Au(II) dimers and methods of their use in cancer treatment

Abstract

Synthesis and characterization of Au(II) dimeric complexes with pyridine dipyrrolinone (H2PyDP) ligands. Unique stability of these Au(II) dimers is disclosed when tested against thiol-containing reductants and other biomolecules. In addition, these complexes present antiproliferative activity at sub-micromolar levels in ovarian carcinoma cells, including cisplatin-resistant cells.

Description

AU(II) DIMERS AND METHODS OF THEIR USE IN CANCER TREATMENTRELATED APPLICATION

[0001] This application claims priority to US Provisional Application 63 / 643,009 filed on May 6, 2024, the content of which is incorporated herein by reference in its entireties for all purposes.GOVERNMENT RIGHTS

[0002] This invention was made with government support under Grant No. GM153364 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0003] Investigations of gold complexes as drug candidates for cancer chemotherapy have gained increasing attention in recent years.1 2Au(I)-based compound auranofin (Ridaura®), which was approved by FDA in 1985 for the treatment of rheumatoid arthritis,3-4is being evaluated as an anticancer agent. In particular, auranofin was found to disrupt antioxidant defensive systems, ubiquitin proteasome machinery, signaling of cell proliferation, and ultimately induce apoptosis in malignant cells.5Given the promising findings in preclinical studies,6auranofin has been tested as an anticancer drug in phase I and II clinical trials.7

[0004] Additionally, because gold(III) is isoelectronic to platinum(II), several gold(III) complexes are being considered as potential alternatives to cisplatin and other platinum-based anticancer drugs. Although several Au(III) complexes are found to be unstable in the presence of biological reductants, recent efforts have focused on the careful design of gold(III) complexes that are stable when exposed to bioreductants and biological nucleophiles.6SUMMARY

[0005] The present disclosure provides a new class of Au (II) dimeric complexes, which has a different set of structural parameters and reactivity properties as compared to previously tested compounds.

[0006] In some embodiments, a composition is disclosed which comprises an Au(II) dimeric complex with two or more ligands, wherein the Au(II)-Au(II) interaction in the Au(II) dimer holds the dimeric complex together. In one aspect, the two or more ligands comprise pyridine dipyrrolinone (H2PyDP) or derivatives thereof. In another aspect, the two or more ligands arethe same, for example, both ligands are the same pyridine dipyrrolinone ( I PPy DP) or derivatives thereof.

[0007] In some embodiments, a composition is disclosed which comprises an Au(II) dimeric complex, the Au(II) dimeric complex comprising an Au(II)-Au(II) bond and two or more ligands, wherein each of the two or more ligands binds covalently to one of the Au(II) atoms. In one aspect, the Au(II) dimeric complex comprises one Au(II)-Au(II) bond and two ligands, and each ligand binds covalently to one of the Au(II) atoms.

[0008] In some embodiments, no direct interaction (for example, bonds) exists between the two ligands in the Au(II) dimeric complex other than the Au(II)-Au(II) interaction.

[0009] In one aspect, the composition comprising the Au(II) dimeric complex is a pharmaceutical composition. In another aspect, the Au(II) dimeric complex is (AuPyDPR)2, wherein R is H, or NMe2 or OMe.

[0010] In some embodiments, the two or more ligands comprise pyridine dipyrrolinone (JDPy DP) or derivatives thereof. In one aspect, the two or more ligands are the same ligand. In another aspect, the Au(II) dimeric complex comprises two ligands, each of the two ligands binds covalently to one of the Au(II) atoms.

[0011] In some embodiments, the Au(II) dimeric complex has anti-proliferative activity and is stable when exposed to bio-reductants or biological nucleophiles. In one aspect, the Au(II) dimeric complex inhibits cell growth with IC50 less than 1 micro molar, IC50 equal to or less than 0.8 micro molar, or IC50 equal to or less than 0.5 micro molar, in a cisplatin-resistant cell.

[0012] In one embodiment, a method of using the composition for treating cancer in a subject is disclosed. In another embodiment, the subject has been treated with cisplatin and is resistant to cisplatin treatment. In another embodiment, a method is disclosed for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising an Au(II) dimeric complex having a formula, (AuPyDPj )2, wherein PyDP is pyridine dipyrrolinone, and R is H, or NMe2 or OMe.

