Abstract
Starting from the active ingredient shikimic acid (SA) of traditional Chinese medicine and NH2(CH2)nOH, (n = 2–6), we have synthesized a series of new water-soluble Pt(II) complexes PtLa–eCl2, where La–e are chelating diamine ligands with carbon chain covalently attached to SA (La–e = SA-NH(CH2)nNHCH2CH2NH2; La, n = 2; Lb, n = 3; Lc, n = 4; Ld, n = 5; Le, n = 6). The results of the elemental analysis, LC-MS, capillary electrophoresis, and 1H, 13C NMR indicated that there was only one product (isomer) formed under the present experimental conditions, in which the coordinate mode of PtLa–eCl2 was two-amine bidentate. Their in vitro cytotoxic activities were evaluated by MTT method, where these compounds only exhibited low cytotoxicity towards BEL7404, which should correlate their low lipophilicity. The interactions of the five Pt(II) complexes with DNA were investigated by agarose gel electrophoresis, which suggests that the Pt(II) complexes could induce DNA alteration. We also studied the interactions of the Pt(II) complexes with 5′-GMP with ESI-MS and 1H NMR and found that PtLbCl2, PtLcCl2, and PtLdCl2 could react with 5′-GMP to form mono-GMP and bis-GMP adducts. Furthermore, the cell-cycle analysis revealed that PtLbCl2, PtLcCl2 cause cell G2-phase arrest after incubation for 72 h. Overall, these water-soluble Pt(II) complexes interact with DNA mainly through covalent binding, which blocks the DNA synthesis and replication and thus induces cytotoxicity that weakens as the length of carbon chain increases.
Highlights
As Pt(II) complexes have demonstrated successful clinical application of cisplatin for its anticancer effects, new platinum-based anticancer drugs are highly desired [1,2,3,4,5,6,7,8,9,10,11,12]
There have been five platinum-based anticancer drugs used in clinical applications, including three FDAapproved platinum compounds: cisplatin, carboplatin, oxaliplatin, nedaplatin used in Japan, and lobaplatin approved for use in China
Bioinorganic Chemistry and Applications the water-soluble platinum complexes archived by means of amine ligands instead of ammonia are most intriguing because the carrier ligands provide broad spectrum of antitumor activity [30]
Summary
As Pt(II) complexes have demonstrated successful clinical application of cisplatin for its anticancer effects, new platinum-based anticancer drugs are highly desired [1,2,3,4,5,6,7,8,9,10,11,12]. New and nontraditional compounds picoplatin (AMD473) [13] and ProLindac [14] as well as platinum(IV) complexes, such as satraplatin [15], tetraplatin, tetrachloro-trans-R, R-cyclohexane-1,2-diamine platinum (IV), and ipropltin (dichlorodihydroxobis(isopropylamine)platinum (IV) [16, 17], are being evaluated for clinical trials. Their effectiveness is still hindered by clinical problems, such as acquired or intrinsic resistance that limits the spectrum of cancers that can be treated, and high toxicity leading to side effects and limiting the dose that can be registered [18].
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