Mono- and Polynuclear Complexes of the Model Nucleobase 1-Methylcytosine. Synthesis and Characterization of <i>cis</i>-[(PMe₂Ph)₂Pt{(1-MeCy(−H)}]₃(NO₃)₃ and <i>cis</i>-[(PPh₃)₂Pt{1-MeCy(−H)}(1-MeCy)]NO₃

The hydroxo complex cis-[L2Pt(μ-OH)]2(NO3)2 (L = PMe2Ph), in various solvents, reacts with 1-methylcytosine (1-MeCy) to give as the final product the cyclic species cis-[L2Pt{1-MeCy(−H),N 3N 4}]3(NO3)3 (1) in high or quantitative yield. X-ray analysis of 1 evidences a trinuclear species with the NH2-deprotonated nucleobases bridging symmetrically the metal centers through the N3 and N4 donors. A multinuclear NMR study of the reaction in DMSO-d6 reveals the initial formation of the dinuclear species cis-[L2Pt{1-MeCy(−H),N 3N 4}]22+ (2), which quantitatively converts into 1 following a first-order kinetic law (at 50 °C, t1/2 = 5 h). In chlorinated solvents, the deprotonation of the nucleobase affords as the major product (60−70%) the linkage isomer of 1, cis-[L2Pt{1-MeCy(−H)}]33+ (3), in which three cytosinate ligands bridge unsymmetrically three cis-L2Pt2+ units. In solution, 3 slowly converts quantitatively into the thermodynamically more stable isomer 1. No polynuclear adducts were obtained with the hydroxo complex stabilized by PPh3. cis-[(PPh3)2Pt(μ-OH)]2(NO3)2 reacts with 1-MeCy, in DMSO or CH2Cl2, to give the mononuclear species cis-[(PPh3)2Pt{1-MeCy(−H)}(1-MeCy)](NO3) (4) containing one neutral and one NH2-deprotonated 1-MeCy molecule, coordinated to the same metal center at the N3 and N4 sites, respectively. X-ray analysis and NMR studies show an intramolecular H bond between the N4 amino group and the uncoordinated N3 atom of the two nucleobases

Mono- and Polynuclear Complexes of the Model Nucleobase 1-Methylcytosine. Synthesis and Characterization of <i>cis</i>-[(PMe₂Ph)₂Pt{(1-MeCy(−H)}]₃(NO₃)₃ and <i>cis</i>-[(PPh₃)₂Pt{1-MeCy(−H)}(1-MeCy)]NO₃

The hydroxo complex cis-[L2Pt(μ-OH)]2(NO3)2 (L = PMe2Ph), in various solvents, reacts with 1-methylcytosine (1-MeCy) to give as the final product the cyclic species cis-[L2Pt{1-MeCy(−H),N 3N 4}]3(NO3)3 (1) in high or quantitative yield. X-ray analysis of 1 evidences a trinuclear species with the NH2-deprotonated nucleobases bridging symmetrically the metal centers through the N3 and N4 donors. A multinuclear NMR study of the reaction in DMSO-d6 reveals the initial formation of the dinuclear species cis-[L2Pt{1-MeCy(−H),N 3N 4}]22+ (2), which quantitatively converts into 1 following a first-order kinetic law (at 50 °C, t1/2 = 5 h). In chlorinated solvents, the deprotonation of the nucleobase affords as the major product (60−70%) the linkage isomer of 1, cis-[L2Pt{1-MeCy(−H)}]33+ (3), in which three cytosinate ligands bridge unsymmetrically three cis-L2Pt2+ units. In solution, 3 slowly converts quantitatively into the thermodynamically more stable isomer 1. No polynuclear adducts were obtained with the hydroxo complex stabilized by PPh3. cis-[(PPh3)2Pt(μ-OH)]2(NO3)2 reacts with 1-MeCy, in DMSO or CH2Cl2, to give the mononuclear species cis-[(PPh3)2Pt{1-MeCy(−H)}(1-MeCy)](NO3) (4) containing one neutral and one NH2-deprotonated 1-MeCy molecule, coordinated to the same metal center at the N3 and N4 sites, respectively. X-ray analysis and NMR studies show an intramolecular H bond between the N4 amino group and the uncoordinated N3 atom of the two nucleobases

Role of the Phosphine Ligands on the Stabilization of Monoadducts of the Model Nucleobases 1-Methylcytosine and 9-Methylguanine in Platinum(II) Complexes

