Cis-Dichloroplatinum (II) complexes with aminomethylnicotinate and -isonicotinate ligands

Article abstract of DOI:10.1016/j.ica.2005.05.015

6-Aminomethylnicotinic acid (1a) and 2-aminomethylisonicotinic acid (1b) were each reacted with K₂PtCl₄ in aqueous 1 M HCl to give the corresponding N,N-chelated cis-dichloroplatinum(II) complexes 2. These were converted into amides

Full text of DOI:10.1016/j.ica.2005.05.015

Inorganica Chimica Acta 358 (2005) 3369–3376
www.elsevier.com/locate/ica
cis-Dichloroplatinum (II) complexes with aminomethylnicotinate
and -isonicotinate ligands
*
Rainer Schobert , Bernhard Biersack
Organisch-chemisches Laboratorium der Universita¨t, University of Bayreuth, Universitaetsstrasse 30, D-95447 Bayreuth, Germany
Received 17 February 2005; received in revised form 26 April 2005; accepted 11 May 2005
Available online 16 June 2005
Abstract
6-Aminomethylnicotinic acid (1a) and 2-aminomethylisonicotinic acid (1b) were each reacted with K2PtCl4 in aqueous 1 M HCl
to give the corresponding N,N-chelated cis-dichloroplatinum(II) complexes 2. These were converted into amides 3 via their mixed
anhydrides by treating them first with ethyl chloroformate and then with the respective 1ꢀ or 2ꢀ amine. The analogous 6-amin-
omethylnicotinic acid ester complexes 7 were obtained by reaction of the preformed ligands with K2PtCl4.
ꢁ 2005 Elsevier B.V. All rights reserved.
Keywords: Platinum complexes; Nicotinic acid; Amidation; Yamaguchi esterification; GMP interactions
1. Introduction
num source such as K2PtCl4 [12]. In this way we
obtained new cis-dichloroplatinum complexes with var-
ious alcohols linked to a 6-aminomethylnicotinoyl che-
late ligand. We also report a conceptually reverse
method that links ancillary amines to preformed car-
boxy functionalized cis-dichloroplatinum (II) complexes
via amide bond formation under mild conditions and in
good yields. These complementary approaches should
also be applicable to hydroxy- or amino-terminated
co-drugs with further delicate functionalities.
Cisplatin and its three marketed congeners carbo-
platin, oxaliplatin and nedaplatin are still widely used
in the treatment of solid tumours although resistance
poses an increasingly severe problem for the clinician
[1–3]. Attempts to circumvent it by employing new plat-
inum complexes with modified structures and modes of
action are as numerous as are the various pathways of
tumour resistance themselves [4,5]. More recent exam-
ples include trans-Pt(II) and Pt(IV) compounds [6] or
cis-Pt(II) complexes with planar [6] or with non-NH li-
gands [7–9]. Particularly attractive appear conjugates
of platinum complexes with other drugs that are either
cytostatic [1,5,10], or which can act as shuttle systems,
homing devices, or scavengers for deactivating mole-
cules in the cell [11]. These conjugates are customarily
prepared by complexation of a preformed ligand–ancil-
lary drug combination onto a suitable inorganic plati-
2. Experimental
2.1. Synthesis of 6-aminomethylnicotinic acid (1a) and 2-
aminomethylisonicotinic acid (1b)
6-Cyanonicotinic acid or 2-cyanoisonicotinic acid
(1.48 g, 10.0 mmol), as obtained [13] from nicotinic acid
N-oxide or isonicotinic acid N-oxide (4.67 g, 33.6 mmol)
and a mixture of NaCN (4.92 g, 100 mmol), TMSCl
(25.6 mL, 200 mmol) and NEt3 (24.7 mL, 180 mmol)
in dry DMF, was added to a suspension of Pd (10%)
*
Corresponding author. Fax: +49 0921 552671.
E-mail address: rainer.schobert@uni-bayreuth.de (R. Schobert).
0020-1693/$ - see front matter ꢁ 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2005.05.015

3370
R. Schobert, B. Biersack / Inorganica Chimica Acta 358 (2005) 3369–3376
on charcoal (100 mg) in methanol (50 mL) and pressur-
ised with 1 bar of hydrogen gas for 4 h. The formed pre-
cipitate was redissolved by addition of water and the
resulting mixture was filtered over a plug of celite. The
filtrate was evaporated to dryness and the residue thus
obtained was recrystallized from hot water/ethanol to
leave off-white powdery solids.
(75.5 MHz, DMF-d7): d 53.6 (CH2), 121.8 (C-5), 124.0
(C-3), 140.2 (C-4), 148.7 (C-6), 165.6 (C-2), 167.8
(CO); 195Pt NMR (64.4 MHz, DMF-d7): d 2466.
2.3. Synthesis of amides (3)
Under exclusion of air and moisture a solution of 2
(100 mg, 0.24 mmol) in dry DMF (15 mL) was chilled
to 0 ꢀC and treated with NEt3 (34 lL, 0.24 mmol) and
ethyl chloroformate (26 lL, 0.26 mmol). After stirring
for 30 min at 0 ꢀC the respective amine (0.24 mmol)
was added and stirring was continued for another 12 h
at room temperature. For workup, a mixture of metha-
nol and CH2Cl2 (1:20, v/v; 50 mL) was added, the result-
ing crude was extracted with water (20 mL) and the
aqueous phase was re-extracted with the above solvent
mixture (5 · 20 mL). The combined organic phases were
finally concentrated in vacuo and the yellow residue thus
obtained was purified by column chromatography (silica
gel 60; CH2Cl2/acetone 1:1, v/v).
Compound 1a: 1.21 g (80%); m.p. 280 ꢀC [14]; mmax
(KBr)/cmꢀ1: 3038, 2839, 1596, 1580, 1527, 1380; 1H
NMR (300 MHz, D2O): d 4.37 (2H, s, CH2), 7.49 (1H,
d, 3J 8.06 Hz, 5-H), 8.19 (1H, d, 3J 8.06 Hz, 4-H),
8.91 (1H, s, 2-H); 13C NMR (75.5 MHz, D2O/1 M
HCl): d 42.5 (CH2), 123.4 (C-5), 126.8 (C-3), 140.5 (C-
4), 149.3 (C-2), 155.0 (C-6), 167.7 (CO); m/z (EI) 153
(37), 152 (47), 125 (43), 124 (72), 78 (67), 51 (100).
Compound 1b: 1.06 g (70%); m.p. 230 ꢀC (dec.).
