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Synthesis, Structure, and Biological Activity of New Azine‐Bridged Dinuclear Platinum( II ) Complexes − a New Class of Anticancer Compounds
Author(s) -
Kalayda Ganna V.,
Komeda Seiji,
Ikeda Kyoko,
Sato Takaji,
Chikuma Masahiko,
Reedijk Jan
Publication year - 2003
Publication title -
european journal of inorganic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.667
H-Index - 136
eISSN - 1099-0682
pISSN - 1434-1948
DOI - 10.1002/ejic.200300315
Subject(s) - chemistry , pyrazine , azine , stereochemistry , pyridazine , steric effects , platinum , phthalazine , pyrimidine , medicinal chemistry , quinazoline , organic chemistry , catalysis
A recently described new class of dinuclear platinum anticancer compounds, represented so far by the isomeric azine‐bridged complexes [{ cis ‐Pt(NH 3 ) 2 Cl} 2 (µ‐pzn)]Cl 2 ( 1 ) (pzn = pyrazine), [{ cis ‐Pt(NH 3 ) 2 Cl} 2 (µ‐pmn)]Cl 2 ( 2 ) (pmn = pyrimidine) and [{ cis ‐Pt(NH 3 ) 2 Cl} 2 (µ‐pdn)](NO 3 ) 2 ( 3 ) (pdn = pyridazine), has been added to. Three new dinuclear complexes of this type, [{ cis ‐Pt(NH 3 ) 2 Cl} 2 (µ‐2,5pzn)]Cl 2 ( 4 ) (2,5pzn = 2,5‐dimethylpyrazine), [{ cis ‐Pt(NH 3 ) 2 Cl} 2 (µ‐qzn)]Cl 2 ( 5 ) (qzn = quinazoline), and [{ cis ‐Pt(NH 3 ) 2 Cl} 2 (µ‐pht)](NO 3 ) 2 ( 6 ) (pht = phthalazine), have been newly synthesized and characterized by 1 H and 195 Pt NMR spectroscopy. The interaction of the new compounds with 2 equiv. of 9EtG in D 2 O at 310 K has been investigated. Complexes 4 and 5 undergo substitution of both chloride ligands by 9EtG similarly to the related complexes 1 and 2 , respectively. The methyl substituents on the pyrazine ring induce steric hindrance in 4 resulting in a slower reaction rate as compared to 1 . Similarly to the case of 3 , interaction of complex 6 with 9EtG results in cleavage of the Pt−N(pht) bond and subsequent formation of the polymeric species. A cytotoxicity assay of 4 − 6 has been performed on seven human tumor cell lines and on L1210 murine leukemia cell lines, sensitive and resistant to cisplatin. Compounds 4 and 5 exhibit lower cytotoxicity than the analogous complexes with unsubstituted azines. Complex 6 is more active: its cytotoxicity in the L1210 cell lines is similar to that of cisplatin. Analysis of nuclear DNA fragmentation in L1210 cells treated with the azine‐bridged complexes 1 − 6 has been carried out. The results clearly indicate induction of apoptosis by all the compounds, implying considerable anticancer potential. The structure‐activity relationship for this class of dinuclear platinum( II ) complexes is discussed. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)