[0013] In some embodiments, a method of making the Au (II) dimeric complex is disclosed, comprising at least one scheme selected from the group consisting of Schemes 1, 2, 3 and combination thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 shows Scheme 1 for the synthesis of pyridine dipyrrolinone ligands HiPyDPu and H2PyDPci.

[0015] Figure 2 shows Scheme 2 for the synthesis of H2PyDPNMe2 and H2PyDPoMe via aromatic substitutions.

[0016] Figure 3 shows Scheme 3 for the synthesis of Au(II) dimers featuring pyridine dipyrrolinone ligands.

[0017] Figure 4 shows structure of (AuPyDPn , which crystallizes as a helical dimer, a) Front view emphasizing the p stacking between the pyrrolinone units, b) side view of the dimer showing the twisting of each ligand, and c) space-filling model highlighting the shielding of the Au(II) centers. Carbon-bound hydrogens in calculated positions and alkyl substituents have been omitted for clarity in the front and side views. Non-hydrogen atoms are displayed as thermal ellipsoids set at 50% probability level.

[0018] Figure 5 shows a) Comparison of the]H NMR spectrum of (AuPyDPu and the spectrum of a mixture of (AuPyDPu and NAC (6 mM, DMSO-de) after 24 h. The green stars refer to NAC resonances, b) Reactivity study of (AuPyDPNMe2)2 and (AuPyDPoMeh (250 pM) with biomolecules (5 mM) after 24 h in a mixture of 100 mM phosphate buffer / DMSO (pH 7.5, 1:1, v / v). The percentages of remaining complex are relative to the start of observation (0 h), and reactivities were monitored by HPLC at 400 nm. c) Representative sigmoidal curves of the inhibitory effects of HAuCH, (AuPyDPNMe2)2, and (AuPyDPoMeh on thioredoxin reductase.DETAILED DESCRIPTION

[0019] The present disclosure discloses synthesis and characterization of Au(II) dimeric complexes with pyridine dipyrrolinone (H2PyDP) ligands. Unique stability of these Au(II) dimers is reported here when tested against thiol-containing reductants and other biomolecules. In addition, these complexes present antiproliferative activity at submicromolar levels in ovarian carcinoma cells, including cisplatin-resistant cells.

[0020] The disclosure is further illustrated by the following Items:

[0021] Item 1. A composition comprising an Au(II) dimeric complex, said Au(II) dimeric complex comprising an Au(II)-Au(II) bond and two or more ligands, wherein each of the two or more ligands binds covalently to one of the Au(II) atoms.

[0022] Item 2. The composition of Item 1 , wherein the two or more ligands comprise pyridine dipyrrolinone (H2PyDP) or derivatives thereof.

[0023] Item 3. The composition of any preceding Items, wherein the two or more ligands are the same.

[0024] Item 4. The composition of any preceding Items, wherein no direct interaction exists between the two or more ligands in the Au(II) dimeric complex other than through the Au(II)- Au(II) interaction.

[0025] Item 5. The composition of any preceding Items, wherein Au(II)-Au(II) interaction in the dimeric complex holds the dimeric complex together.Item 6. The composition of any preceding Items, wherein said Au(II) dimeric complex comprises two ligands, each of the two ligands binding covalently to one of the Au(II) atoms

[0026] Item 7. The composition of any preceding Items, wherein the Au(II) dimeric complex has a formula:(AuPyDPR)? (formula I) wherein PyDP is pyridine dipyrrolinone, and R is H, or NMe2 or OMe.

[0027] Item 8. The composition of Item 7, wherein R is NMe2 or OMe.

[0028] Item 9. The composition of any preceding Items, wherein the Au(ll) dimeric complex has anti-proliferative activity.

[0029] Item 10. The composition of any preceding Items, wherein the Au(II) dimeric complex is stable when exposed to bioreductants or biological nucleophiles.

[0030] Item 11. The composition of any preceding Items, wherein the Au(II) dimeric complex inhibits cell growth with ICso less than 1 micro molar in a cisplatin-resistant cell.

[0031] Item 12. A method of making the composition of any preceding Items, comprising one or more schemes selected from the group consisting of Schemes 1, 2, 3 and combination thereof.

[0032] Item 13. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the composition of any of Items 1-11.