C7H8N2O2 requires: C, 55.26; H, 5.30; N, 18.41. Found:
C, 55.22; H, 5.32; N, 18.29%. mmax (KBr)/cmꢀ1: 3198,
2839, 1596, 1549, 1505, 1375; 1H NMR (300 MHz,
3
D2O): d 4.38 (2H, s, CH2), 7.70 (1H, d, J 5.12 Hz, 5-
3
H), 7.74 (1H, s, 3-H), 8.63 (1H, d, J 5.12 Hz, 6-H);
Complex 3a: 45 mg (40%) from pyrrolidine (20 lL);
yellow solid, m.p. > 250 ꢀC; Rf = 0.14 (CH2Cl2/acetone
1:1, v/v). C11H15Cl2N3OPt requires: C, 28.04; H, 3.20;
N, 8.92. Found: C, 27.96; H, 3.16; N, 8.88%. mmax
(KBr)/cmꢀ1: 3158, 1607, 1438; mmax (polyethylene)/
13C NMR (75.5 MHz, D2O): d 43.3 (CH2), 121.7 (C-
5), 122.8 (C-3), 146.1 (C-4), 149.4 (C-6), 152.2 (C-2),
172.6 (CO); m/z (EI) 152 (99), 124 (100), 106 (10), 78
(35), 51 (63).
1
cmꢀ1: 358, 351, 330, 324; H NMR (300 MHz, DMF-
2.2. Synthesis of cis-dichloro(6-aminomethylnicotinic
acid)platinum (II) (2a) and cis-dichloro(2-
aminomethylisonicotinic acid)platinum (II) (2b)
d7): d 1.9–2.0 (4H, m, CCH2C), 3.5–3.6 (4H, m,
NCH2CH2), 4.42 (2H, t, 3J 5.92 Hz, H2NCH2), 6.3–
3
6.4 (2H, m, NH2), 7.81 (1H, d, J 8.13 Hz, 5-H), 8.39
3
3
(1H, d, J 8.13 Hz, 4-H), 9.47 (1H, s, JPtH 36 Hz, 2-
H); 13C NMR (75.5 MHz, DMF-d7): d 24.3, 26.5,
46.6, 49.4, 53.6 (NCH2), 121.9 (C-5), 133.7 (C-3),
137.3 (C-4), 146.6 (C-2), 164.3 (CO), 167.6 (C-6); 195Pt
NMR (64.4 MHz, DMF-d7): d 2439; m/z (EI) 205 (26)
[M+ ꢀ PtCl2], 177 (14), 135 (48), 36 (100) [Cl+]; m/z
(ESI) 494.08 (100) [M+ + Na].
A solution of 1 (185 mg, 1.22 mmol) and K2PtCl4
(505 mg, 1.22 mmol) in aqueous 1 M HCl (20 mL)
was gently stirred at 50 ꢀC for 3 days under exclusion
of air and sun light. The eventually formed yellow pre-
cipitate was collected on a Buchner funnel, thoroughly
¨
washed with water (100 mL), acetone (50 mL) and
diethyl ether (50 mL) and finally dried on an oil pump.
Complex 2a: 433 mg (85%); yellow solid, m.p. > 250 ꢀC.
C7H8Cl2N2O2Pt requires: C, 20.11; H, 1.93; N, 6.70.
Complex 3b: 87 mg (75%) from piperidine (24 lL);
yellow solid, m.p. > 250 ꢀC; Rf = 0.19 (CH2Cl2/acetone
1:1, v/v). C12H17Cl2N3OPt requires: C, 29.70; H, 3.53;
N, 8.66. Found: C, 29.80; H, 3.56; N, 8.45%. mmax
(KBr)/cmꢀ1: 3157, 1612, 1470; mmax (polyethylene)/
Found: C, 20.21; H, 2.02; N, 6.52%. mmax (KBr)/cmꢀ1
:
3435, 3264, 3206, 1724, 1571, 1384, 1232; mmax (polyeth-
1
ylene)/cmꢀ1: 335, 327; 1H NMR (300 MHz, DMF-d7): d
4.48 (2H, t, J 5.92 Hz, CH2), 6.3–6.4 (2H, m, NH2),
cmꢀ1: 355, 335, 329, 319; H NMR (300 MHz, DMF-
3
d7): d 1.6–1.7 (6H, m, CCH2C), 3.4–3.7 (4H, m,
NCH2CH2), 4.43 (2H, t, 3J 5.84 Hz, H2NCH2), 6.2–
3
3
7.88 (1H, d, J 8.20 Hz, 5-H), 8.64 (1H, d, J 8.20 Hz,
4-H), 9.86 (1H, s,3JPtH 37 Hz, 2-H); 13C NMR (75.5
MHz, DMF-d7): d 53.7 (CH2), 122.4 (C-5), 128.0 (C-
3), 139.1 (C-4), 148.7 (C-2), 164.8 (C-6), 170.4 (CO);
195Pt NMR (64.4 MHz, DMF-d7): d 2439.
3
6.4 (2H, m, NH2), 7.82 (1H, d, J 8.10 Hz, 5-H), 8.26
3
3
(1H, d, J 8.10 Hz, 4-H), 9.32 (1H, d, JPtH 32 Hz, 2-
H); 13C NMR (75.5 MHz, DMF-d7): d 24.4, 25.7,
26.5, 43.1, 53.6 (NCH2), 122.2 (C-5), 133.1 (C-3),
137.2 (C-4), 145.9 (C-2), 165.0 (CO), 167.5 (C-6); m/z
(EI) 219 (11) [M+ ꢀ PtCl2], 218 (16), 189 (9), 135 (24),
84 (19), 36 (100) [Cl+]; m/z (ESI) 508.07 (100)
[M+ + Na].
Complex 2b: 356 mg (70%); yellow solid, m.p. > 250 ꢀC.
C7H8Cl2N2O2Pt requires: C, 20.11; H, 1.93; N, 6.70.
