Neutral and ionic platinum compounds containing a cyclometallated chiral primary amine: synthesis, antitumor activity, DNA interaction and topoisomerase I–cathepsin B inhibition

Abstract

The synthesis and preliminary biological evaluation of neutral and cationic platinum derivatives of chiral 1-(1-naphthyl)ethylamine are reported, namely cycloplatinated neutral complexes [PtCl{(R or S)-NH(2)CH(CH(3))C(10)H(6)}(L)] [L = SOMe(2) ( 1-R or 1-S ), L = PPh(3) (2-R or 2-S), L = P(4-FC(6)H(4))(3) (3-R), L = P(CH(2))(3)N(3)(CH(2))(3) (4-R)], cycloplatinated cationic complexes [Pt{(R)-NH(2)CH(CH(3))C(10)H(6)}{L}]Cl [L = Ph(2)PCH(2)CH(2)PPh(2) (5-R), L = (C(6)F(5))(2)PCH(2)CH(2)P(C(6)F(5))(2) (6-R)] and the Pt(ii) coordination compound trans-[PtCl(2){(R)-NH(2)CH(CH(3))C(10)H(6)}(2)] (7-R). The X-ray molecular structure of 7-R is reported. The cytotoxic activity against a panel of human adenocarcinoma cell lines (A-549 lung, MDA-MB-231 and MCF-7 breast, and HCT-116 colon), cell cycle arrest and apoptosis, DNA interaction, topoisomerase I and cathepsin B inhibition, and Pt cell uptake of the studied compounds are presented. Remarkable cytotoxicity was observed for most of the synthesized Pt(ii) compounds regardless of (i) the absolute configuration R or S, and (ii) the coordinated/cyclometallated (neutral or cationic) nature of the complexes. The most potent compound 2-R (IC(50) = 270 nM) showed a 148-fold increase in potency with regard to cisplatin in HCT-116 colon cancer cells. Preliminary biological results point out to different biomolecular targets for the investigated compounds. Neutral cyclometallated complexes 1-R and 2-R, modify the DNA migration as cisplatin, cationic platinacycle 5-R was able to inhibit topoisomerase I-promoted DNA supercoiling, and Pt(ii) coordination compound 7-R turned out to be the most potent inhibitor of cathepsin B. Induction of G-1 phase ( 2-R and 5-R ), and S and G-2 phases (6-R) arrests are related to the antiproliferative activity of some representative compounds upon A-549 cells. Induction of apoptosis is also observed for 2-R and 6-R.

Synthesis, characterization and molecular docking of new C,N‐palladacycles containing pyridinium‐derived ligands: DNA and BSA interaction studies and evaluation as anti‐tumor agents

“…As the results show, complexes A and B are more effective than C and D against two cancer cells. This refers to higher biological activity of primary amine metallacycles than secondary amines due to the possibility of being involved in hydrogen bonds through the NH 2 group . Although the IC 50 values of complexes against MCF‐7 cells are close to or higher than cisplatin, they are comparable with other similar palladium complexes …”

Luminescent PtII and PtIV Platinacycles with Anticancer Activity Against Multiplatinum‐Resistant Metastatic CRC and CRPC Cell Models

“…[24,25] However,noc orrelation was observed between the cytotoxicity in cancer cells and Pt accumulation within the series of compounds, asp reviously reported for other metal complexes. revealed that cellular accumulationf or all platinum cyclometallated compounds was significantly higher than for cisplatin.…”

“…Previous evidence gathered by our group on different related sets of cyclometallated Pt II and Pt IV complexes extensively revealed that cellular accumulation for all platinum cyclometallated compounds was significantly higher than for cisplatin . However, no correlation was observed between the cytotoxicity in cancer cells and Pt accumulation within the series of compounds, as previously reported for other metal complexes .…”

Anticancer platinum‐based complexes with non‐classical structures

“…The antitumor properties of cyclometallated Pt(II) compounds have been studied by several groups in the last few years . These compounds displayed high stability and increased lability of the leaving groups, which was attributed to the strong trans effect of C‐donor ligands.…”

“…These compounds displayed high stability and increased lability of the leaving groups, which was attributed to the strong trans effect of C‐donor ligands. Recently, Albert et al . discussed and designed several cyclometallated Pt(II) compounds ( 101 – 106 ; Figure ) containing a chiral primary amine ligand (( R or S )‐1‐(1‐naphthyl)ethylamine), and a coordination compound containing two non‐cyclometallated chiral ( R ) amines ( 107 ; Figure ).…”