T. Srinivasa Reddy , Steven H. Privér , Ruchika Ojha , Nedaossadat Mirzadeh , Ganga Reddy Velma , Ranjithkumar Jakku , Tayebeh Hosseinnejad , Rodney Luwor , Sistla Ramakrishna , Donald Wlodkowic , Magdalena Plebanski , Suresh K. Bhargava
{"title":"AuL{κC-2-C6H4P(S)Ph2}] [L = PTA、PPh3、PPh2(C6H4-3-SO3Na) 和 PPh2(2-py)] 类型的金（I）配合物：合成、表征、晶体结构以及体外和体内抗癌特性。","authors":"T. Srinivasa Reddy , Steven H. Privér , Ruchika Ojha , Nedaossadat Mirzadeh , Ganga Reddy Velma , Ranjithkumar Jakku , Tayebeh Hosseinnejad , Rodney Luwor , Sistla Ramakrishna , Donald Wlodkowic , Magdalena Plebanski , Suresh K. Bhargava","doi":"10.1016/j.ejmech.2024.117007","DOIUrl":null,"url":null,"abstract":"<div><div>Four new mononuclear gold (I) compounds of the type [AuL{κ<em>C</em>-2-C<sub>6</sub>H<sub>4</sub>P(S)Ph<sub>2</sub>}] {L = PTA (<strong>1</strong>), PPh<sub>3</sub> (<strong>2</strong>), PPh<sub>2</sub>(C<sub>6</sub>H<sub>4</sub>-3-SO<sub>3</sub>Na) (<strong>3</strong>), and PPh<sub>2</sub>(2-py) (<strong>4</strong>)} were prepared by scission of the dinuclear compound [Au<sub>2</sub>{μ-2-C<sub>6</sub>H<sub>4</sub>P(S)Ph<sub>2</sub>}<sub>2</sub>] by L or via a transmetalation reaction using the organotin reagent 2-Me<sub>3</sub>SnC<sub>6</sub>H<sub>4</sub>P(S)Ph<sub>2</sub> and a suitable gold halide precursor. The cytotoxic potential of complexes <strong>1</strong>–<strong>4</strong> was evaluated against four human cancer cell lines of diverse cellular origin: cervical (HeLa), prostate (PC-3), non-small cell lung adenocarcinoma (A549), and fibrosarcoma (HT-1080). The <em>in vitro</em> cytotoxicity results showed that <strong>1</strong> demonstrated exceptional anticancer activity with IC<sub>50</sub> values ranging from 0.08 to 3.5 μM. Complex <strong>3</strong>, which contains a sulfonated triphenyl phosphine ligand, displayed the weakest anticancer activity with IC<sub>50</sub> values ranging from 3.1 to >50 μM. When compared to the standard chemotherapeutic drug cisplatin, <strong>1</strong> displayed approximately 27-fold greater cytotoxic activity against cervical cancer cells and 3.5- and 7.5-fold greater activities against prostate and fibrosarcoma cancer cells, respectively. Additionally, <strong>1</strong> exhibited 3-fold selectivity for cervical cancer cells compared to non-cancerous HEK-293 cells. Mechanistic investigations revealed that <strong>1</strong> induced apoptosis, which was associated with elevated reactive oxygen species (ROS) and inhibition of the intracellular enzyme thioredoxin reductase. Furthermore, <strong>1</strong> exhibited notable antiangiogenic characteristics in an <em>in vivo</em> model using transgenic zebrafish Tg(fli1a:EGFP). <em>In vivo</em> studies using mouse xenograft models showed that complex <strong>1</strong> displayed superior inhibition of tumour growth (82 %) compared to the clinical drug cisplatin (29 %). Overall, these results highlight the potential of gold (I) compounds as novel antitumour agents.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117007"},"PeriodicalIF":6.0000,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Gold(I) somplexes of the type [AuL{κC-2-C6H4P(S)Ph2}] [L = PTA, PPh3, PPh2(C6H4-3-SO3Na) and PPh2(2-py)]: Synthesis, characterisation, crystal structures, and In Vitro and In Vivo anticancer properties.\",\"authors\":\"T. Srinivasa Reddy , Steven H. Privér , Ruchika Ojha , Nedaossadat Mirzadeh , Ganga Reddy Velma , Ranjithkumar Jakku , Tayebeh Hosseinnejad , Rodney Luwor , Sistla Ramakrishna , Donald Wlodkowic , Magdalena Plebanski , Suresh K. Bhargava\",\"doi\":\"10.1016/j.ejmech.2024.117007\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Four new mononuclear gold (I) compounds of the type [AuL{κ<em>C</em>-2-C<sub>6</sub>H<sub>4</sub>P(S)Ph<sub>2</sub>}] {L = PTA (<strong>1</strong>), PPh<sub>3</sub> (<strong>2</strong>), PPh<sub>2</sub>(C<sub>6</sub>H<sub>4</sub>-3-SO<sub>3</sub>Na) (<strong>3</strong>), and PPh<sub>2</sub>(2-py) (<strong>4</strong>)} were prepared by scission of the dinuclear compound [Au<sub>2</sub>{μ-2-C<sub>6</sub>H<sub>4</sub>P(S)Ph<sub>2</sub>}<sub>2</sub>] by L or via a transmetalation reaction using the organotin reagent 2-Me<sub>3</sub>SnC<sub>6</sub>H<sub>4</sub>P(S)Ph<sub>2</sub> and a suitable gold halide