Found: C, 20.32; H, 1.99; N, 6.71%. mmax (KBr)/cmꢀ1
:
3231, 3189, 1738, 1567, 1376, 1260; mmax (polyethyl-
1
ene)/cmꢀ1: 342, 325, 318; H NMR (300 MHz, DMF-
Complex 3c: 42 mg (36%) from piperidine (24 lL);
yellow solid, m.p. > 250 ꢀC; Rf = 0.40 (CH2Cl2/acetone
1:1, v/v). C12H17Cl2N3OPt requires: C, 29.70; H, 3.53;
N, 8.66. Found: C, 29.77; H, 3.44; N, 8.60%. mmax
3
d7): d 4.47 (2H, t, J 5.98 Hz, CH2), 6.3–6.4 (2H, m,
NH2), 7.97 (1H, d, J 6.09 Hz, 5-H), 8.15 (1H, s, 3-H),
3
3
9.45 (1H, d, 3J 6.09, JPtH 31 Hz, 6-H); 13C NMR

R. Schobert, B. Biersack / Inorganica Chimica Acta 358 (2005) 3369–3376
3371
(KBr)/cmꢀ1: 3266, 1627, 1572, 1451; mmax (polyethylene)/
[M+ ꢀ PtCl2 ꢀ CH2NH2], 198 (31), 154 (30), 127 (39)
1
cmꢀ1: 367, 343, 330; H NMR (300 MHz, DMF-d7): d
1.5–1.7 (6H, m, CCH2C), 3.3–3.4 (2H, m, NCH2CH2),
[C10H9+], 115 (22), 43 (100), 36 (97) [Cl+].
3
3.6–3.7 (2H, m, NCH2CH2), 4.41 (2H, t, J 5.96 Hz,
2.4. Synthesis of ester functionalized complexes (7)
3
H2NCH2), 6.2–6.4 (2H, m, NH2), 7.55 (1H, d, J 6.04
3
3
Hz, 5-H), 7.73 (1H, s, 3-H), 9.30 (1H, d, J 6.04, JPtH
34 Hz, 6-H); 13C NMR (75.5 MHz, DMF-d7): d 24.4,
25.6, 26.4, 42.7, 48.3, 53.7 (NCH2), 122.1 (C-3, C-5),
146.5 (C-4), 148.3 (C-6), 166.1 (C-2), 167.4 (CO); m/z
(EI) 219 (19) [M+ ꢀ PtCl2], 190 (13), 136 (15), 108
(19), 36 (100) [Cl+].
2.4.1. Synthesis of 6-(N-t-butoxycarbonylaminomethyl)
nicotinic acid (4)
Compound 4 (330 mg, 91%) was prepared according
to a known procedure [15,16] from 1a (200 mg, 1.32
mmol) and di-t-butyl dicarbonate (530 mg, 2.43 mmol)
in water/t-butanol (20 mL, 1:1, v/v) at pH 9–10 and 0
ꢀC ! r.t. mmax (KBr)/cmꢀ1: 3314, 2977, 1686, 1529,
1288; 1H NMR (300 MHz, MeOD): d 1.47 (9H, s,
Complex 3d: 71 mg (60%) from aniline (33 lL); yel-
low solid, m.p. > 250 ꢀC; Rf = 0.39 (CH2Cl2/acetone
1:1, v/v). C13H13Cl2N3OPt requires: C, 31.65; H, 2.65;
N, 8.52. Found: C, 31.45; H, 2.48; N, 8.41%. mmax
(KBr)/cmꢀ1: 3197, 1644, 1602, 1533, 1443; 1H NMR
3
CH3), 4.41 (2H, s, CH2), 7.47 (1H, d, J 8.14 Hz, 5-
3
H), 8.35 (1H, d, J 8.14 Hz, 4-H), 9.04 (1H, s, 2-H);
13C NMR (75.5 MHz, MeOD): d 28.9 (CH3), 46.7
(CH2), 80.8 (CMe3), 122.0 (C-5), 127.0 (C-3), 139.8 (C-
4), 151.2 (C-2), 158.7 (OCON), 164.8 (C-6), 168.0
(CO2); m/z (EI) 252 (1) [M+], 197 (30), 179 (15), 151
(15), 136 (10), 78 (5), 57 (100).
3
(300 MHz, DMF-d7): d 4.46 (2H, t, J 5.90 Hz, CH2),
6.3–6.4 (2H, m, NH2), 7.1–7.2 (1H, m, Ph-H), 7.3–7.4
(2H, m, Ph-H), 7.8–7.9 (3H, m, Ph-H, 5-H), 8.75 (1H,
3
d, J 8.24 Hz, 4-H), 9.76 (1H, s, 2-H), 10.83 (1H, s,
NH); 13C NMR (75.5 MHz, DMF-d7): d 54.4 (CH2),
121.4 (Ph-Cm), 122.7 (C-5), 125.3 (Ph-Cp), 129.8 (Ph-
Co), 132.9 (C-3), 138.2 (C-4), 140.2 (Ph-Cipso), 148.3
(C-2), 169.7 (C-6); 195Pt NMR (64.4 MHz, DMF-d7):
d 2437; m/z (EI) 494 (8) [M+ + 1], 225 (52), 199 (49),
78 (11), 36 (100) [Cl+].
2.4.2. Synthesis of esters (5)
Compound 4 (200 mg, 0.79 mmol) was dissolved in
dry DMF (2 mL) and treated with triethylamine (110
lL, 0.79 mmol). 2,4,6-Trichlorobenzoyl chloride (127
lL, 0.79 mmol) was added and the suspension was stir-
red under argon at room temperature for 20 min. Benzyl
alcohol (163 ll, 1.58 mmol), 2-methyl-2,4-pentanediol
(202 mL, 1.58 mmol), (–)-menthol (247 mg, 1.58 mmol)
or cholesterol (611 mg, 1.58 mmol), respectively, and
DMAP (192 mg, 1.58 mmol) in dry toluene (20 mL)
were added and the resulting mixture was stirred under
argon at room temperature for a further 16 h. After
dilution with diethyl ether (100 mL) and washing with
water (100 mL) the organic phase was dried over
Na2SO4 and concentrated in vacuum. The residue was
purified by column chromatography (silica gel 60; sol-
vent as indicated).
Complex 3e: 47 mg (40%) from aniline (33 lL); yellow
solid, m.p. > 250 ꢀC; Rf = 0.66 (CH2Cl2/acetone 1:1, v/
v). C13H13Cl2N3OPt requires: C, 31.65; H, 2.65; N,
8.52. Found: C, 31.56; H, 2.55; N, 8.50%. mmax (KBr)/
cmꢀ1: 3137, 1668, 1528, 1439;1H NMR (300 MHz,
3
DMF-d7): d 4.47 (2H, t, J 5.97 Hz, H2NCH2), 6.3–6.4
(2H, m, NH2), 7.1–7.3 (1H, m, Ph-H), 7.4–7.5 (2H, m,
Ph-H), 7.8–7.9 (2H, m, Ph-H), 8.18 (1H, s, 3-H), 9.41
(1H, d, 3J 6.17 Hz, 6-H), 10.77 (1H, s, NH); 13C
NMR (75.5 MHz, DMF-d7): d 54.4 (CH2), 121.3 (Ph-
Cp), 121.4 (Ph-Co), 123.3 (C-5), 125.5 (C-3), 129.9 (Ph-
Cm), 139.9 (Ph-Cipso), 144.7 (C-4), 148.9 (C-6), 164.0
(C-2), 168.1 (CO); 195Pt NMR (64.4 MHz, DMF-d7): d
2459; m/z (EI) 232 (8), 205 (7), 110 (12), 36 (100) [Cl+].
