Verification of the Necessity of the Tolyl Group of PF-543 for Sphingosine Kinase 1 Inhibitory Activity
PF-543, the most potent sphingosine kinase (SK) inhibitor, does not demonstrate effective anticancer activity in some cancer cells, unlike other known SK1 inhibitors. PF-543 has a non-lipid structure with a unique toluene backbone; however, the importance of this structure remains unclear. Therefore...
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MDPI AG
2020-05-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/11/2484 |
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| author | Su Bin Kim Taeho Lee Hong Seop Moon Sung Hwan Ki Yoon Sin Oh Joo-Youn Lee Sang-Bum Kim Jeong-Eun Park Yongseok Kwon Sanghee Kim Dong Jae Baek Eun-Young Park |
| author_facet | Su Bin Kim Taeho Lee Hong Seop Moon Sung Hwan Ki Yoon Sin Oh Joo-Youn Lee Sang-Bum Kim Jeong-Eun Park Yongseok Kwon Sanghee Kim Dong Jae Baek Eun-Young Park |
| author_sort | Su Bin Kim |
| collection | DOAJ |
| description | PF-543, the most potent sphingosine kinase (SK) inhibitor, does not demonstrate effective anticancer activity in some cancer cells, unlike other known SK1 inhibitors. PF-543 has a non-lipid structure with a unique toluene backbone; however, the importance of this structure remains unclear. Therefore, the purpose of this study was to investigate changes in SK inhibitory and anticancer activities and to explore the role of the tolyl group structure of PF-543 through various modifications. We transformed the methyl group of PF-543 into hydrogen, fluorine, and hydroxy. PF-543 derivatives in which the methyl group was substituted by hydrogen and fluorine (compound <b>5</b>) demonstrated SK1 inhibitory and anticancer activities similar to PF-543. Moreover, we performed molecular modeling studies of PF-543 and compound <b>5</b>. To assess the metabolic stability of PF-543 and compound <b>5</b>, we determined their degree of degradation using the liver microsomes of four different animal species (human, dog, rat, and mouse). However, both PF-543 and compound <b>5</b> showed poor microsomal stability. Therefore, for the medical applications of PF-543, the structural modifications of its other parts may be necessary. Our results provide important information for the design of additional PF-543 analogs. |
| first_indexed | 2024-03-10T19:33:56Z |
| format | Article |
| id | doaj.art-ae7cbe18662943c287953e75da58e771 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T19:33:56Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-ae7cbe18662943c287953e75da58e7712023-11-20T01:54:56ZengMDPI AGMolecules1420-30492020-05-012511248410.3390/molecules25112484Verification of the Necessity of the Tolyl Group of PF-543 for Sphingosine Kinase 1 Inhibitory ActivitySu Bin Kim0Taeho Lee1Hong Seop Moon2Sung Hwan Ki3Yoon Sin Oh4Joo-Youn Lee5Sang-Bum Kim6Jeong-Eun Park7Yongseok Kwon8Sanghee Kim9Dong Jae Baek10Eun-Young Park11College of Pharmacy, Mokpo National University, Jeonnam 58554, KoreaCollege of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, KoreaCollege of Pharmacy, Mokpo National University, Jeonnam 58554, KoreaCollege of Pharmacy, Chosun University, Gwangju 61452, KoreaDepartment of Food and Nutrition, Eulji University, Seongnam 13135, KoreaChemical Data-Driven Research Center, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, KoreaNew Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, 80 Cheombok-ro, Dong-gu, Daegu 41061, KoreaNew Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, 80 Cheombok-ro, Dong-gu, Daegu 41061, KoreaDepartment of Chemistry, Sogang University, Seoul 04107, KoreaCollege of Pharmacy, Seoul National University, Seoul 08826, KoreaCollege of Pharmacy, Mokpo National University, Jeonnam 58554, KoreaCollege of Pharmacy, Mokpo National University, Jeonnam 58554, KoreaPF-543, the most potent sphingosine kinase (SK) inhibitor, does not demonstrate effective anticancer activity in some cancer cells, unlike other known SK1 inhibitors. PF-543 has a non-lipid structure with a unique toluene backbone; however, the importance of this structure remains unclear. Therefore, the purpose of this study was to investigate changes in SK inhibitory and anticancer activities and to explore the role of the tolyl group structure of PF-543 through various modifications. We transformed the methyl group of PF-543 into hydrogen, fluorine, and hydroxy. PF-543 derivatives in which the methyl group was substituted by hydrogen and fluorine (compound <b>5</b>) demonstrated SK1 inhibitory and anticancer activities similar to PF-543. Moreover, we performed molecular modeling studies of PF-543 and compound <b>5</b>. To assess the metabolic stability of PF-543 and compound <b>5</b>, we determined their degree of degradation using the liver microsomes of four different animal species (human, dog, rat, and mouse). However, both PF-543 and compound <b>5</b> showed poor microsomal stability. Therefore, for the medical applications of PF-543, the structural modifications of its other parts may be necessary. Our results provide important information for the design of additional PF-543 analogs.https://www.mdpi.com/1420-3049/25/11/2484sphingosine kinasePF-543BODIPYanticancerinhibitorderivative |
| spellingShingle | Su Bin Kim Taeho Lee Hong Seop Moon Sung Hwan Ki Yoon Sin Oh Joo-Youn Lee Sang-Bum Kim Jeong-Eun Park Yongseok Kwon Sanghee Kim Dong Jae Baek Eun-Young Park Verification of the Necessity of the Tolyl Group of PF-543 for Sphingosine Kinase 1 Inhibitory Activity Molecules sphingosine kinase PF-543 BODIPY anticancer inhibitor derivative |
| title | Verification of the Necessity of the Tolyl Group of PF-543 for Sphingosine Kinase 1 Inhibitory Activity |
| title_full | Verification of the Necessity of the Tolyl Group of PF-543 for Sphingosine Kinase 1 Inhibitory Activity |
| title_fullStr | Verification of the Necessity of the Tolyl Group of PF-543 for Sphingosine Kinase 1 Inhibitory Activity |
| title_full_unstemmed | Verification of the Necessity of the Tolyl Group of PF-543 for Sphingosine Kinase 1 Inhibitory Activity |
| title_short | Verification of the Necessity of the Tolyl Group of PF-543 for Sphingosine Kinase 1 Inhibitory Activity |
| title_sort | verification of the necessity of the tolyl group of pf 543 for sphingosine kinase 1 inhibitory activity |
| topic | sphingosine kinase PF-543 BODIPY anticancer inhibitor derivative |
| url | https://www.mdpi.com/1420-3049/25/11/2484 |
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