The addition of 1-methylcytosine (1-MeCy) or 9-methylguanine (9-MeGu) to solutions of cis-(PPh3)2Pt(ONO2)2 (1a), in a molar ratio of 1:1, affords the monoadducts cis-[(PPh3)2Pt(1-MeCy)(ONO2)]NO3 (2a) and cis-[(PPh3)2Pt(9-MeGu)(ONO2)]NO3 (3a) and only trace amounts of the bisadducts cis-[(PPh3)2Pt(1-MeCy)2](NO3)2 (4a) and cis-[(PPh3)2Pt(9-MeGu)2](NO3)2 (5a), respectively. The X-ray structural determination of 2a and 3a indicates a strong π−π stacking interaction between one of the PPh3 phenyl groups and the pyrimydinic N3-platinated cytosine or the imidazole part of the N7-coordinated guanine base. The addition of a further equiv of nucleobase to the monoadducts forms quantitatively the bisadducts that have been isolated as pure compounds 4a and 5a. Under the same experimental conditions, the dinitrato analogue cis-[(PMePh2)2Pt(ONO2)2] (1b) forms the monoadducts 2b and 3b in equilibrium with a relatively high concentration (20–30%) of the bisadducts cis-[(PMePh2)2Pt(1-MeCy)2](NO3)2 (4b) and cis-[(PMePh2)2Pt(9-MeGu)2](NO3)2 (5b), which have been structurally characterized by single-crystal X-ray analysis. The characterization of the isolated complexes by multinuclear NMR spectroscopy is also described

Role of the Phosphine Ligands on the Stabilization of Monoadducts of the Model Nucleobases 1-Methylcytosine and 9-Methylguanine in Platinum(II) Complexes

The addition of 1-methylcytosine (1-MeCy) or 9-methylguanine (9-MeGu) to solutions of cis-(PPh3)2Pt(ONO2)2 (1a), in a molar ratio of 1:1, affords the monoadducts cis-[(PPh3)2Pt(1-MeCy)(ONO2)]NO3 (2a) and cis-[(PPh3)2Pt(9-MeGu)(ONO2)]NO3 (3a) and only trace amounts of the bisadducts cis-[(PPh3)2Pt(1-MeCy)2](NO3)2 (4a) and cis-[(PPh3)2Pt(9-MeGu)2](NO3)2 (5a), respectively. The X-ray structural determination of 2a and 3a indicates a strong π−π stacking interaction between one of the PPh3 phenyl groups and the pyrimydinic N3-platinated cytosine or the imidazole part of the N7-coordinated guanine base. The addition of a further equiv of nucleobase to the monoadducts forms quantitatively the bisadducts that have been isolated as pure compounds 4a and 5a. Under the same experimental conditions, the dinitrato analogue cis-[(PMePh2)2Pt(ONO2)2] (1b) forms the monoadducts 2b and 3b in equilibrium with a relatively high concentration (20–30%) of the bisadducts cis-[(PMePh2)2Pt(1-MeCy)2](NO3)2 (4b) and cis-[(PMePh2)2Pt(9-MeGu)2](NO3)2 (5b), which have been structurally characterized by single-crystal X-ray analysis. The characterization of the isolated complexes by multinuclear NMR spectroscopy is also described

Platinum(II)-Mediated Coupling Reactions of Acetonitrile with the Exocyclic Nitrogen of 9-Methyladenine and 1-Methylcytosine. Synthesis, NMR Characterization, and X-ray Structures of New Azametallacycle Complexes