[0033] Item 14. The method of Item 13, wherein the cancer is ovarian cancer.

[0034] Item 15. The method of any of Items 13 and 14, wherein the subject is resistant to cisplatin treatment.

[0035] Item 16. An intermediary compound having a formula of ITPyDPci.

[0036] Item 17. A composition comprising an Au(II) dimeric complex having a formula: (AuPyDPR)2 (formula I) wherein PyDP is pyridine dipyrrolinone, and R is H, or NMe2 or OMe.

[0037] Item 18. The composition of Item 16, wherein R is NMe2 or OMe.

[0038] The disclosure will now be illustrated with working examples, which are intended to illustrate the working of disclosure and not intended to restrict the scope of the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice of the disclosed methods and compositions, the exemplary methods, devices and materials are described herein.

[0039] Example 1 Synthesis of a new class of Au(II) dimeric complexes

[0040] The ligand fUPyDPn was synthesized following a previously reported procedure for an analogous pyridine dipyrrolinone ligand:82,6-pyridine-dicarbaldehyde was condensed under basic conditions with 3-ethyl-4-methyl-3-pyrrolin-2-one to give JUPyDPu as a yellow solid (Scheme 1).

[0041] Scheme 1. Synthesis of pyridine dipyrrolinone ligands fUPyDPu and H PyDPci.

[0042] Similar conditions gave ligand HzPyDPci when using 4-chloro-2,6-pyridine- dicarbaldehyde as a precursor. This pura-chloro substituted ligand serves as a valuable precursor to synthesize a variety of ra-substiluled analogs via nucleophilic aromatic substitution. Two such analogs were synthesized by adding ITPyDPci to a pressure vessel charged with either dimethylamine or sodium methoxide and heating the mixture overnight at 160 °C (Scheme 2). Subsequent workup and purification by column chromatography yielded H2PyDPNMe2 or H2PyDPOMe as pale yellow solids.

[0043] Scheme 2. Synthesis of H2PyDPNMe2 and H2PyDPOMe via aromatic substitutions.

[0044] The ability of ligands such as porphyrins and / V-heterocyclic carbenes to stabilize gold(III) has made them suitable candidates as anticancer chemotherapeutics.9To explore the possibility of stabilizing the gold (II) complex, coordination of gold within the tridentate nitrogen-rich scaffold of the FEPyDPR ligands was investigated. The ligand, gold (III) acetate, and potassium carbonate were added to a flask containing DMSO and heated at 70 °C under argon for four hours (Scheme 3). Subsequent aqueous workup and extraction with dichloromethane afforded a crude orange solid, which was purified via column chromatography. The1H NMR spectra presented resonances consistent with a symmetric ligand framework.

[0045] Scheme 3. Synthesis of Au(II) dimers featuring pyridine dipyrrolinone ligands.

[0046] To elucidate the structure of the complexes, single crystals suitable for X-ray crystallography were grown from slow diffusion of hexanes into a solution in CH2CI2. The obtained structure shows a neutral gold(II) dimer, in which the Au(II)-Au(II) interaction is not supported by bridging ligands (Figure 4a). Each pyridine dipyrrolinone coordinates one Au(II) as a tridentate dianion, and the gold centers are in a distorted square planar geometry with a Au- Au bond length of 2.524 A, which is comparable to previously reported unsupported gold(II) dimers.10 11

[0047] The isolated Au(II) dimer exhibits chirality induced by the twisting of the pyrrolinone ligands and p-stacking interactions of the pyrrolinone rings on both sides (Figure 4a, b). The space-filling model indicated that the Au(II) centers are rather buried in the ligand scaffolds (Figure 4c), which may be blocking attacks from nucleophiles (vide infra). Although only the M enantiomer was crystallized, high-performance liquid chromatography (HPLC) analysis on a purified sample of the reaction product using a chiral column indicated that the M and P enantiomers are present in 1 : 1 ratio as expected for a racemic mixture.

[0048] Example 2 Reactivity with redox-active hiomolecides

[0049] Before evaluating the biological activity of the Au(II) dimers in cancer cells, their stability against biologically relevant species was investigated. (AuPyDPu (6 mM) and NAC (6 mM) were dissolved in DMSO-<76 and monitored by!H NMR spectroscopy over 24 h (Figure 5a). After 24 h, the resonance of the m<?.w-proton was unaffected, and the disappearance of the thiol proton was not observed. Overall, this result indicated the memoposition was not susceptible to nucleophilic attack of a thiol.

