
The chemotherapy of malignant tumors is extremely problematic because of the narrow therapeutic range of the cytostatics currently available and the resulting side effects."]
The goal of our work['] is to exploit phenotypic differences between malignant and normal cells for the development of tumor-selective cytostatic drugs. Several groups
have independently shown that, owing to an increase in the
blood-sugar level of a tumor-bearing host, the rate of glycolysis in malignant cells is increased relative to that in the
normal cell population.131 The resulting increase in the
amount of lactic acid results in a lowering of the pH value in
the tumor tissue to 6.2 on the average, whereas the pH value
of normal tissue remains nearly constant @H 7.2). We use
this pH difference to release selectively within the tumor
tissue a cytostatic drug generated from a nontoxic precursor
by acid-catalyzed hydrolysis. A crucial problem here is the
development of functional groups that, on the one hand,
guarantee the detoxification of the cytocidal component
and, on the other, ensure sufficient acid lability that, at pH
6.2, the active species is released fast enough. To this end, we
have developed the acetal glycosidest4Iof general formula 1,
which can release a cytotoxic aldehyde or ketone, 3, together
with an alcohol, 4 and a sugar, 2. Although the compounds
we have so far synthesized exhibited increased selectivity in
~ ~ we devitro, their rate of hydrolysis was too I O W . ~Here
scribe the preparation of the glucoside 10c, which satisfies
the above requirements very well.
Reaction of trimethy~silyl-2,3,4,6-tetra-O-acetyl-p-~-glucopyranoside (5) with three equivalents of 4-(tert-butyldiphenylsiloxy)butan-2-one (6)and one equivalent of the
corresponding acetal 7 in the presence of a catalytic amount
of trimethylsilyl trifluoromethanesulfonate (TMSOTQ in
dichloromethane at - 70 "C gave exclusively the acetal-pglucoside 8 a @:a >99: 1) in 39% yield. Owing to the minimal difference between the substituents at the carbonyl
group, however, a nearly 1:l mixture of C-2' epimers was
obtained. The lower yield, compared with the formation of
acetal glucosides from aldehydes, is due to the lower reactivity of
Trehaloses were formed as side products in
the reaction. Cleavage of the trialkylsilyl group with tetrabutylammonium fluoride (TBAF) led to a 94% yield of an
epimeric mixture of alcohols 8b, which, upon treatment with
[(bis(2-chloroethyl)amido]phosphoric acid dichloride (9)@]
in the presence of triethylamine (CH,CI,, 36 h, 20 "C) followed by reaction with NH, (CH,CI,, 1.5 h, 20 "C),afforded
the diamidophosphate 10 bin 74 % yield via 10a. Cleavage of
the acetyl groups to give 10c was accomplished by solvolysis
II
1. TMSOTf, -7OOC
2. TBAF
CH20Ac
Ac
- AcO
0
8a, R = S i ( P h ) , t B u
8b. R=H
1. Cl,P(O)N(CH,CH,Cl),
9 / Et,N
2. NH,
[*I
[**I
782
Prof. Dr. L. F. Tietze, Dr. M. Beller, Dr. R. Fischer,
DiplLChem. M. Logers
Institut fur Organische Chemie der Universitat
Tammannstrasse 2, D-3400 Gottingen (FRG)
Prof. Dr. M. F. Rajewsky, Dr. E. Jahde, Dr. K.-H. Gliisenkamp
Institut fur Zellbiologie (Tumorforschung) der Universitat
Hufelandstrasse 58, D-4300 Essen (FRG)
Glycosidation, Part 16; Anticancer Drugs, Part 12. This work was supported by the Bundesminister fur Forschung und Technologie (Forderkennzeichen 03189-52A9) and the Fonds der Chemischen Industrie. Glycosidation, Part 18, and Anticancer Drugs, Part 11 : L. F. Tietze, M. Beller,
Liebigs Ann. Chem. (1990), in press.
0 VCH
VerlagsgeseIlrchaJi mbH, 0-6940 Weinheim. 1990
3 . K,CO,/MeOH
CH,OR
RO
10a, R=Ac, X=C1
lob, R=Ac, X=NH,
lOc, R = H , X=NH,
0570-0833/9010707-0782 $03.50+ .2510
Angew. Chem. I n t . Ed. Engl. 29 (1990) Nu. 7
with potassium carbonate in methanol. Compound 10cr7]
was obtained as a mixture of four stereoisomers, since the
phosphorus atom is also a stereogenic center and the phosphorylation with 9 proceeded, as expected, in a nonstereoselective fashion. All the compounds reported here are very
acid labile, so that chromatography is only possible in the
presence of triethylamine.
