Platinum-based drugs, such as cisplatin, are clinically used for the treatment of many solid tumors with great success; however, outcomes are limited by toxicity and resistance of some tumors. Recently, the interest towards the use of natural products as anti-cancer drugs has grown worldwide since they are easily available and relatively safe. In particular, the main and distinctive fatty acid in Royal Jelly, trans-10-hydroxy-2-decenoic acid (10-HDA) demonstrated to have anti-tumor, immunomodulatory, collagen promoting, and antimelanogenesis properties. Thus, in this study we aimed to combine the 10-HDA functionality with a platinum moiety. The first compounds that we isolated were: [Pt(O-10-HDA)2(1R,2R-DACH)] (1; DACH = diaminocyclohexane), which can be considered a multifunctional prodrug analog of oxaliplatin in which the oxalate has been substituted by two carboxylate-bonded 10-HDA ligands, and the organometallic complex [Pt(O,C-10-HDA)(1R,2R-DACH)] (2) in which a single 10-HDA ligand coordinates to Pt through both a carboxylate oxygen and the deprotonated C(3) vinylic carbon. Cyclometalated complexes with a (Pt-C) bond have also proved to be endowed with relevant anticancer activity. Our investigation has also been extended to the Pt(IV) derivatives of 2, [Pt(OH)2(O,C-10-HDA)(1R,2R-DACH)] and [Pt(BzO)2(O,C-10-BzODA)(1R,2R-DACH)] (10-BzODA = benzoate in place of hydroxyl group in 10-HDA), having in axial position either two hydroxido or two benzoato ligands (3 and 4, respectively). For comparison, analogues of compounds 2, 3, and 4 having ethylenediamine in place of diaminocyclohexane as carrier ligand (compounds 2a, 3a, and 4a, respectively) were also synthesized. All compounds were fully characterized by elemental analysis, ESI-MS, and NMR spectroscopy. The mechanism of formation of complexes 1 and 2 was also investigated by solution NMR. Finally, as a preliminary investigation, the in vitro cytotoxicity of the new Pt(II) and Pt(IV) compounds was tested against a panel of human tumor cell lines. Interestingly, the Pt(IV) benzoate-derivates 4 and 4a showed a discrete activity against most of the tested tumor cell lines while the metallate complex 2 resulted to be more active than cisplatin and oxaliplatin only against the pancreatic tumor cell line PSN-1.
Pt(ii) and Pt(iv) complexes with a major component of royal jelly as innovative antitumor drug candidates
Alessandra Barbanente;Carmela Ilaria Pierro;Giovanni Natile;Nicola Margiotta
2023-01-01
Abstract
Platinum-based drugs, such as cisplatin, are clinically used for the treatment of many solid tumors with great success; however, outcomes are limited by toxicity and resistance of some tumors. Recently, the interest towards the use of natural products as anti-cancer drugs has grown worldwide since they are easily available and relatively safe. In particular, the main and distinctive fatty acid in Royal Jelly, trans-10-hydroxy-2-decenoic acid (10-HDA) demonstrated to have anti-tumor, immunomodulatory, collagen promoting, and antimelanogenesis properties. Thus, in this study we aimed to combine the 10-HDA functionality with a platinum moiety. The first compounds that we isolated were: [Pt(O-10-HDA)2(1R,2R-DACH)] (1; DACH = diaminocyclohexane), which can be considered a multifunctional prodrug analog of oxaliplatin in which the oxalate has been substituted by two carboxylate-bonded 10-HDA ligands, and the organometallic complex [Pt(O,C-10-HDA)(1R,2R-DACH)] (2) in which a single 10-HDA ligand coordinates to Pt through both a carboxylate oxygen and the deprotonated C(3) vinylic carbon. Cyclometalated complexes with a (Pt-C) bond have also proved to be endowed with relevant anticancer activity. Our investigation has also been extended to the Pt(IV) derivatives of 2, [Pt(OH)2(O,C-10-HDA)(1R,2R-DACH)] and [Pt(BzO)2(O,C-10-BzODA)(1R,2R-DACH)] (10-BzODA = benzoate in place of hydroxyl group in 10-HDA), having in axial position either two hydroxido or two benzoato ligands (3 and 4, respectively). For comparison, analogues of compounds 2, 3, and 4 having ethylenediamine in place of diaminocyclohexane as carrier ligand (compounds 2a, 3a, and 4a, respectively) were also synthesized. All compounds were fully characterized by elemental analysis, ESI-MS, and NMR spectroscopy. The mechanism of formation of complexes 1 and 2 was also investigated by solution NMR. Finally, as a preliminary investigation, the in vitro cytotoxicity of the new Pt(II) and Pt(IV) compounds was tested against a panel of human tumor cell lines. Interestingly, the Pt(IV) benzoate-derivates 4 and 4a showed a discrete activity against most of the tested tumor cell lines while the metallate complex 2 resulted to be more active than cisplatin and oxaliplatin only against the pancreatic tumor cell line PSN-1.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