Complex 3f: 32 mg (26%) from 1-naphthylamine (34
mg); yellow solid, m.p. > 250 ꢀC; Rf = 0.42 (CH2Cl2/ace-
tone 2:1, v/v). C17H15Cl2N3OPt requires: C, 37.58; H,
2.78; N, 7.73. Found: C, 37.66; H, 2.70; N, 7.64%. mmax
(KBr)/cmꢀ1: 3196, 1652, 1532, 1504; 1H NMR (300
Compound 5a: 244 mg (90%); colourless oil; Rf = 0.37
(ethyl acetate/n-hexane 1:2, v/v);mmax (KBr)/cmꢀ1: 3358,
2977, 1711, 1589, 1498, 1365, 1271, 1164, 1108; 1H
NMR (300 MHz, CDCl3): d 1.42 (9H, s, CH3), 4.45
3
(2H, d, J 5.63 Hz, CH2), 5.34 (2H, s, OCH2), 5.7–5.8
(1H, m, NH), 7.2–7.5 (6H, m, Ph-H, 5-H), 8.23 (1H,
3
d, J 8.16 Hz, 4-H), 9.12 (1H, s, 2-H); 13C NMR (75.5
3
MHz, DMF-d7): d 4.51 (2H, t, J 5.89 Hz, H2NCH2),
6.40 (2H, m, NH2), 7.5–7.7 (3H, m, Ph-H), 7.82 (1H,
MHz, CDCl3): d 28.3 (CH3), 45.7 (CH2), 66.9 (OCH2),
79.6 (CMe3), 121.0 (C-5), 124.5 (C-3), 128.1 (Ph-Co),
128.4 (Ph-Cp), 128.6 (Ph-Cm), 135.4 (Ph-Cipso), 137.7
(C-4), 150.4 (C-2), 155.9 (OCON), 162.2 (C-6), 164.9
(CO2); m/z (EI) 342 (5) [M+], 287 (100), 269 (31), 243
(30), 241 (24), 214 (16), 179 (15), 161 (8), 135 (29), 106
(8), 91 (98).
Compound 5b: 222 mg (80%); colourless oil; Rf = 0.20
(ethyl acetate/n-hexane 1:1, v/v); mmax (KBr)/cmꢀ1: 3364,
2975, 1694, 1599, 1517, 1365, 1281, 1164, 1115; 1H
NMR (300 MHz, DMSO-d6): d 1.08 (3H, s, 10-H),
3
3
d, J 7.31 Hz, Ph-H), 7.94 (1H, d, J 8.21 Hz, Ph-H),
8.1–8.3 (2H, m, Ph-H), 8.32 (1H, s, 30-H), 9.47 (1H, d,
3J 6.12 Hz, 60-H), 10.90 (1H, s, NH); 13C NMR (75.5
MHz, DMF-d7): d 54.5 (CH2), 121.6 (C-8a), 123.6 (C-
50), 124.2 (C-2), 124.3 (C-4), 126.6 (C-7), 127.2 (C-3),
127.3 (C-8), 127.8 (C-5), 129.3 (C-6), 129.9 (C-4a),
134.4 (C-1), 135.4 (C-30), 144.6 (C-40), 149.0 (C-
60), 165.0 (C-20), 168.2 (CO); 195Pt NMR (64.4
MHz, DMF-d7):
d
2459; m/z (EI) 247 (4)

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R. Schobert, B. Biersack / Inorganica Chimica Acta 358 (2005) 3369–3376
1.12 (3H, s, 20-CH3), 1.30 (3H, d, 3J 6.29 Hz, 50-H), 1.40
(9H, s, Boc-CH3), 1.66 (1H, dd, 2J14.56 Hz, 3J 3.28 Hz,
30-Ha), 1.92 (1H, dd, 2J14.56 Hz, 3J 8.15 Hz, 30-Hb), 4.28
(2H, d, 3J 6.12 Hz, CH2N), 4.34 (1H, s, 20-OH), 5.2–5.4
(1H, m, 40-H), 7.40 (1H, d, 3J 8.20 Hz, 5-H), 7.52 (1H, t,
3J 6.12 Hz, NHBoc), 8.27 (1H, d, 3J 8.20 Hz, 4-H), 8.99
(1H, s, 2-H); 13C NMR (75.5 MHz, DMSO-d6): d 21.6
(C-50), 28.2 (CMe3), 28.8 (C-10), 30.8 (20-CH3), 45.5
(CH2N), 48.6 (C-30), 68.0 (C-20), 69.3 (C-40), 78.1
(CMe3), 120.3 (C-5), 124.5 (C-3), 137.4 (C-4), 149.4
(C-2), 155.9 (OCON), 164.1 (C-6), 164.2 (CO2); m/z
(EI) 352 (6) [M+], 297 (100), 279 (31), 197 (55), 179
(62), 152 (45), 135 (20), 57 (99).
2.4.3. Synthesis of 6-aminomethylnicotinates (6)
Compound 6a: Benzyl 6-(t-butoxycarbonylaminom-
ethyl)nicotinate 5a (238 mg, 0.69 mmol) was treated
with 4 M HCl/dioxane (10 ml) and stirred for 30 min.
The colourless precipitate of benzyl 6-aminomethylnico-
tinate hydrochloride was collected, washed with diethyl
ether and dried. Yield: 154 mg (71%), m.p. 155–156 ꢀC;
mmax (KBr)/cmꢀ1: 2962, 2858, 1731, 1614, 1496, 1453,
1
1387, 1295; H NMR (300 MHz, D2O): d 4.44 (2H, s,
CH2N), 5.34 (2H, s, OCH2), 7.4–7.6 (5H, m, Ph-H),
3
3
7.61 (1H, d, J 8.22 Hz, 5-H), 8.44 (1H, d, J 8.22 Hz,
4-H), 9.15 (1H, s, 2-H); 13C NMR (75.5 MHz, D2O): d
42.8 (CH2), 67.8 (PhCH2), 122.8 (C-5), 125.9 (C-3),
128.4 (Ph-Co), 128.8 (Ph-Cp), 128.9 (Ph-Cm), 135.3
(Ph-Cipso), 139.2 (C-4), 149.9 (C-2), 156.0 (C-6), 166.3
(CO); m/z (EI) 242 (100) [M+], 214 (86), 197 (6), 151
(9), 135 (97), 107 (11), 91 (100).