[0050] Because the cellular environment is a complex mixture, it was critical to explore different classes of biomolecules that could potentially react with the Au(Il) centers and / or the dipyrrolinone ligand. In this context, glutathione (GSH), A-acetyl cysteine (NAC), and dithiothreitol (DTT) served as thiol-containing nucleophiles and reductants. Sodium ascorbate and pyridine nucleotides (e.g., NADH and NADPH) were included as standard bioreductants. Finally, H2O2 was tested as an example of intracellular reactive oxygen species. The stability / reactivity tests were carried out in a mixture of 100 mM phosphate buffer / DMSO (pH 8.0, 1 :1, v / v) and the Au(II) dimers were treated with the selected reagents at ambient temperature for 24 hours. Para-unsubstituted (AuPyDPii): precipitated out of the buffer mixture over time and thus it was not included in this study and future experiments. No reactivity with any of the tested biomolecules was observed (Figure 2b).

[0051] The thioredoxin reductase (TrxR) enzyme is considered the most relevant target for bioactive gold-based metallocompounds.13 14Several gold compounds are recognized as selective antimitochondrial drugs due to their ability to inhibit TrxR in mitochondria.13 15In addition, mitochondria play an important role in the regulation of the intracellular redox state, so inhibiting mitochondrial TrxR would lead to altered mitochondrial functions and initiation of apoptotic pathways. The inhibition ability of Au(II) dimers on TrxR activity was evaluated by following a reported procedure.1611 AuCU was included as a positive control, showing strong inhibitory effects against TrxR with an IC50 value of 0.2 uM. consistent with the range reported for Au(III) compounds.17In contrast, the novel Au(II) dimeric complexes did notshow inhibitory activities in the enzymatic studies (Figure 5c). Collectively, the in vitro and enzymatic experiments show that both Au(II) dimers are inert to the reactivity of cysteine and selenocysteine residues, and the space-filling model of crystal structure supports the notion that the tridentate, twisted ligands of the Au(II) dimers provide steric hindrance and protect the Au center from nucleophilic attacks.

[0052] Example 3 Antiproliferative activity

[0053] The Au(II) dimers were investigated in A2780 ovarian cancer cells. Cisplatin was included as a control because it is well studied and known for the treatment of ovarian cancers.18 19A2780 cells were exposed to the test compounds for 72 hours, and the antiproliferative activity was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay. (AuPyDPNMe2)2 and (AuPyDPoMe exhibited antiproliferative effects comparable to those of the cisplatin control,20with IC50 values ranging from 0.18 to 0.4 pM (Table 1). For comparison, the compounds were also tested in MRC-5 cells, which are normal lung fibroblasts and found to be significantly less toxic in all cases (Table 1).

[0054] Table 1. Antiproliferative activity of Au(H) dimers.[a]IC50 (pM)A2780 A2780cisR MRC-5Compound (ovary) (cisplatin-resistant) (normal lung)Cisplatin 0.6 ± 0.1 16 ± 2 3.2 ± 0.5(AuPyDPNMe2)2 0.18 ± 0.03 0.8 ± 0.1 3.5 ± 0.8(AuPyDPoMe)2 0.4 ± 0.1 0.5 ± 0.1 1.9 ± 0.1[a] ICso values (pM) of test compounds after 72-hour incubations.

