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Project Details
Funding Scheme : General Research Fund
Project Number : 704812
Project Title(English) : Exploring the Anti-Cancer Properties of Gold(III) Complexes with Bidentate S-Donor Ligand 
Project Title(Chinese) : 抗癌活性的金化合物 
Principal Investigator(English) : Prof Wong, Alice Sze-Tsai 
Principal Investigator(Chinese) : 黃思齊 
Department : School of Biological Sciences
Institution : The University of Hong Kong
E-mail Address : awong1@hku.hk 
Tel : 22990865 
Co - Investigator(s) :
Panel : Physical Sciences
Subject Area : Physical Sciences
Exercise Year : 2012 / 13
Fund Approved : 775,000
Project Status : Completed
Completion Date : 30-6-2015
Project Objectives :
To prepare gold(III) compounds having bidentate S-donor ligand with low toxicities and capability in overcoming platinum resistance;
To uncover the anti-cancer and anti-angiogenic activities of the new derivatives;
To examine their mechanism of action by transcriptomics/ advanced proteomics approaches;
To have the metabolomics examination;
To improve their therapeutic efficacies by encapsulation/ synergistic addition approaches; and
To file patents and publish results in high-impact journals.
Abstract as per original application
(English/Chinese):
鉑化合物順鉑在抗癌臨床上的運用激發了研究者去研發新的有抗癌功能的金屬化合物。儘管在過去的四十年中付出了很多的努力，只有很少的金屬抗癌藥物進入了臨床試驗，其中包括幾個順鉑衍生物和釕化合物。在金屬化合物治療的發展中遇到了一些問題，比如由於金屬和多肽或者蛋白中的巰基相互作用引起的毒副作用，藥物解毒作用和細胞抗藥性。金屬，特別是鉑，跟含有巰基的腎臟酶之間很強的不可逆轉性的作用被認為是導致一些接受鉑化合物化療的病人腎出問題的主要原因。 金屬離子及其配合物有獨特的結構特點和特別的物理，化學，生物特點。跟一般的有機物比起來， 這些特點給與金屬離子及其配合物在生物體系中不可替代的位置。通過正確的選擇配體，金屬化合物可以被調節和合理的設計成有親硫性，或者相反，跟比如半胱氨酸或者蛋氨酸這些含硫供體的生物分子有很弱的親和性。我們被最近報導的和我們目前研究的關於有潛在的抗癌活性和低的急性或者腎臟毒性的金的二硫代氨基甲酸化合物及其衍生物所吸引。雙齒二硫代氨基甲酸配體上的硫原子有強的反位效應，可以禁止生物分子中的硫供體跟金離子配位， 這有可能提高其抗癌活性或者降低毒副作用。 為了解決當今化療劑的有問題的副作用和繼續努力鑑定出新的有抗癌活性的金化合物， 這個課題的主要目的是戰略性的極大促進含硫雙齒供體的金屬化合物在醫學方面的發展。通過合適的選擇和修飾雙齒含硫供體的配體，設計有增強的生物利用度，抗癌效果，生理條件穩定性和癌細胞的選擇性的金化合物是可行的。這些化合物對一系列的癌細胞，抗藥性細胞和正常細胞的體外廣泛的細胞毒性篩选和與其他生物分子的協同作用，還有抗血管增生的活性將會被檢查。那些有潛在作用的藥將會被選擇進行體內抗癌，毒性和代謝學（內源性或異種代謝物）的研究，而且會通過轉錄或者高等蛋白組學的研究方法去研究其活性的機理。這個課題的成功可以促進策略性的設計金屬化合物，尤其是那些有抗癌活性的金化合物，最終會使那些接受著有限治療選擇的經常性的癌症病人或者產生抗藥性的癌症病人收益。
Realisation of objectives: (i) By appropriate selection and design of different coordinating ligands, we have successfully prepared a series of twenty gold(I) and gold(III) complexes with bidentate S-donor ligands, phosphine ligand or N-heterocyclic carbenes (NHCs) ligands. These complexes were found to display promising anti-cancer activities against a variety of cancer cell lines including the cisplatin-resistant ovarian A2780cis cell line. (ii) By a series of in vitro cell-based experiments, most of the gold(III) and gold(I) complexes were found to show potent anti-migration activities towards cancer cells and growth inhibitory effects on cancer stem cells. The in vivo anti-cancer activities of two gold complexes containing dithiocarbamato ligands have also been examined. These complexes show potent inhibitory activities on the growth of ovarian carcinoma in nude mice models. (iii) The molecular pathways of some highly active gold complexes have been identified by mean of transcriptomics and proteomics approaches. Some of them were found to inhibit thioredoxin reductase, induce oxidative stress, enhance death receptor 4’s expression, activate apoptosis, induce expression of caspase 3, caspase 8 and caspase 9 and/or even inhibit HBV DNA replication. (iv) Most gold complexes are stable in water with minimum amount of organic solvent such as DMSO or EtOH. In the presence of biological reductant glutathione (GSH), the complexes were found capable to form complexes with GSH and/or nanoparticles. Most of the complexes were stable in the presence of the digestive enzyme S9 for 1 hour, indicating that the gold(III) complexes have adequate solution stability and bioavailability. (v) Some gold complexes were successfully encapsulated by PEG or by metal-organic frameworks (MOFs). The encapsulation retains or even enhances the cytotoxicity and anti-migration of the gold complexes. (vi) With the support of the GRF, articles directly related to these works have been published in high-impact journals.