Compound 5c: 240 mg (78%); colourless oil; Rf = 0.35
(ethyl acetate/n-hexane 1:3, v/v);mmax (KBr)/cmꢀ1: 3363,
2956, 2929, 1713, 1599, 1503, 1366, 1288, 1275, 1167,
1
1115, 1023, 731; H NMR (300 MHz, CDCl3): d 0.73
3
(3H, d, J 6.95 Hz, 90-H), 0.8–1.0 (7H, m, 80-H, 100-
Compound 6b: Compound 5b (275 mg, 0.78 mmol)
was treated with 4 M HCl/dioxane (20 mL) and stirred
for 45 min. Diethyl ether was added and the colourless
precipitate of 4-hydroxy-4-methylpent-20-yl 6-aminom-
ethylnicotinate hydrochloride was collected, washed
with THF and diethyl ether and dried. Yield: 164 mg
(65%), m.p. 105 ꢀC; mmax (KBr)/cmꢀ1: 3384, 3049,
2970, 1725, 1644, 1478, 1461, 1357, 1293; 1H NMR
(300 MHz, D2O): d 1.21 (3H, s, 50-H), 1.23 (3H, s, 40-
H, 40-Hax), 1.0–1.2 (2H, m, 30-Hax, 60-Hax), 1.41 (9H,
s, Boc-CH3), 1.5–1.6 (2H, m, 20-H, 50-H), 1.6–1.7 (2H,
m, 30-Heq, 40-Heq), 1.8–2.0 (1H, m, 70-H), 2.0–2.1 (1H,
3
m, 60-Heq), 4.44 (2H, d, J 5.61 Hz, CH2N), 4.89 (1H,
3
dt, J 10.86 Hz, 4.40 Hz, 10-H), 5.6–5.8 (1H, m,
3
NHBoc), 7.31 (1H, d, J 8.15 Hz, 5-H), 8.20 (1H, d,
3J 8.15 Hz, 4-H), 9.08 (1H, s, 2-H); 13C NMR (75.5
MHz, CDCl3): d 16.5 (C-90), 20.6 (C-80), 21.9 (C-90),
23.6 (C-30), 26.5 (C-70), 28.3 (CMe3), 31.4 (C-50), 34.2
(C-40), 40.8 (C-60), 45.8 (CH2N), 47.1 (C-20), 75.4 (C-
10), 79.6 (C Me3), 121.0 (C-5), 125.2 (C-3), 137.7 (C-
4), 150.4 (C-2), 155.9 (OCON), 161.9 (C-6), 164.6
(CO2); m/z (EI) 390 (17) [M+], 335 (26), 197 (17), 179
(21), 153 (30), 135 (18), 95 (28), 81 (20), 57 (100), 41
(54).
3
2
CH3), 1.37 (3H, d, J 6.28 Hz, 10-H), 1.82 (1H, dd, J
3
2
15.16 Hz, J 2.76 Hz, 30-Ha), 2.13 (1H, dd, J 15.16
Hz, J 8.72 Hz, 30-Hb), 4.44 (2H, s, CH2N), 5.3–5.5
3
3
(1H, m, 20-H), 7.63 (1H, d, J 8.22 Hz, 5-H), 8.47 (1H,
d, J 8.22 Hz, 4-H), 9.15 (1H, s, 2-H); 13C NMR (75.5
3
MHz, D2O): 20.7 (C-10), 27.9 (C-50), 28.1 (40-CH3),
42.7 (CH2N), 47.7 (C-30), 70.5 (C-40), 71.1 (C-20),
123.0 (C-5), 126.6 (C-3), 139.6 (C-4), 149.6 (C-2),
155.5 (C-6), 165.8 (CO); m/z (EI) 252 (7) [M+ ꢀ 2HCl],
152 (41), 135 (52), 124 (69), 107 (18), 79 (38), 59 (100).
Compound 6c: Compound 5c (200 mg, 0.51 mmol)
was treated with 4 M HCl/dioxane (15 mL) and stirred
for 1 h. The formed colourless precipitate was collected,
washed with diethyl ether and dried. Yield: 152 mg
(82%), m.p. 194 ꢀC; mmax (KBr)/cmꢀ1: 3043, 2940,
Compound 5d: 350 mg (80%); white solid; m.p. 159
ꢀC; Rf = 0.22 (ethyl acetate/n-hexane 1:3, v/v); mmax
(KBr)/cmꢀ1: 3244, 2932, 1711, 1702, 1598, 1365, 1290,
1
1120; H NMR (300 MHz, CDCl3): d 0.67 (3H, s, 180-
3
H), 0.84 (6H, d, J 6.60 Hz, 260-H, 270-H), 0.90 (3H,
3
d, J 6.51 Hz, 210-H), 0.9–2.0 (38H, sterol-H, Boc-
3
3
CH3), 2.44 (2H, d, J 7.54 Hz, 40-H), 4.47 (2H, d, J
5.45 Hz, CH2N), 4.8–4.9 (1H, m, 30-H), 5.3–5.4 (1H,
3
1
m, 60-H), 5.5–5.6 (1H, m, NH), 7.32 (1H, d, J 8.24
1723, 1644, 1358, 1292, 1120, 1084, 959, 891, 755; H
3
Hz, 5-H), 8.23 (1H, d, J 8.24 Hz, 4-H), 9.10 (1H, s, 2-
3
NMR (300 MHz, D2O): d 0.70 (3H, d, J 6.91 Hz, 90-
13
H); C NMR (75.5 MHz, CDCl3): d 11.9 (C-180), 18.7
H), 0.8–1.0 (7H, m, 80-H, 100-H, 40-Hax), 1.0–1.2 (2H,
m, 30-Hax, 60-Hax), 1.3–1.7 (4H, m, 20-H, 30-Heq, 40-
Heq, 50-H), 1.8–1.9 (1H, m, 70-H), 2.0–2.1 (1H, m, 60-
(C-210), 19.4 (C-190), 21.1 (C-110), 22.6 (C-260), 22.8
(C-270), 23.8 (C-230), 24.3 (C-150), 27.8 (CMe3), 28.0
(C-250), 28.2 (C-160), 31.9 (C-70), 31.9 (C-80), 35.8 (C-
200), 36.2 (C-220), 36.6 (C-100), 37.0 (C-10), 38.1 (C-20),
39.5 (C-240), 39.7 (C-120), 42.3 (C-40), 42.3 (C-130),
45.8 (CH2N), 50.0 (C-90), 56.1 (C-170), 56.7 (C-140),
75.2 (C-30), 79.7 (C Me3), 121.0 (C-60), 123.0 (C-5),
125.3 (C-3), 137.7 (C-4), 139.4 (C-50), 150.4 (C-2),
156.0 (OCON), 161.8 (C-6), 164.6 (CO2); m/z (EI)
622 (1) [M+ + 1], 368 (23), 247 (5), 178 (9), 145 (12),
121 (12), 105 (18), 91 (21), 81 (37), 57 (36), 55 (49), 43
(100).
