Platinum-based drugs, such as cisplatin, are clinically used for the treatment of many solid tumors with great success; however, outcomes are limited by the 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), has been 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 with 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 s (Pt-C) bond have also proven to be endowed with relevant anticancer activity. Our investigation has also been extended to the Pt(iv) derivatives of 2, trans-[Pt(OH)(2)(O,C-10-HDA)(1R,2R-DACH)] and trans-[Pt(BzO)(2)(O,C-10-BzODA)(1R,2R-DACH)] (10-BzODA = benzoate in place of the hydroxyl group in 10-HDA), having in the 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 the 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 derivatives 4 and 4a showed discrete activity against most of the tested tumor cell lines while the metallate complex 2 was found 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
Gandin, Valentina;Donati, Chiara;
2023
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 the 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), has been 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 with 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 s (Pt-C) bond have also proven to be endowed with relevant anticancer activity. Our investigation has also been extended to the Pt(iv) derivatives of 2, trans-[Pt(OH)(2)(O,C-10-HDA)(1R,2R-DACH)] and trans-[Pt(BzO)(2)(O,C-10-BzODA)(1R,2R-DACH)] (10-BzODA = benzoate in place of the hydroxyl group in 10-HDA), having in the 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 the 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 derivatives 4 and 4a showed discrete activity against most of the tested tumor cell lines while the metallate complex 2 was found to be more active than cisplatin and oxaliplatin only against the pancreatic tumor cell line PSN-1.
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