The hydroxo complex cis-[L2Pt(μ-OH)]2(NO3)2, (L = PMePh2, 1a), in CH3CN solution, deprotonates the NH2 group of 9-methyladenine (9-MeAd) to give the cyclic trinuclear species cis-[L2Pt{9-MeAd(−H)}]3(NO3)3, (L = PMePh2, 2a), in which the nucleobase binds the metal centers through the N(1), N(6) atoms. In solution at room temperature, 2a slowly reacts with the solvent to form quantitatively the mononuclear azametallacycle cis-[L2PtNHC(Me){9-MeAd(−2H)}]NO3 (L = PMePh2, 3a), containing as anionic ligand the deprotonated form of molecule N-(9-methyl-1,9-dihydro-purin-6-ylidene)-acetamidine. In the same experimental conditions, the hydroxo complex with PPh3 (1b) forms immediately the insertion product 3b. Single-crystal X-ray analyses of 3a and 3b show the coordination of the platinum cation at the N(1) site of the purine moiety and to the N atom of the inserted acetonitrile, whereas the exocyclic amino nitrogen binds the carbon atom of the same CN group. The resulting six-membered ring is slightly distorted from planarity, with carbon−nitrogen bond distances for the inserted nitrile typical of a double bond [C(3)−N(2) = 1.292(7) Å in 3a and 1.279(11) Å in 3b], while the remaining CN bonds of the metallocycle are in the range of 1.335(8)−1.397(10) Å. A detailed multinuclear 1H, 31P, 13C, and 15N NMR study shows that the nitrogen atom of the inserted acetonitrile molecule binds a proton suggesting for 3a,b an imino structure in solution. In DMSO and chlorinated solvents, 3a slowly releases the nitrile reforming the trinuclear species 2a, whereas 3b forms the mononuclear derivative cis-[L2Pt{9-MeAd(−H)}]NO3 (L = PPh3, 4b), in which the adeninate ion chelates the metal center through the N(6) and N(7) atoms. Complex 4b is quantitatively obtained when 1b reacts with 9-MeAd in DMSO and can be easily isolated if the reaction is carried out in CH2Cl2. In CH3CN solution, at room temperature, 4b slowly converts into 3b indicating that the insertion of acetonitrile is a reversible process. A similar metal-mediated coupling reaction occurs when 1a,b react with 1-methylcytosine (1-MeCy) in CH3CN. The resulting complexes, cis-[L2PtNHC(Me){1-MeCy(−2H)}]NO3, (L = PMePh2, 5a and PPh3, 5b), contain the deprotonated form of the ligand N-(1-methyl-2-oxo-2,3-dihydro-1H-pyrimidin-4-ylidene)-acetamidine. The X-ray analysis of 5a shows the coordination of the metal at the N(3) site of the pyrimidine cycle and to the nitrogen atom of the acetonitrile, with features of the six-membered metallocycle only slightly different from those found in 3a and 3b. In CD3CN/CH313CN solution complexes 5a,b undergo exchange of the inserted nitrile, while in DMSO or chlorinated solvents they irreversibly release CH3CN to form species not yet fully characterized. No insertion of CH3CN occurs when the hydroxo complexes are stabilized by PMe3 and PMe2Ph

Irreversible Insertion of Benzonitrile into Platinum(II)−Nitrogen Bonds of Nucleobase Complexes. Synthesis and Structural Characterization of Stable Azametallacycle Compounds

Deprotonation of 1-methylcytosine (1-MeCy) and 9-methyladenine (9-MeAd) promoted by cis-[L2Pt(μ-OH)]2(NO3)2 (L = PPh3, PMePh2, 1/2dppe) in PhCN causes the irreversible insertion of a nitrile molecule into the Pt−N4 and Pt−N6 bonds of the cytosinate and adeninate ligands, respectively, to form the stable azametallacycle complexes cis-[L2PtNHC(Ph){1-MeCy(−2H)}]NO3 (L = PPh3, 1; PMePh2, 2; 1/2dppe, 3) and cis-[L2PtNHC(Ph){9-MeAd(−2H)}]NO3 (L = PPh3, 4; PMePh2, 5) containing the deprotonated form of the molecules (Z)-9-N-(1-methyl-2-oxo-2,3-dihydropyrimidin-4(1H)-ylidene)benzimidamide and (Z)-N-(9-methyl-1H-purin-6(9H)-ylidene)benzimidamide. Single-crystal X-ray analyses of 2 and 4 show the metal coordinated to the N3 cytosine site [Pt−N3 = 2.112(7) Å̊] and to the N1 site of adenine [Pt−N1 = 2.116(6) Å̊] and to the nitrogen atom of the inserted benzonitrile [Pt−N2 = 2.043(6) and 2.010(6) Å̊ in 2 and 4, respectively], with the exocyclic nucleobase amino nitrogen bound to the carbon atom of the CN group. Complex 2, in solution, undergoes a dynamic process related to a partially restricted rotation around Pt−P bonds, arising from a steric interaction of the oxygen atom of the cytosine with one ring of the phosphine ligands. The reaction of 4 with acetylacetone (Hacac) causes the quantitative protonation of the anionic ligand, affording the acetylacetonate complex cis-[(PPh3)2Pt(acac)]NO3 and the free benzimidamide NHC(Ph){9-MeAd(−H)}. In the same experimental conditions, complex 3 reacts with Hacac only partially

Synthesis, characterisation and in vitro antitumour potential of novel Pt(II) estrogen linked complexes