3
Heq), 4.43 (2H, s, CH2N), 4.87 (1H, dt, J 10.80 Hz,
4.39 Hz, 10-H), 7.62 (1H, d, 3J 8.18 Hz, 5-H), 8.33
3
(1H, d, J 8.18 Hz, 4-H), 9.06 (1H, s, 2-H); 13C NMR
(75.5 MHz, DMSO-d6): d 17.6 (C-90), 21.3 (C-80), 22.8
(C-100), 24.4 (C-30), 27.5 (C-70), 32.0 (C-50), 34.6 (C-
40), 41.4 (C-60), 43.5 (CH2N), 47.6 (C-20), 76.8 (C-10),
123.6 (C-5), 126.6 (C-3), 139.2 (C-4), 150.7 (C-2),
157.9 (C-6), 165.8 (CO); m/z (EI) 290 (12) [M+ ꢀ 2HCl],
262 (5), 152 (100), 135 (46), 124 (60), 95 (28), 81 (21), 55
(31), 41 (41).

R. Schobert, B. Biersack / Inorganica Chimica Acta 358 (2005) 3369–3376
3373
2.4.4. Synthesis of 6-aminomethylnicotinate complexes
(7)
32 Hz, 2-H); 13C NMR (75.5 MHz, DMF-d7): d 16.4
(C-90), 20.5 (C-80), 21.8 (C-100), 23.7 (C-30), 26.8 (C-
70), 31.5 (C-50), 34.2 (C-40), 40.9 (C-60), 47.4 (C-20),
53.7 (CH2N), 76.2 (C-10), 122.6 (C-5), 127.3 (C-3),
138.9 (C-4), 148.5 (C-2), 163.1 (C-6), 170.8 (CO); 195Pt
NMR (64.4 MHz, DMF-d7): d 2439; m/z (EI) 290 (7)
[M+ ꢀ PtCl2], 152 (42), 124 (30), 95 (50), 36 (100).
Complex 7d: Compound 5d (166 mg, 0.27 mmol) was
dissolved in CH2Cl2 (10 mL) and TFA (10 mL) was
added [12]. The mixture was stirred for 1 h at room tem-
perature. After evaporation of the solvent the residue
was dissolved in THF (10 mL) and treated with a solu-
tion of K2PtCl4 in water (5 mL); the pH was adjusted to
5–6 with aqueous NaHCO3. After stirring for 24 h at
room temperature the formed precipitate was collected,
washed with water, acetone and diethyl ether and dried.
Yield: 84 mg (40%), yellow solid of m.p. 240 ꢀC (dec.).
C34H52Cl2N2O2Pt requires: C, 51.90; H, 6.66; N, 3.58.
Complex 7a: Compound 6a (120 mg, 0.38 mmol) was
dissolved in water (10 mL), the pH value was adjusted to
ca. 6 with aqueous NaOH, and K2PtCl4 (158 mg, 0.38
mmol) in water (10 mL) was added. The resulting mix-
ture was stirred for 24 h at room temperature while
the pH was kept at 5–6. The yellow solid precipitate
was collected, washed with water, acetone and diethyl
ether and dried. Yield: 152 mg (80%), m.p. > 250 ꢀC.
C14H14Cl2N2O2Pt requires: C, 33.08; H, 2.78; N, 5.51.
Found: C, 33.34; H, 2.92; N, 5.55%. mmax (KBr)/cmꢀ1
:
3253, 3195, 3049, 1721, 1622, 1573, 1375, 1290, 1148;
3
1H NMR (300 MHz, DMF-d7): d 4.48 (2H, t, J 5.94
Hz, CH2N), 5.48 (2H, s, PhCH2), 6.3–6.4 (2H, m,
3
NH2), 7.3–7.6 (5H, m, Ph-H), 7.91 (1H, d, J 8.25 Hz,
3
3
5-H), 8.69 (1H, d, J 8.25 Hz, 4-H), 9.91 (1H, s, JPtH
33 Hz, 2-H); 13C NMR (75.5 MHz, DMF-d7): d 53.7
(CH2), 67.5 (PhCH2), 122.6 (C-5), 127.0 (C-3), 128.5
(Ph-Co), 128.7 (Ph-Cp), 128.9 (Ph-Cm), 136.2 (Ph-Cipso),
139.0 (C-4), 148.5 (C-2), 163.4 (C-6), 170.9 (CO); 195Pt
NMR (64.4 MHz, DMF-d7): d 2441; m/z (EI) 509 (1)
[M+], 507 (1) [M+], 419 (5), 330 (23), 302 (7), 242 (29),
214 (25), 135 (31), 91 (100).
Found: C, 52.70; H, 6.73; N, 3.53. mmax (KBr)/cmꢀ1
:
3234, 2934, 1725, 1622, 1466, 1293, 1276, 1131, 751;
1H NMR (300 MHz, DMF-d7): d 0.73 (3H, s, 180-H),
0.88 (6H, d, 3J 6.61 Hz, 260-H, 270-H), 0.9–2.1 (32H, ste-
3
rol-H), 2.4–2.6 (2H, m, 40-H), 4.48 (2H, t, J 5.93 Hz,
CH2N), 4.7–4.9 (1H, m, 30-H), 5.4–5.5 (1H, m, 60-H),
3
6.3–6.4 (2H, m, NH2), 7.91 (1H, d, J 8.21 Hz, 5-H),
Complex 7b: 97 mg (60%) from 6b (100 mg, 0.31
mmol) and K2PtCl4 (129 mg, 0.31 mmol); yellow solid
of m.p. > 250 ꢀC. C13H20Cl2N2O3Pt requires: C, 30.13;
H, 3.98; N, 5.40. Found: C, 29.58; H, 4.06; N, 5.39%.
mmax (KBr)/cmꢀ1: 3425, 3198, 2972, 1719, 1622, 1366,
1296, 1147; 1H NMR (300 MHz, DMF-d7): d 1.20
(3H, s, 50-H), 1.22 (3H, s, 40-CH3), 1.38 (3H, d, 3J
3
8.68 (1H, d, J 8.21 Hz, 4-H), 9.87 (1H, s, 2-H); m/z
(EI) 368 (44), 353 (11), 255 (13), 213 (10), 147 (27),
105 (38), 81 (45), 55 (51), 41 (88), 36 (100).