[0055] Moreover, a cisplatin-resistant A2780 sub-line (A2780cisR) was cultured, which was derived from the original A2780 cell line by gradually introducing cisplatin in the growth media.20Indeed, the IC50 for cisplatin increased from 0.6 to 16 pM in the A2780cisR subline. Critically, both Au(II) dimers maintained sub-micromolar IC50 values in the A2780cisR cells, suggesting a different mechanism of action when compared to cisplatin. When combined with their antiproliferative activities at sub-micromolar levels, the ability of these Au(II) dimers to overcome resistance to cisplatin in cultured cells highlights promising properties for future testing in pre-clinical studies.ReferencesThe references listed below are cited here or throughout the disclosure, and are hereby incorporated by reference into this disclosure.(1) Nobili, S.; Mini, E.; Landini, I.; Gabbiani, C.; Casini, A.; Messori, L. Gold Compounds as Anticancer Agents: Chemistry, Cellular Pharmacology, and Preclinical Studies. Med. Res. Rev. 2010, 30 (3), 550-580. https: / / doi.org / 10.1002 / med.20168.(2) Moreno- Alcantar, G.; Picchetti, P.; Casini, A. Gold Complexes in Anticancer Therapy: From New Design Principles to Particle-Based Delivery Systems. Angew. Chem. frit. Ed. 2023, 62 (22), e202218000. https: / / doi.org / 10.1002 / anie.202218000.(3) Heuer, M. A.; Pietrusko, R. G.; Morris, R. W; Scheffler, B. J. An Analysis of Worldwide Safety Experience with Auranofin. J Rheumatol 1985, 72 (4), 695-699.(4) Shaw, C. F. Gold-Based Therapeutic Agents. Chem. Rev. 1999, 99 (9), 2589-2600. https: / / doi.org / 10.1021 / cr980431o.(5) Shen, S.; Shen, J.; Luo, Z.; Wang, F.; Min, J. Molecular Mechanisms and Clinical Implications of the Gold Drug Auranofin. Coord. Chem. Rev. 2023, 493, 215323. https: / / doi.Org / 10.1016 / j.ccr.2023.215323.(6) Yeo, C .; Ooi, K.; Tiekink, E. Gold-Based Medicine: A Paradigm Shift in Anti-Cancer Therapy? Molecules 2018, 23 (6), 1410. https: / / doi.org / 10.3390 / molecules23061410.(7) Abdalbari, F. H ; Telleria, C. M. The Gold Complex Auranofin: New Perspectives for Cancer Therapy. Discov. Oncol. 2021, 72, 42. https: / / doi.org / 10.1007 / sl2672-021- 00439-0.(8) Falk, H.; Suste, A. On the Chemistry of Pyrrole Pigments, XC: Pyridinologous Linear Tri- and Tetrapyrroles. Monatsh. Chem. 1993, 124 (8-9), 881-891. https: / / doi.org / 10. 1007 / BF00816411.(9) Tong, K.-C.; Hu, D ; Wan, P.-K.; Lok, C.-N.; Che, C.-M. Anticancer Gold(III) Compounds With Porphyrin or N-Heterocyclic Carbene Ligands. Front. Chem. 2020, 8, 587207. https: / / doi.org / 10.3389 / fchem.2020.587207.(10) Coetzee, J.; Gabrielli, W. F.; Coetzee, K.; Schuster, O.; Nogai, S. D.; Cronje, S.: Raubenheimer, H. G. Structural Studies of Gold(I, II, and III) Compounds with Pentafluorophenyl and Tetrahydrothiophene Ligands. Angew. Chem. Int. Ed. 2007, 46 (14), 2497-2500. https: / / doi.org / 10.1002 / anie.200604592.(11) Zopes, D.; Hegemann, C.; Tyrra, W; Mathur, S. [(CF3)4Au2(C5H5N)2] - a New Alkyl Gold(II) Derivative with a Very Short Au-Au Bond. Chem. Commun. 2012, 48 (70),8805. https: / / doi.org / 10.1039 / c2cc33735e.(12) Vickovic, I.; Suste, A.; Falk, H.; Hulita, N. K.; Tonejic, A. M. Synthesis and Structures of Pyridinologous Linear Tri- and Tetrapyrrole Metal Complexes. Monatsh. Chem. 1995, 726 (8-9), 971-982. https: / / doi.org / 10.1007 / BF00811017.(13) Bindoli, A.; Rigobello, M. P.; Scutari, G.; Gabbiani, C.; Casini, A. Thioredoxin Reductase: A Target for Gold Compounds Acting as Potential Anticancer Drugs. Coord. Chem. Rev. 2009, 253 (11-12), 1692-1707. https: / / doi.Org / 10.1016 / j.ccr.2009.02.026.(14) Ott, I. On the Medicinal Chemistry of Gold Complexes as Anticancer Drugs. Coord. Chem. Rev. 2009, 253 ( 11-12), 1670-1681. https: / / doi.Org / 10.1016 / j.ccr.2009.02.019.(15) Barnard, P. J.; Bemers-Price, S. J. Targeting the Mitochondrial Cell Death Pathway with Gold Compounds. Coord. Chem. Rev. 2007, 257 (13-14), 1889-1902. https: / / doi.Org / 10.1016 / j.ccr.2007.04.006.(16) Rubbiani, R.; Kitanovic, I.; Alborzinia, H.; Can, S.; Kitanovic, A.; Onambele, L. A.; Stefanopoulou, M.; Geldmacher, Y; Sheldrick, W. S.; Wolber, G.; Prokop, A.; Wblfl, S.; Ott, I. Benzimidazol-2-Ylidene Gold(I) Complexes Are Thioredoxin Reductase Inhibitors with Multiple Antitumor Properties. J. Med. Chem. 2010, 53 (24), 8608-8618. https: / / doi.org / 10.1021 / jml00801e.(17) Coronnello, M.; Mini, E.; Caciagli, B.; Cinellu, M. A.; Bindoli, A.; Gabbiani, C.; Messori, L. Mechanisms of Cytotoxicity of Selected Organogold(III) Compounds. J. Med. Chem. 2005, 48 (21), 6761-6765. https: / / doi.org / 10.1021 / jm050493o.(18) Dasari, S.; Tchounwou. P B. Cisplatin in Cancer Therapy: Molecular Mechanisms of Action. Ear. J. Pharmacol. 2014, 740, 364-378. https: / / doi.org / 10.1016 / j-ejphar.2014.07.025.(19) Sherman, S. E.; Gibson, D.; Wang, A. H.-J.; Lippard, S. J. X-Ray Structure of the Major Adduct of the Anticancer Drug Cisplatin with DNA: Cis -[Pt(NH 3 ) 2 {d(pGpG)}]. Science 1985, 230 (4724), 412-417. https: / / doi.org / 10.1126 / science.4048939.(20) Wang, Z.; Xu, Z.; Zhu, G. A Platinum(IV) Anticancer Prodrug Targeting Nucleotide Excision Repair To Overcome Cisplatin Resistance. Angew. Chem. 2016, 128 (50), 15793-15797. https: / / doi.org / 10.1002 / ange.201608936.