Summary of objectives addressed:
Objectives Addressed Percentage achieved
1.To prepare gold compounds having bidentate S-donor ligands with lower toxicities and capability in overcoming platinum resistanceYes100%
2.To uncover their anti-cancer, anti-angiogenic and anti-cancer stem cell activitiesYes100%
3.To examine their mechanism of action by advanced transcriptomics/ proteomics approachesYes100%
4.To have the metabolomics examinationYes100%
5.To improve their therapeutic efficacies by encapsulation and synergistic addition approachesYes100%
6.To file patents on new drug leads / publish results in high-impact journalsYes100%
Research Outcome
Major findings and research outcome: (i) Gold complexes. We have synthesized >20 gold(I) or gold(III) complexes, with physical properties including solubility and solution stability examined. Some gold(III) dithiocarbamato complexes were found to form nanoparticles in solutions. The size of nanoparticles is close to irregular vascular structure of tumor-associated blood vessels, suggesting their preference in entering tumor tissue. (ii) Biological activities. Most complexes displayed anti-cancer activities with cytotoxic IC50 values ranging from 200 nM to 18 µM. By wound healing assay, several gold complexes containing carbene and dithiocarbamato ligands were found to exhibit anti-metastatic properties toward cisplatin-resistant ovarian cancers. Sphere-formation assay revealed that some gold(III) complexes could display anti-cancer-stem-cell activities towards drug-resistant cancers. By using ovarian carcinoma-bearing nude mice, two gold complexes containing dithiocarbamato ligands were found to exhibit potent in vivo anti-tumor effects upon 14 days of treatment. (iii) Mechanistic studies. Transcriptomics studies revealed that gold(III) dithiocarbamato complexes exhibit inhibition on the ubiquitin-proteasome systems. Gold(III) complexes containing phosphine ligands could exhibit promising anti-cancer activities via the inhibition of thioredoxin reductase and production of reactive oxygen species. By proteomic approaches, most gold complexes were found to enhance the expression of caspase 3, 8 and 9, and in association with the activation of PARP-1. Hoechst 33258 staining showed that gold complexes could induce DNA fragmentation. A gold(III) pyrrolidinedithiocarbamate (PDTC) exhibited promising anti-hepatitis B virus (HBV) and anti-hepatocellular carcinoma activities. By RT-PCR, this complex showed ability in inhibiting HBV formation intracellularly and extracellularly. (iv) Stability and bioavailability. By UV-vis spectrometry, gold complexes were found to stable in aqueous solutions. Yet, hydrolysis occurs upon prolonged standing. Spectroscopic examination revealed that these gold complexes could form gold-GSH adducts. In the presence of the liver digestive enzyme S9, most gold complexes were stable in the solution, indicating that they exhibit adequate solution stability. By ICP-AES, the gold(III) complexes were found to disintegrate and form metal complexes with different free ions. (v) Encapsulation. We have employed metal-organic frameworks (MOFs) which consist of adenine and zinc to encapsulate some anti-cancer gold complexes. Through Transwell® assay, we proved that the encapsulated gold complexes exhibit a less cytotoxicity towards different cancer cells. Some gold(III) complexes which have good leaving groups display better anti-cancer activities than the gold complexes alone. (vi) Publication. Based on the results directly from this work, we have published articles in journals with high impact factors.
Potential for further development of the research
and the proposed course of action:		 With the support from the GRF, a series of anti-cancer active gold complexes have been identified. Given that some of these complexes show adequate bioavailability and specificity towards cancerous cells and tissues, and notably some complexes developed in this project are highly potent towards drug-resistant cancer strains, more detailed and extensive in vitro and in vivo anti-cancer studies have to be launched for these drug leads in the next stage. After that, some anti-cancer active complexes can also be examined for their in vivo toxicity. Large rodent animal can also be employed for the acute and long term toxicological studies.
Layman's Summary of
Completion Report:		 Despite effort and achievement have been made in the identifications of novel anti-cancer drug candidates as well as development of therapeutic options of cancer treatments, cancer remains a global threatened issue nowadays. A number of highly anti-cancer active gold complexes have been developed and identified under the support of this GRF. Some of these complexes are highly potent towards drug-resistant cancer cells and could significantly reduce the size of tumor in mice. Their action mechanisms for their anti-cancer activities have been examined, giving clues for scientists in optimizing the anti-cancer activities of some related gold complexes. Some new materials coined as metal-organic frameworks (MOFs) have been identified and employed to carry and enhance the stability of the gold complexes in biological systems. All these studies pave the ways for the medical development of novel anti-cancer drugs and give hope to cancer patients who are suffering from relapsed cancers and drug-resistant cancer strains.