2.5. Reaction of the complexes (2a), (2b), (3b) and (7b)
with disodium 50-GMP
2
3
6.28, 10-H), 1.77 (1H, dd, J14.62 Hz, J 3.50 Hz, 30-
Ha), 2.00 (1H, dd, 2J 14.62 Hz, J 7.94 Hz, 30-Hb),
The reactions were carried out in Eppendorf vials in
D2O/10% DMF-d7. Two equivalents of disodium gua-
nosine 50-monophosphate (50-GMP; Sigma-Aldrich)
were dissolved and added to the respective complex to
yield a concentration of 8 mM in a total volume of 1
mL. The resulting mixture was shaken at 37 ꢀC for 48
3
3
4.42 (1H, s, OH), 4.47 (2H, t, J 5.95 Hz, CH2N), 5.4–
5.5 (1H, m, 20-H), 6.3–6.4 (2H, m, NH2), 7.90 (1H, d,
3J 8.24 Hz, 5-H), 8.67 (1H, d, J 8.24 Hz, 4-H), 9.87
3
(1H, s, JPtH 30 Hz, 2-H); 13C NMR (75.5 MHz,
3
DMF-d7): d 21.5 (C-10), 29.1 (C-50), 30.9 (40-CH3),
49.2 (C-30), 53.7 (CH2N), 68.5 (C-40), 71.0 (C-20),
122.5 (C-5), 127.6 (C-3), 138.9 (C-4), 148.5 (C-2),
163.0 (C-6), 170.7 (CO); 195Pt NMR (64.4 MHz,
DMF-d7): d 2438; m/z (EI) 252 (5) [M+ ꢀ PtCl2], 152
(38), 135 (33), 124 (28), 67 (49), 59 (46), 36 (100).
1
h while monitor H NMR spectra were taken at inter-
vals of 1 h for 12 h and in addition at the times indicated
in Fig. 1 and after 24 and 48 h (DMF signal at 8.03 ppm
taken as an internal shift standard).
Complex 7c: 147 mg (78%) from 6c (124 mg, 0.34
mmol) and K2PtCl4 (140 mg, 0.34 mmol); yellow solid
of m.p. > 250 ꢀC. C17H26Cl2N2O2Pt requires: C, 36.70;
H, 4.71; N, 5.04. Found: C, 37.17; H, 4.85; N, 5.04%.
mmax (KBr)/cmꢀ1: 3215, 2954, 1727, 1618, 1406, 1289,
3. Results and discussion
3.1. Synthesis
1
1124, 954, 753; H NMR (300 MHz, DMF-d7): d 0.80
Planar monodentate as well as chelating arylamines
such as pyridine, quinoline, dipyridyl [1] or 2-aminom-
ethylpyridine [11a] were found to confer enhanced antit-
umour activity to both cis- and trans-Pt(II) complexes.
We chose 6-aminomethylnicotinic acid (1a) and 2-
aminomethylisonicotinic acid (1b) as chelate ligands
that provide a carboxylic group as an anchor for the
attachment of ancillary amino or hydroxy moieties.
3
(3H, d, J 6.95 Hz, 90-H), 0.8–1.0 (7H, m, 80-H, 100-H,
40-Hax), 1.1–1.3 (2H, m, 30-Hax, 60-Hax), 1.5–1.6 (2H,
m, 20-H, 50H), 1.7–1.8 (2H, m, 30-Heq, 40-Heq), 1.9–2.0
3
(1H, m, 70-H), 2.0–2.2 (1H, m, 60-Heq), 4.48 (2H, t, J
3
5.92 Hz, CH2N), 4.95 (1H, dt, J 10.86 Hz, 4.41 Hz,
3
10-H), 6.3–6.4 (2H, m, NH2), 7.91 (1H, d, J 8.24 Hz,
3
5-H), 8.68 (1H, d, J 8.24 Hz, 4-H), 9.89 (1H, s, JPtH
3

3374
R. Schobert, B. Biersack / Inorganica Chimica Acta 358 (2005) 3369–3376
HO2C
4
HO2C
3
K2PtCl4, 1 M HCl
50˚C
N
N
Cl Pt NH2
Cl
NH2
1
2a: 3-CO2H (85%)
b: 4-CO2H (70%)
Scheme 2. Synthesis of cis-diamine(dichloro)platinum(II) complexes 2.
3JPtH = 37 Hz) and H-6 in 2b (Dd = ꢀ0.82 ppm;
3JPtH = 31 Hz). The 195Pt NMR spectra also showed dis-
tinct signals [2a: d = 2439 ppm; 2b: d = 2466 ppm, rela-
tive to N(195Pt) = 21.4 MHz] with line widths of 250–
300 Hz which is typical of N-ligated platinum. The far
IR spectra, recorded of samples embedded in polyethyl-
ene disks, were diagnostic of the cis-PtCl2 moiety [2a:
m = 335, 327 cmꢀ1; 2b: m = 342, 325, 318 cmꢀ1].
Fig. 1. 1H NMR monitoring of reactions of 2a (top) and 7b (bottom)
with 50-GMP in 10% DMF-d7/D2O at 37 ꢀC to give complexes as
shown in the middle (X = Cl or GMP).
3.3. Amide bond formation
Compounds 1 were readily obtained from nicotinic and
isonicotinic acid, respectively, by modified literature
procedures [13,14] via the corresponding N-oxides and
a-cyano derivatives (Scheme 1).
Brunner [11a] obtained cis-2-aminomethylpyri-
dine(dichloro)platinum (II) from reaction of 2-aminom-
ethylpyridine with K2PtCl4 under slightly acidic
conditions. While the analogous reaction of 3,4-diami-
nobenzoic acid in our hands only led to the formation
of a dark-green compound which we think is a salt of
the Magnus-type [Pt(diamine)]2+ [PtCl4]2ꢀ [17], the reac-
tion of 1 with K2PtCl4, carried out in 1 M HCl at 50 ꢀC,
gave the complexes 2 as yellow crystalline precipitates
(Scheme 2).
Attachment of amines to the carboxylic acid group of
complexes 2 was accomplished by amide formation via
the mixed anhydrides generated by treatment with ethyl
chloroformate and triethylamine at room temperature
or below. Subsequent addition of primary amines (ani-
line, 1-naphthylamine) or secondary amines (pyrroli-
dine, piperidine) to these highly reactive anhydrides
yielded the corresponding amides in 25–75% (Scheme
3). Other amidation methods employing condensation
reagents such as DCC/DMAP (Steglich conditions)
failed to give pure products in reasonable yields.
