Platinum-Based Antitumor Drugs Containing Enantiomerically Pure α-Trifluoromethyl Alanine as Ligand

Abstract

Synthetic amino acids such as fluorinated alpha-amino acids are currently actively investigated for their biological activity. Herein, we report on the synthesis and characterization of platinum complexes containing an N,O-chelated pure enantiomer of alpha-trifluoromethylalanine (alpha-Tfm-Ala). The compounds are either anionic, K[PtCl2(alpha-Tfm-Ala)], or cationic, [PtAm2(alpha-Tfm-Ala)](NO3) (Am2= (NH3)2, ethylendiamine (en), 1,10-phenanthroline (phen), and 2,9-dimethyl-1,10-phenanthroline (Me2phen)). All complexes are highly soluble in water and have been fully characterized by NMR spectroscopy. In vitro cytotoxicity assays on different human tumor cell lines have been performed on some of the isolated compounds. [Pt(NH3)2(alpha-Tfm-Ala)] with R configuration of the amino acid proved to have an activity comparable to that of the reference compound cisplatin. Flow cytometric analysis on NCI-H460 tumor cells (absence of G2/M arrest, which instead is observed in the case of cisplatin) suggests a mechanism of action different from that of cisplatin.

Sterically hindered complexes of platinum(II) with planar heterocyclic nitrogen donors. A novel complex with 1-methyl-cytosine has a spectrum of activity different from cisplatin and is able of overcoming acquired cisplatin resistance

“…Platinum compounds with 1,10-phenanthroline and 2,9-dimethyl-1,10-phenanthroline (Me 2 phen) have already been investigated for antitumor activity [9][10][11][12]. We anticipate that one of the compounds here reported is more active than cisplatin in vitro, has a different spectrum of activity, and is able to overcome acquired cisplatin resistance.…”

Intracellular uptake and inhibitory activity of aromatic fluorinated amino acids in human breast cancer cells

“…The in vitro IC 50 values of the most potent derivatives (3-15 mm) are similar to those of known anticancer agents, for example cisplatin or doxorubicin. [40][41][42] To the best of our knowledge, l-(4-F)Trp has the highest antitumor efficacy of any amino acid-derived drug, known to date.…”

Monofunctional Platinum(II) Complexes with Potent Tumor Cell Growth Inhibitory Activity: The Effect of a Hydrogen‐Bond Donor/Acceptor N‐Heterocyclic Ligand

“…We too prepared and tested some monofunctional cationic platinum complexes, which, however, differed from classical Hollis-type compounds for the lack of the amine ligands ([PtI-(Me 2 phen)(MeCY)]I, 2, Me 2 phen = 2,9-dimethyl-1,10-phenanthroline, MeCY = 1-methyl-cytosine; Figure 1) [11] or of the heterocyclic base ([Pt(NH 3 ) 2 (a-Tfm-Ala-N,O)](NO 3 ), a-Tfm-Ala = synthetic fluorinated aminoacid a-trifluoromethyl-alanine with R configuration). [12] Interestingly, compound 2, one of the several platinum complexes with Me 2 phen investigated for antitumor activity, [12][13][14][15] was found to be endowed with a potent growth inibitory activity in a panel of 11 human tumor cell lines and was markedly more effective than cisplatin towards colon (COLO205: 19-fold; HCT116: 11-fold; KM12: 9-fold), breast (MDA: 16-fold), and ovary (SKOV-3: 14-fold) cancer cells. [11] Compound 2 was also able to completely overcome the acquired cisplatin resistance in A2780cisR and 41McisR ovarian cancer lines.…”