Cisplatin-N-Mustard Conjugates
Conjugate 2: The pH of a solution of the free ligand 15 (96 mg,
0.12 mmol, 1.0 equiv.) and K2[PtCl4] (13 mg, 31 μmol, 0.3 equiv.)
in D2O (0.86 mL) was raised from pH 1.0 to 8.0 by the dropwise
addition of a 1 m solution of NaOD (0.20 mL). The precipitate
formed was collected and washed with D2O to yield conjugate 2 as
a pinkish solid (22 mg, 30 μmol, 97%), m.p. Ͼ240 °C (decomp.).
slightly smaller than with cisplatin) and therefore they
could be promising compounds for further biological in-
vestigations.
IR (neat): ν = 2918 (m), 2850 (m), 1687 (m), 1540 (m), 1456 (m),
˜
1258 (m), 1099 (s), 1038 (s), 799 (m), 720 (m) cm–1. FIR (PE): ν =
˜
332 (s br, Pt–Cl), 322 (s br, Pt–Cl) cm–1. C19H40Cl4N4O5Pt (741.45):
calcd. C 30.78, H 5.44, N 7.56; found C 30.85, H 5.35, N 7.26.
Acknowledgments
S. S. thanks the Fonds der Chemischen Industrie for a pre-doctoral
fellowship. M. V. thanks the Ludwig Maximilians University
(LMU), Munich for a postdoctoral fellowship. Financial support
from the Excellence Cluster CiPSM (SFB749, SFB646 and CA-
275/8-4) is acknowledged.
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Figure 9. Microscopic pictures of E. coli cells incubated
with DMSO alone (A), cisplatin (B), conjugate 1 (C), or conjugate
2 (D) at 37 °C for 9 h (for further experimental details see the Sup-
porting Information).
Conclusions
We have synthesized two novel cisplatin-N-mustard con-
jugates 1 and 2 with the two different cytotoxic functionali-
ties separated by one or four ethylene glycol units. Key to
the synthesis was the tight control of the pH during the
complexation reaction to prevent hydrolysis of the highly
sensitive N-mustard functionality. Reactions of the com-
plexes with DNA duplexes showed that the cisplatin as well
as the N-mustard moiety are capable of reacting with
guanine residues. The reactions lead to clustered DNA
lesions that contain 1,2-d(GpG)–cisplatin adducts and ab-
asic sites, which go hand-in-hand with the formation of
strand breaks. Furthermore, the ability of these novel con-
jugates to inhibit cell division was shown by the elongation
of E. coli cells when incubated with these compounds. We
believe that our work will stimulate further research into
new cisplatin-based anti-cancer drugs with novel modes of
action.
Experimental Section
Conjugate 1: A 1 m solution of NaOD (0.3 mL) was added drop-
wise to a solution of the free ligand 9 (0.12 g, 0.17 mmol, 1.0 equiv.)
and K2[PtCl4] (16 mg, 39 μmol, 0.2 equiv.) in D2O (1.23 mL) to
increase the pH of the solution from 1.0 to 8.0. The precipitate
formed was filtered off and washed with D2O (0.6 mL) to obtain
conjugate 1 as a pinkish solid (16 mg, 26 μmol, 67%), m.p.
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Ͼ280 °C (decomp.). IR (neat): ν = 2934 (m br), 1650 (s), 1542 (m),
˜
1457 (m), 1438 (m), 1262 (w), 1119 (s), 1038 (m), 779 (m) cm–1.
FIR (PE): ν = 322 cm–1 (s br, Pt–Cl). C14H30Cl4N4O2Pt (623.32):
˜
calcd. C 26.98, H 4.85, N 8.99; found C 27.11, H 5.11, N 8.76.
Eur. J. Org. Chem. 2015, 2654–2660
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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