3.4. Ester bond formation
Contrary to the amidation described above, the
attachment of alcohols to the preformed complexes 2
failed when attempted under the usual conditions,
including the mixed anhydride method. Hence the nico-
tinate complexes 7 were best prepared following the
opposite strategy: synthesis of the required 6-aminometh-
ylnicotinates 6 (not shown) by Yamaguchi esterification
3.2. Spectroscopy
1H NMR spectra of complexes 2 were recorded of
solutions in DMF-d7 and found to be quite well resolved
and sharp. All protons exhibited a downfield shift when
compared with the signals of the free ligands, most sig-
nificantly so the protons H-2 in 2a (Dd = ꢀ0.95;
R1
O
CO2H
4
N
4
CO2H
CO2H
CO2H
1) ClCO2Et, Et3N
DMF, 0˚C, 30 min
R2
3
(i)
(ii)
NC
(iii)
2
1
N
2) NR1R2H, r.t., 12 h
N
N
N
O
N
R1
R2
[%]
position
3
NH2
-(CH2)4-
H2N Pt Cl
Cl
a
b
c
d
e
f
3
3
4
3
4
4
40
75
36
60
40
26
-(CH2)5-
-(CH2)5-
Ph
Ph
1a: 3-CO2H
b: 4-CO2H
H
H
Scheme 1. Reagents and conditions: (i) H2O2 (30%), AcOH, 90 ꢀC,
85%; (ii) NEt3, TMSCl, NaCN, DMF, 105 ꢀC, 55%; (iii) H2, Pd/C
(10%), MeOH, r.t., (1a: 80%; 1b: 70%).
1-naphthyl H
Scheme 3. Amidation of complexes 2 to give 3.

R. Schobert, B. Biersack / Inorganica Chimica Acta 358 (2005) 3369–3376
3375
of the Boc-protected [15] acids 4 and subsequent depro-
tection, and finally ligation of 6 by treatment with
K2PtCl4 in H2O at pH 5–6 (Scheme 4). The Yamaguchi
protocol [18] is quite effective under mild conditions and
allows to discriminate between primary/secondary and
between secondary/tertiary hydroxy groups which might
be advantageous for the conjugation of more complex
hydroxy substituted co-drugs.
of 2a reflects the presence of a stereogenic centre in the
(racemic) ester side chain leading to diastereoisomers.
However, in principle, multiple signals can also arise
from rotamers. Interestingly, the protons 4-HN and 5-
HN of the aminomethylnicotinic acid ligand also shifted
downfield, e.g., in the case of 2a from 8.53 and 7.71 ppm
in the starting complex to 8.58 and 7.85 ppm, respec-
tively, in the platinum bis–GMP adduct. An intermedi-
ate signal at 7.77 ppm, observable between 1 and 4.5 h
after reaction start can be assigned to a relatively long-
lived platinum mono–GMP adduct. Also worthy of note
is that 2-HN, peaking at 9.48 ppm for the dichloro com-
plex 2a, is no longer visible in the respective bis–GMP
adduct, presumably due to hydrogen bond formation
with nearby groups on the GMP ligand cis to the pyri-
dine N atom, while a small signal at 9.51 ppm is likely
to stem from the 2-HN of the trans-mono–GMP adduct.
In summation we found that cis-dichloro[methyla-
mino(iso-)nicotinate]platinum (II) complexes of types
2, 3 and 7 readily interact with guanosine. The syntheses
of the amide and ester conjugate complexes 3 and 7 are
straightforward. Amines can be attached in one step to
the carboxylic acid group of cis-dichloro[amino-
methyl(iso-)nicotinic acid]platinum (II) 2 to give 3, while
the ester complexes 7 are best prepared from the pre-
formed ligands and K2PtCl4. We are currently applying
both methods to the synthesis of conjugates of com-
plexes 2 with various natural and synthetic NH2- and
OH-functionalized electrophiles and intercalators of
proven bioactivity.
3.5. Interaction of complexes 2, 3 and 7 with guanosine 50-
monophosphate disodium salt
Antineoplastic platinum (II) complexes target the
DNA by binding irreversibly to N-7 of accessible guan-
ine residues. Hence prospective drug candidates of this
type, apart from other requirements such as sufficient
accumulation by the cell and robustness against deacti-
vation and damage–repair mechanisms, should readily
react with free guanosine 50-monophosphate (50-
1
GMP). This process is easily monitored by H NMR
spectroscopy [12,19]. We shook Eppendorf vials con-
taining solutions of complexes 2a, 2b, 3b or 7b, respec-
tively, and two equivalents of disodium 50-GMP in
10% DMF-d7/D2O at 37 ꢀC and recorded 1H NMR
spectra at regular intervals of 1 h for up to 48 h. In
the case of 2a,b half of the GMP became coordinated
to platinum within 2 to 3 h and formation of the respec-
tive bis–GMP adducts was found complete after ca. 20
h. Longer half times of GMP in the presence of 3b
and 7b were probably due not to a lower reactivity but
to their lower solubilities. While the reaction progressed
the intensity of the 8-HG signal of unbound 50-GMP at
8.26 decreased and new signals cropped up between 8.7
and 9.1 originating from the 8-HG protons in the plati-
num (N-7)GMP adducts. Fig. 1 shows the representative
1H NMR spectra for the reactions of 50-GMP with 2a
(top) and 7b (bottom). The multiplying of the 8-HG sig-
nals in the GMP adducts of 7b when compared to those
Acknowledgements
We are grateful to the Deutsche Forschungsgemeins-
chaft for financial support (Grant Scho 402/8) and to
Bayer, BASF and Degussa for donations of chemicals.
References
O
O
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OR
OR
(iii)
(iv)
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N
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H2N Pt Cl
NHBoc
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4: R = H (91%)
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186.
CMeCH2CMe2OH
menthyl
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d
cholesteryl
Scheme 4. Reagents and conditions: (i) Boc2O, H2O/t-BuOH, r.t., 24
h; (ii) Et3N, C6H2Cl3COCl, DMAP, ROH, DMF/toluene (1:10), r.t.;
(iii) 4M HCl/dioxane, r.t. (for 5a-c), TFA/CH2Cl2, r.t. (for 5d); (iv)
K2PtCl4, H2O, pH 5-6, r.t. *Yield with respect to 5d; 6d not isolated.
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