Research Output
Peer-reviewed journal publication(s)
arising directly from this research project :
(* denotes the corresponding author)
Year of
Publication		 Author(s) Title and Journal/Book Accessible from Institution Repository
2013 Lum, C. T.; Wong, A. S.-T.; Lin, M. C. M.; Che, C.-M.*; Sun, R. W.-Y.*  A gold(III) porphyrin complex as an anti-cancer candidate to inhibit growth of cancer-stem cells. Chemical Communications (impact factor: 6.378), 2013, 49, 4364-4366.  No 
2013 Zhang, J. J.; Ng, K.-M.; Lok, C.-N.; Sun, R. W.-Y.; Che, C.-M.*  Deubiquitinases as potential anti-cancer targets for gold(III) complexes. Chemical Communications (impact factor: 6.378), 2013, 49, 5153-5155.  No 
2013 Sun, R. W.-Y.; Lok, C.-N.; Fong, T. T.-H.; Li, C. K.-L.; Yang, Z.-F.; Zou, T.; Siu, A. F.-M.; Che, C.-M.*  A dinuclear cyclometalated gold(III)–phosphine complex targeting thioredoxin reductase inhibits hepatocellular carcinoma in vivo. Chemical Science (impact factor: 8.314), 2013, 4, 1979-1988.  No 
2014 Lum, C. T.; Sun, R. W.-Y., Zou, T.; Che, C.-M.*  Gold(III) complexes inhibit growth of cisplatinresistant ovarian cancer in association with upregulation of proapoptotic PMS2 gene. Chemical Science (impact factor: 8.314), 2014, 5, 1579-1584.  No 
2015 Sun, R. W.-Y.*, Zhang, M., Li, D., Zhang, Z.-F., Cai, H., Li, M., Xian, Y.-J., Ng, S. W., Wong, A. S. T.  Dinuclear gold(I) pyrrolidinedithiocarbamato complex: cytotoxic and antimigratory activities on cancer cells and the use of metal–organic framework, Chemistry - A European Journal (impact factor: 5.731), 2015, 21, 18534  No 
Zhang, M., Siant-Germain, C., Sun, R. W.-Y.*  Drug delivery systems for anti-cancer active complexes of some coinage metals. Current Medicinal Chemistry (impact factor: 3.853), 2016, submitted.  No 
Sun, R. W.-Y.*, Zhang, M., Li, D., Li, M., Wong, A. S. T.  Enhanced anti-cancer activities of a gold(III) pyrrolidinedithiocarbamato complex incorporated in a biodegradable metal-organic framework. Journal of Inorganic Biochemistry (impact factor: 3.444), 2016, in press.  No 
Recognized international conference(s)
in which paper(s) related to this research
project was/were delivered :
Month/Year/City Title Conference Name
Nov/2012/ Hong Kong Strategies to improve the anti-cancer efficacy of gold(III) compounds  The 6th Asian Biological Inorganic Chemistry Conference (AsBIC VI) 
Aug/2014/ Zurich, Switzerland Transition metals alter the biological properties of dithiocarbamates: formation of metal complexes and the uses of metal-organic frameworks  12th European Biological Inorganic Chemistry Conference (EuroBIC) 
Jan/2015/ Galway, Ireland Interaction of Cysteine with a Gold(I) Complex: Getting Three Birds with a Stone  The 13th International Symposium on Applied Bioinorganic Chemistry (ISABC13) 
Nov/2015/ Guangzhou, China Gold(I) Complexes: Fluorescent Probes of Cysteine and Anti-Migratory Agents of Cisplatin-Resistant Cancer Cells  Sadler's Symposium on Metals in Life Processes, Sun Yat-sen University 
Dec/2015/ Hawaii, USA Gold(I) Complexes: Fluorescent Probes of Cysteine, Anti-Migratory Agents of Cisplatin-Resistant Cancer Cells and the Synergism with Metal-Organic Framework  1st International Symposium on Clinical and Experimental Metallodrugs in Medicine: Cancer Chemotherapy (CEMM1) 
Other impact
(e.g. award of patents or prizes,
collaboration with other research institutions,
technology transfer, etc.):		 The research achievement of Dr. Raymond W.-Y. Sun (Collaborator & Former Principal Investigator of this project) on gold medicines had been featured in the ChemComm Emerging Investigators Issue 2013 of Chemical Communications (impact factor: 6.169) to recognize Dr. Sun as an Emerging Scientist in having potential to influence future directions in Chemistry.
  SCREEN ID: SCRRM00542