The Cu(I) alkyne azide click reaction of 17α-ethynylestradiol and di-tert-butyl (2-azidopropane-1,3-diyl)dicarbamate afforded the novel 1,4 disubstituted 1,2,3 triazole and estrogen-based ligand 2-(4-(estradiol)-1H-1,2,3-triazol-1-yl)propane-1,3-diamine, EDiolDap. Reaction of EDiolDap with Pt(II) DMSO precursors, cis-[PtCl2(DMSO)2] and cis-[Pt(CBDCA)(DMSO)2] gave the corresponding Pt(II) estrogen linked complexes [PtCl2(EDiolDap)] and [Pt(CBDCA)(EDiolDap)] respectively in good yield. Both Pt(II) estrogen linked complexes exhibited superior activity as compared to cisplatin and carboplatin in 2D culture and exhibited ca. 30 fold higher activity, in terms of IC50 values, against ER+ cancer cells (cervical, breast and ovarian) as compared to the reference ER− colon cancer line. [PtCl2(EDiolDap)] and [Pt(CBDCA)(EDiolDap)] retained their anti-tumour activity in an ovarian 3D spheroid culture model and reduced the viability of ovarian cancer cell spheroids ca. 9-fold and 5-fold better, respectively, as compared to cisplatin

Synthesis, characterisation and in vitro antitumour potential of novel Pt(II) estrogen linked complexes

The Cu(I) alkyne azide click reaction of 17α-ethynylestradiol and di-tert-butyl (2-azidopropane-1,3-diyl)dicarbamate afforded the novel 1,4 disubstituted 1,2,3 triazole and estrogen-based ligand 2-(4-(estradiol)-1H-1,2,3-triazol-1-yl)propane-1,3-diamine, EDiolDap. Reaction of EDiolDap with Pt(II) DMSO precursors, cis-[PtCl2(DMSO)2] and cis-[Pt(CBDCA)(DMSO)2] gave the corresponding Pt(II) estrogen linked complexes [PtCl2(EDiolDap)] and [Pt(CBDCA)(EDiolDap)] respectively in good yield. Both Pt(II) estrogen linked complexes exhibited superior activity as compared to cisplatin and carboplatin in 2D culture and exhibited ca. 30 fold higher activity, in terms of IC50 values, against ER+ cancer cells (cervical, breast and ovarian) as compared to the reference ER− colon cancer line. [PtCl2(EDiolDap)] and [Pt(CBDCA)(EDiolDap)] retained their anti-tumour activity in an ovarian 3D spheroid culture model and reduced the viability of ovarian cancer cell spheroids ca. 9-fold and 5-fold better, respectively, as compared to cisplatin

DataSheet1_Click Pt(IV)-Carbohydrates Pro-Drugs for Treatment of Osteosarcoma.pdf

The selectivity vs. cancer cells has always been a major challenge for chemotherapeutic agents and in particular for cisplatin, one of the most important anticancer drugs for the treatment of several types of tumors. One strategy to overtake this challenge is to modify the coordination sphere of the metallic center with specific vectors whose receptors are overexpressed in the tumoral cell membrane, such as monosaccharides. In this paper, we report the synthesis of four novel glyco-modified Pt(IV) pro-drugs, based on cisplatin scaffold, and their biological activity against osteosarcoma (OS), a malignant tumor affecting in particular adolescents and young adults. The sugar moiety and the Pt scaffold are linked exploiting the Copper Azide Alkyne Cycloaddition (CUAAC) reaction, which has become the flagship of click chemistry due to its versatility and mild conditions. Cytotoxicity and drug uptake on three different OS cell lines as well as CSCs (Cancer Stem Cell) are described.</p

DataSheet1_2D and 3D anticancer properties of C2-functionalised glucosamine-Pt (IV) prodrugs based on cisplatin scaffold.PDF

A series of C2-functionalied Pt (IV) glycoconjugates based on glucosamine have been synthesised, characterised and tested as anticancer agents on a series of different 2D and 3D cancer cell lines. The carbohydrate will act as a targeted delivery system to improve the selectivity, exploiting the Warburg Effect and the GLUTs receptors that are overexpressed in most of the cancer cells. The hydroxyl at C2 of the carbohydrates does not participate in hydrogen bonding with the GLUTs receptors, making C2 an attractive position for drug conjugation as seen in literature. In this study, we use the amino functionality at the C2 position in glucosamine and Copper-catalysed Azide-Alkyne Cycloaddition “click” (CuAAC) reaction to connect the prodrug Pt (IV) scaffold to the carbohydrate. We have investigated complexes with different linker lengths, as well as acetyl protected and free derivatives. To the best of our knowledge, this study represents the first series of Pt (IV) glucosamine-conjugates functionalised at C2.</p