precursor. The cytotoxic potential of complexes <strong>1</strong>–<strong>4</strong> was evaluated against four human cancer cell lines of diverse cellular origin: cervical (HeLa), prostate (PC-3), non-small cell lung adenocarcinoma (A549), and fibrosarcoma (HT-1080). The <em>in vitro</em> cytotoxicity results showed that <strong>1</strong> demonstrated exceptional anticancer activity with IC<sub>50</sub> values ranging from 0.08 to 3.5 μM. Complex <strong>3</strong>, which contains a sulfonated triphenyl phosphine ligand, displayed the weakest anticancer activity with IC<sub>50</sub> values ranging from 3.1 to >50 μM. When compared to the standard chemotherapeutic drug cisplatin, <strong>1</strong> displayed approximately 27-fold greater cytotoxic activity against cervical cancer cells and 3.5- and 7.5-fold greater activities against prostate and fibrosarcoma cancer cells, respectively. Additionally, <strong>1</strong> exhibited 3-fold selectivity for cervical cancer cells compared to non-cancerous HEK-293 cells. Mechanistic investigations revealed that <strong>1</strong> induced apoptosis, which was associated with elevated reactive oxygen species (ROS) and inhibition of the intracellular enzyme thioredoxin reductase. Furthermore, <strong>1</strong> exhibited notable antiangiogenic characteristics in an <em>in vivo</em> model using transgenic zebrafish Tg(fli1a:EGFP). <em>In vivo</em> studies using mouse xenograft models showed that complex <strong>1</strong> displayed superior inhibition of tumour growth (82 %) compared to the clinical drug cisplatin (29 %). Overall, these results highlight the potential of gold (I) compounds as novel antitumour agents.</div></div>\",\"PeriodicalId\":314,\"journal\":{\"name\":\"European Journal of Medicinal Chemistry\",\"volume\":\"281 \",\"pages\":\"Article 117007\"},\"PeriodicalIF\":6.0000,\"publicationDate\":\"2024-10-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0223523424008894\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0223523424008894","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Gold(I) somplexes of the type [AuL{κC-2-C6H4P(S)Ph2}] [L = PTA, PPh3, PPh2(C6H4-3-SO3Na) and PPh2(2-py)]: Synthesis, characterisation, crystal structures, and In Vitro and In Vivo anticancer properties.
Four new mononuclear gold (I) compounds of the type [AuL{κC-2-C6H4P(S)Ph2}] {L = PTA (1), PPh3 (2), PPh2(C6H4-3-SO3Na) (3), and PPh2(2-py) (4)} were prepared by scission of the dinuclear compound [Au2{μ-2-C6H4P(S)Ph2}2] by L or via a transmetalation reaction using the organotin reagent 2-Me3SnC6H4P(S)Ph2 and a suitable gold halide precursor. The cytotoxic potential of complexes 1–4 was evaluated against four human cancer cell lines of diverse cellular origin: cervical (HeLa), prostate (PC-3), non-small cell lung adenocarcinoma (A549), and fibrosarcoma (HT-1080). The in vitro cytotoxicity results showed that 1 demonstrated exceptional anticancer activity with IC50 values ranging from 0.08 to 3.5 μM. Complex 3, which contains a sulfonated triphenyl phosphine ligand, displayed the weakest anticancer activity with IC50 values ranging from 3.1 to >50 μM. When compared to the standard chemotherapeutic drug cisplatin, 1 displayed approximately 27-fold greater cytotoxic activity against cervical cancer cells and 3.5- and 7.5-fold greater activities against prostate and fibrosarcoma cancer cells, respectively. Additionally, 1 exhibited 3-fold selectivity for cervical cancer cells compared to non-cancerous HEK-293 cells. Mechanistic investigations revealed that 1 induced apoptosis, which was associated with elevated reactive oxygen species (ROS) and inhibition of the intracellular enzyme thioredoxin reductase. Furthermore, 1 exhibited notable antiangiogenic characteristics in an in vivo model using transgenic zebrafish Tg(fli1a:EGFP). In vivo studies using mouse xenograft models showed that complex 1 displayed superior inhibition of tumour growth (82 %) compared to the clinical drug cisplatin (29 %). Overall, these results highlight the potential of gold (I) compounds as novel antitumour agents.
期刊介绍：
The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers.
A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.
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