The stereochemistry of 1Oc at the anomeric center is revealed by the doublet for 1-H at 6 = 4.53 (J = 8 Hz) in the
'H NMR spectrum.[*]The configuration at C-2' is assigned
on the basis of the I3C NMR signals for C-1' and C-3'. We
assume that, by analogy to the NMR datac4]for the acetal
glycosides of aldehydes, the signals in the spectrum of the
(2'R) epimer lie at lower field for C-I' and higher field for
C-3', compared to the corresponding signals of the (2's)
isomer.
The kinetics of the acid-catalyzed hydrolysis[91of 1Oc was
determined using NMR spectroscopy. The first-order rate
constant for deuterolysis at pD = 6.10 in phosphate buffer
at 35 " c (0.10 M, I = 0.5 M) is k = 2.45 X
S-'.
Assumvalue of 1.5,['011Oc has a half-time for hydroling a kDm/kH,
ysis of 15 h at pH = 6.2 and 35 "C. This value roughly corresponds to the desired value. Cleavage of 1Oc yields besides
glucose and methanol, the diamidophosphate 11 (ketophosphamide)," 'I which, via either elimination or hydrolysis, is
converted into the cytotoxic phosphoramide mustard 12 in
the cell. This compound is also the active metabolite of the
clinically used cytostatic drug cyclophosphamide.[' 21
The dependence of the cytostatic activity of 1Oc on pH
was determined in vitro by treating mammary carcinoma
cells (MI R) of Marshall rats for 24 h. At physiological extracellular pH (pH, = 7.4) and a concentration of 10 pg mL-',
nearly no toxicity was observed; at pH, = 6.2, however, under otherwise indentical conditions, the survival rate of the
cancer cells decreased by a factor of 5 x lo4.We are currently
using transplanted tumors to investigate whether this surprisingly high selectivity is also exhibited in vivo
Received: February 20, 1990 [Z 3808 IE]
German version: Angew. Chem. 102 (1990) 812
CAS Registry numbers:
5 , 19126-95-5;6, 97250-25-4; 7, 127619-80.1; 8 a (isomer l), 127619-78-7;8 a
(isomer 2). 127619-83-4; 8 b (isomer l), 127619-79-8; 8 b (isomer 2), 12761984-5; 9,127-88-8; 10a (isomer l), 127619-81-2; 10a (isomer 2). 127708-55-8;
10a (isomer 3), 127707-74-8; 10a (isomer 4), 127619-85-6; 10b (isomer l ) ,
127645-49-2; 10b (isomer 2), 127708-56-9; 10b (isomer 3), 127708-57-0; 10b
(isomer 4). 127708-58-1; 1Oc (isomer l), 127619-82-3; 10c (isomer 2), 12770775-9; 10c (isomer 3). 127707-76-0; 1Oc (isomer 4), 127707-77-1; 11, 10099383-7; 12, 10159-53-2.
[I] W. E. G. Muller: Chemotherapie won Tumoren, Biochemische Grundlagen,
Verlag Chemie, Weinheim 1975; D. Schmahl (Ed.): Maligne Tumoren.
Edition Cantor, Aulendorf 1981; W. Forth, D. Henschler, W. Rummel:
Allgemerne und spezielle Pharmakologie und Toxikologre, 5th ed. BI Wissenschaftsverlag, Mannheim 1987; E. Frei 111, Cancer Res. 47 (1987) 3907.
[2j L. F. Tietze in E. Borowski, D. Shugar (Eds.): Molecular Aspects of
Chemotherapy, Pergamon Press, Oxford 1990; L. F. Tietze, Nachr. Chem.
Tech. Lab. 36 (1988) 728.
[3] E. Jahde. M. F. Rajewsky, Cancer Res. 42(1982) 1505; 0. Warburg: Uber
den Stoffwechsel der Tumoren, Springer, Berlin 1926; The Metnbolrsm of
Tumours, Constable, London 1930; A. C. Aisenberg: The Glycolysis and
Respiration of Tumors, Academic Press, New York 1961; F. Schneider,
Angew. Chem. Inr. Ed. Engl. 29 (1990) No. 7
0 VCH
Naiurwissenschaften 68 (1981) 20; I. F. Tannock, D. Rotin, Cancer Rex 49
(1989) 4373; S. Osinsky, L. Bubnovskaja, T. Sergienko, Anticancer Res. 7
(1987) 199; M. von Ardenne, P. G . Reitnauer, Acra Biol. Med. Ger. 25
(1970) 483; J. A. Dickson, S. K. Calderwood, JNCI. J. Narl. Cancer lnst.
63 (1979) 1371.
[a] L. F. Tietze, R. Fischer, Angew. Chem. 93 (1981) 1002; Angew. Chem.
Inr. Ed. Engl. 20 (1981) 969; [b] L. F. Tietze, R. Fischer, H.-J. Guder,
Synthesis 1982, 946; [c] L. F. Tietze, R. Fischer, H.-J. Guder, M Neumann, Liebigs Ann. Chem. 1987, 847.