Claims

Claims1. A composition comprising an Au(II) dimeric complex, said Au(II) dimeric complex comprising an Au(II)-Au(II) bond and two or more ligands, wherein each of the two or more ligands binds covalently to one of the Au(II) atoms.

2. The composition of claim 1 , wherein the two or more ligands comprise pyridine dipyrrolinone (AbPyDP) or derivatives thereof.

3. The composition of claim 1, wherein the two or more ligands are the same.

4. The composition of claim 1 , wherein no direct interaction exists between the two or more ligands in the Au(II) dimeric complex other than through the Au(II)-Au(II) interaction.

5. The composition of claim 1, wherein Au (II)- Au(II) interaction in the dimeric complex holds the dimeric complex together.

6. The composition of claim 1 , wherein said Au(II) dimeric complex comprises two ligands, each of the two ligands binding covalently to one of the Au(II) atoms7. The composition of claim 1, wherein the Au(II) dimeric complex has a formula:(AuPyDPk)2 (formula I) wherein PyDP is pyridine dipyrrolinone, and R is H, or NMe2 or OMe.

8. The composition of claim 7, wherein R is NMe2 or OMe.

9. The composition of claim 1 , wherein the Au(II) dimeric complex has anti-proliferative activity.

10. The composition of claim 1, wherein the Au(II) dimeric complex is stable when exposed to bioreductants or biological nucleophiles.

11. The composition of claim 1 , wherein the Au(II) dimeric complex inhibits cell growth with IC50 less than 1 micro molar in a cisplatin-resistant cell.

12. A method of making the composition of claim 1, comprising one or more schemes selected from the group consisting of Schemes 1, 2, 3 and combination thereof.

13. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the composition of claim 1.

14. The method of claim 13, wherein the cancer is ovarian cancer.

15. The method of claim 14, wherein the subject is resistant to cisplatin treatment.

16. An intermediary compound having a formula of HzPyDPci.

17. A composition comprising an Au(II) dimeric complex having a formula:(AuPyDP )2 (formula I) wherein PyDP is pyridine dipyrrolinone, and R is H, or NMe2 or OMe.

18. The composition of claim 16, wherein R is NMez or OMe.

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