Photocytotoxic trans-diam(m)ine platinum(IV) diazido complexes more potent than their cis isomers.
The photocytotoxicity of a series of anticancer trans-dihydroxido [Pt(N(3))(2)(OH)(2)(NH(3))(X)] (X = alkyl or aryl amine) platinum(IV) diazido complexes has been examined, and the influence of cis-trans isomerism has been investigated. A series of photoactivatable Pt(IV)-azido complexes has been synthesized: The synthesis, characterization, and photocytotoxicity of six mixed-ligand ammine/amine Pt(IV) diazido complexes, cis,trans,cis-[Pt(N(3))(2)(OH)(2)(NH(3))(X)] where X = propylamine (4c), butylamine (5c), or pentylamine (6c) and aromatic complexes where X = pyridine (7c), 2-methylpyridine (8c), or 3-methylpyridine (9c) are reported. Six all-trans isomers have also been studied where X = methylamine (2t), ethylamine (3t), 2-methylpyridine (8t), 4-methylpyridine (10t), 3-methylpyridine (9t), and 2-bromo-3-methylpyridine (11t). All of the complexes exhibit intense azide-to-Pt(IV) LMCT bands (ca. 290 nm for trans and ca. 260 nm for cis). When irradiated with UVA light (365 nm), the Pt(IV) complexes undergo photoreduction to Pt(II) species, as monitored by UV-vis spectroscopy. The trans isomers of complexes containing aliphatic or aromatic amines were more photocytotoxic than their cis isomers. One of the cis complexes (9c) was nonphotocytotoxic despite undergoing photoreduction. Substitution of NH(3) ligands by MeNH(2) or EtNH(2) results in more potent photocytotoxicity for the all-trans complexes. The complexes were all nontoxic toward human keratinocytes (HaCaT) and A2780 human ovarian cancer cells in the dark, apart from the 3-methylpyridine (9t), 2-bromo-3-methylpyridine (11t), and 4-methylpyridine (10t) derivatives.
Farrer
Nicola J
NJ
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, United Kingdom.
Woods
Julie A
JA
Munk
Vivienne P
VP
Mackay
Fiona S
FS
Sadler
Peter J
PJ
D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003979:Diazonium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D015195:Drug Design; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D015603:Keratinocytes / Q000187:drug effects; D008027:Light; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy; D013237:Stereoisomerism
D000588:Amines; D000970:Antineoplastic Agents; D003979:Diazonium Compounds; D009944:Organoplatinum Compounds