L. F. Tietze, M. Neumann, R. Fischer, T. Mollers, K.-H. Glusenkamp,
M. F. Rajewsky, E. Jahde, Cancer Res. 49 (1989) 4179.
0. M. Friedman, A. M. Seligman, J Am. Chem. Soc. 76 (1954) 655.
1Oc: Rt = 0.30 (dichloromethane/petroleum ether/ethanol 3: 1 :1). 'H
NMR ([D,]acetone/D,O): 6 = 1.30, 1.32 (2s, 3H; CH,), 1.95-2.08 (m.
2H; 3'-H,), 3.06-3.44 (m,10H; 2CH,N, 2-H. 3-H, 4-H, 5-H, 6-H,), 3.19
(s, 3H; CH,O), 3.56 (t,J = 7 Hz, 4H; 2CH,Cl), 3.83-4 04 (m. 2H;
CH,OP), 4.55 (d. J = 8 Hz, 1H; I-H). ',C NMR ([D,]acetone/D,O):
b = 21.78, 21.82 (CH,. [2'q),23.47, 23.52 (CH,, [TR]), 37.40 (d,
'JPWc = 7.1 Hz, C-3' [TR]),39.27 (d, 3Jp0cc = 7.9 Hz; C-3', [Z'q), 42.41
(2CH,CI), 48.20, 48.24 (2d. 'JPNc= 4.2,4.7 Hz; 2CH,N), 49.51 (CH,O).
60.99, 61.06(C-6),62.15,62.25,62.48,62.58,62.99. 63.10(CH20P),69.91.
70.06, 73.46, 76.15 (C-2, C-3, C-4, C-5), 95.30 (C-1, [2'5'). 95.41 (C-I,
(C-2'. R), 103.5 (C-2, S). All new compounds were identified
[ TR] ) 103.3
,
spectroscopically; in addition, correct elemental analyses were obtained.
In the NMR spectrum, C-l refers to the anomeric center of the pyranose
and C-1' to the carbon atom of the methyl group of the exocychc acetal.
E. H.Cordes, H. G. Bull, Chem. Rev. 74(1974) 582; M. M. Kreevoy, R. W.
Taft, Jr., J. Am. Chem. Soc. 77 (1955) 5590.
The kinetic solvent isotope effect k,,/k,, was determined for 1-methoxy1-methylethyl-P-~-glucopyranoside
by UV spectroscopy: L. F. Tietze, M.
Logers, unpublished results.
M. Thomson, M. Colvin, Cancer Res. 34 (1974) 981; P. J. Cox, P. B.
Farmer, M. Jarman, Biochem. Pharmacol. 24 (1975) 599; J. A. Montgomery, R. F. Struck, Cancer Trear. Rep. 60 (1976) 381
N. E. Sladek, Pharmacol. Ther. 37 (1988) 301.
Heteronuclear Complexes Containing CuCo(CO),
Structural Units and Nitrogen Ligands **
By Matthias Achternbosch. Heinrich Braun, Ralf Fuchs,
Peter Kliifers,* Alexandra Selle, and Ulf Wilhelm
Dedicated to Professor Hans-Uwe Schuster on the occasion
of his 60th birthday
Bonds between different metal atoms can form according
to Equation (a) if M'L', is a Lewis acidic metal complex
fragment containing ligands capable of being substituted
ML:,
+ ML,
--t
L;M'-ML,
+ (m - 1) L
(a)
(e.g., [CuCl,Je) and ML, is a nucleophilic metalate ion such
as [CO(CO),]~, [(C,H,)MO(CO),]~, or [Fe(CO),]2e.[1.21
Heteronuclear clusters (M'M), are formed when the metalate
ion bridges M'L' fragments with displacement of several ligands L'.
The compounds [{CuCo(CO),),] (1 a) and [(CuCo(CO)4],J (lb), made up of Cu atoms and k,-bridging
Co(CO), fragments, are formed upon reaction of chlorocuprate (I) and tetracarbonylcobaltate (- I) in such a clusterforming reaction.{'a.b1 p,-ML, groups are present in the anions [ C U , F ~ , ( C O ) , , ] ~
and
~ [CU,F~,(CO),,]~~,
in which the
Fe(CO), fragments are each coordinated to three copper
atoms of the cluster.r21Here we report new compounds con[*] Prof. Dr. P. Kliifers, Dip].-Chem. M. Achternbosch, Dr. H. Braun,
DipLChem. R. Fuchs, DipLChem. A. Selle, DipLChem. U. Wdhelm
Institut fur Anorganische Chemie der Universitat
Engesserstrasse, Gebiude 30.45, D-7500 Karlsruhe (FRG)
[**I Heteronuclear Complexes with Metal-Metal Bonds, Part 4. This work was
supported by the Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie. Part 3 - [la]
Verlagsgesellschafr mbH, 0-6940 Weinheim, 1990
0570-0833/90/0707-0783$03.50+ .2S/O
783
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