Anticancer activity of a chelating nitrogen mustard bearing tetrachloridoplatinum(iv) complex: better stability yet equipotent to the Pt(ii) analogue

Abstract

Two Pt(iv) complexes cis,cis,trans-[Pt(IV)(L1)Cl4] (1a) & cis,cis,trans-[Pt(IV)(L2)Cl4] (2a) containing the nitrogen mustard moieties -N(CH2CH2Cl)2 & -NHCH2CH2Cl, were prepared in a single step from the Pt(ii) complexes containing -N(CH2CH2OH)2 (1) & -NHCH2CH2OH (2) moieties respectively using only thionyl chloride. The characterization of both the Pt(iv) complexes was performed by NMR, IR, UV and elemental analysis. Complex 1a was also characterized by single crystal X-ray diffraction. 1a crystallized in the I2/a space group. 1a exhibited much higher solution stability than 2a in kinetic studies by (1)H NMR. 1a shows a prodrug like activity as it converts to its Pt(ii) congener, [Pt(II)(L1)Cl2] (3) after 2 days in buffered solution. The binding experiment of 1a with model nucleobase 9-ethylguanine (9-EtG), showed that 1a converts to 3 and forms mono-adducts with 9-EtG. In the presence of reduced glutathione (GSH), the formation of 3 from 1a is quicker and upon the formation of 3 it binds almost instantaneously to GSH to form cis-[PtCl(L1)SG] (3c). Complex 3c transformed within a day to give a free aziridinium ion of L1 (3b) by dissociation. The in vitro cytotoxicity of the complexes and the clinical anticancer drug cisplatin show that 1a is potent against MCF-7, A549, HepG2 and MIA PaCa-2. The potency is highest against MIA PaCa-2 exhibiting an IC50 value of 4.4 ± 0.5 μM. The in vitro cytotoxicity data also showed that between the two complexes only 1a is active against MCF-7, A549 and MIA PaCa-2 in normoxia and hypoxia, both in the presence and absence of added GSH. Even in the presence of excess GSH in hypoxia, 1a exhibits significant cytotoxicity against MIA PaCa-2 and MCF-7 with IC50 values of 4.5 ± 0.3 and 11.2 ± 1.8 μM respectively. Platinum accumulation studies by ICP-MS display greater internalization of 1a, than 2a, 3 and cisplatin inside MCF-7 cells. 1a arrests cell cycle at the G2/M phase in MCF-7, exhibits capability to inhibit metastasis, induces apoptotic cell death and displays blood compatibility with human blood.

Imine‐N‐Heterocyclic Carbenes as Versatile Ligands in Ruthenium(II) p‐Cymene Anticancer Complexes: A Structure–Activity Relationship Study

“…The binding studies of anticancer metallodrugs with model nucleobase 9‐ethylguanine (9‐EtG) and 9‐methyladenine (9‐MeA) provided insights into their intracellular fate . The reactions of complex 9 with model nucleobase 9‐EtG or 9‐MeA were monitored by using the 1 H NMR technique.…”

“…The binding studies of anticancer metallodrugsw ith model nucleobase 9-ethylguanine (9-EtG) and 9-methyladenine (9-MeA) provided insights into their intracellular fate. [13] The reactions of complex 9 with model nucleobase 9-EtG or 9-MeA were monitored by using the 1 HNMR technique.S olutions of complex 9 (ca. 1mm)a nd 2.0 molar equivalents of 9-EtG or 9-MeA in 50 %C D 3 OD/50 %D 2 O( v/v) werep repared, and 1 HNMR spectra were recorded at different time intervals at 310 K. According to the 1 HNMR spectra at different time intervals, no additional 1 H NMR peaks were observed over ap eriod of 24 h ( Figures S69-S70 in the SupportingI nformation).…”

Synthesis and Reactivity of Cytotoxic Platinum(II) Complexes of Bidentate Oximes – A Step towards the Functionalization of Bioactive Complexes

“…Finally, in the ATR IR spectrum, the broad OH stretching band of 4 had disappeared. The preparation of 5 is interesting, because 2‐chloroethyl residues are typical of strong DNA alkylating agents, and some Pt II and Pt IV complexes containing an analogous fragment were recently found to be active against pancreatic cancer cell lines …”

Oxamusplatin: a cytotoxic Pt(ii) complex of a nitrogen mustard with resistance to thiol based sequestration displays enhanced selectivity towards cancer

“…In this regard, our earlier works show that incorporation of the nitrogen mustard ligand bis(2-chloroethyl)pyridylmethylamine provides higher steric hindrance and improves the stability of a dichlorido-Pt(II) complex. 36,37 The ligand acts as a strong chelating N,Ndonor to the Pt(II) displaying higher stability and high cytotoxicity. In addition to the above, the already known advantages of the kinetic inertness of carboplatin and oxaliplatin led us to improve our design to circumvent sequestration pathways as well as lower the normal cell toxicity.…”