New Oxaliplatin-Pyrophosphato Analogs with Improved In Vitro Cytotoxicity

Abstract

Two new Pt(II)-pyrophosphato complexes containing the carrier ligands cis-1,3-diaminocyclohexane (cis-1,3-DACH) and trans-1,2-diamine-4-cyclohexene (1,2-DACHEX), variants of the 1R,2R-diaminocyclohexane ligand present in the clinically used Pt-drug oxaliplatin, have been synthesized with the aim of developing new potential antitumor drugs with high bone tropism. The complexes are more stable at physiological pH than in acid conditions, with Na2[Pt(pyrophosphato)(cis-1,3-DACH)] (1) slightly more stable than [Pt(dihydrogenpyrophosphato)(1,2-DACHEX)] (2). The greater reactivity at acidic pH ensures a greater efficacy at the tumor site. Preliminary NMR studies indicate that 1 and 2 react slowly with 5’-GMP (used as a model of nucleic acids), releasing the pyrophosphate ligand and affording the bis 5’-GMP adduct. In vitro cytotoxicity assays performed against a panel of four human cancer cell lines have shown that both compounds are more active than oxaliplatin. Flow cytometry studies on HCT116 cells showed that the pyrophosphato compounds with the non-classical 1,3- and 1,4-diaminocyclohexane ligands (1 and 4) are the most capable to induce cells’ death by apoptosis and necrosis.

Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine Sulfonamides as Novel Potential Anticancer Agents: Cytotoxic and Genotoxic Activities In Vitro

“…All investigated sulfonamides are classified as compounds with high cytotoxicity [38]. In addition, the examined MM compounds exhibit significantly stronger cytotoxicity in comparison to various currently used chemotherapeutics, such as 5-fluorouracil (IC 50 -96.1 µM for BxPC-3 and 3.2 µM for HCT 116 [39,40]), cisplatin (IC 50 -9 µM for PC-3 and HCT 116 and 12.3 µM for HeLa [41,42]), oxaliplatin (IC 50 -72 µM for HCT 116 and 100 µM for PC-3 [42]), or irinotecan (IC 50 -2.1 µM for PC-3 and 2.6 µM for HCT 116) [40,43]. The limitation of doses of antineoplastic agents seems to be crucial for the reduction in side effects that occur during chemotherapy treatment.…”

Cisplatin and zoledronic acid: two drugs combined in a Pt(ii) complex with potential antitumor activity towards bone tumors and metastases

“…After 72 h, it could be detected a new peak at 4.02 ppm (full diamond in Fig. 9B) which can be confidently assigned to the cis -[Pt(5′-GMP) 2 (NH 3 ) 2 ] adduct 47 in addition to a tiny peak at 22.01 ppm belonging to the mononuclear Pt–ZL species (full star in Fig. 9B).…”

Pt(ii) and Pt(iv) complexes with a major component of royal jelly as innovative antitumor drug candidates

“…This signal is in the range typical for a Pt( ii ) atom in an O 2 N 2 coordination environment. 33,34…”

“…This signal is in the range typical for a Pt(II) atom in an O 2 N 2 coordination environment. 33,34 Also compound 2 was characterized by elemental analysis, ESI-MS, and multinuclear 1D ( 1 H, 13 C, and 195 Pt) and 2D (COSY, NOESY, [ 1 H, 13 C]-HSQC, and [ 1 H, 195 Pt]-HSQC) NMR spectroscopy in DMSO-d 6 . The ESI-MS spectrum showed the presence of a peak at m/z = 516.1806 corresponding to [2 + Na] + with the experimental isotopic pattern in good agreement with the theoretical one.…”