Synthesis, Anti-Proliferative Evaluation and Mechanism of 4-Trifluoro Methoxy Proguanil Derivatives with Various Carbon Chain Length
Among the known biguanide drugs, proguanil has the best antiproliferative activity. In contrast, newly synthesized biguanide derivatives containing fluorine atoms have excellent biological activity, among which trifluoromethoxy compounds show the strongest ability. Preliminary work in our laboratory...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-09-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/26/19/5775 |
| _version_ | 1797516002360033280 |
|---|---|
| author | Simeng Xu Yufang Cao Yu Luo Di Xiao Wei Wang Zhiren Wang Xiaoping Yang |
| author_facet | Simeng Xu Yufang Cao Yu Luo Di Xiao Wei Wang Zhiren Wang Xiaoping Yang |
| author_sort | Simeng Xu |
| collection | DOAJ |
| description | Among the known biguanide drugs, proguanil has the best antiproliferative activity. In contrast, newly synthesized biguanide derivatives containing fluorine atoms have excellent biological activity, among which trifluoromethoxy compounds show the strongest ability. Preliminary work in our laboratory exhibited that n-heptyl containing proguanil derivatives on one alkyl chain side have better biological activity than those with a shorter carbon chain. However, the relationship between the length of the carbon chain and the activity of the compounds is unknown. In this study, we synthesized 10 new trifluoromethoxy-containing proguanil derivatives with various carbon chain lengths. The phenyl side is fixed as the trifluoromethoxy group with change of carbon chain length in alkyl chain side. It was found that the anti-cancer abilities of <b>5C</b>–<b>8C</b> with n-pentyl to n-octyl groups was significantly better than that of proguanil in the five human cancer cell lines. The colony formation assay demonstrated that <b>6C</b>–<b>8C</b> at 0.5 to 1.0 μM significantly inhibited the colony formation of human cancer cell lines, much stronger than that of proguanil. Pharmacologically, <b>8C</b> activates AMPK, leading to inactivation of the mTOR/p70S6K/4EBP1 pathway. Thus, these novel compounds have a great potential for developing new anti-cancer candidates. |
| first_indexed | 2024-03-10T06:55:09Z |
| format | Article |
| id | doaj.art-971771ea10714f968b94f51cb8d085b6 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T06:55:09Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-971771ea10714f968b94f51cb8d085b62023-11-22T16:32:27ZengMDPI AGMolecules1420-30492021-09-012619577510.3390/molecules26195775Synthesis, Anti-Proliferative Evaluation and Mechanism of 4-Trifluoro Methoxy Proguanil Derivatives with Various Carbon Chain LengthSimeng Xu0Yufang Cao1Yu Luo2Di Xiao3Wei Wang4Zhiren Wang5Xiaoping Yang6Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha 410205, ChinaKey Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha 410205, ChinaTCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Material Medical Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, ChinaKey Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha 410205, ChinaTCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Material Medical Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, ChinaKey Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha 410205, ChinaKey Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha 410205, ChinaAmong the known biguanide drugs, proguanil has the best antiproliferative activity. In contrast, newly synthesized biguanide derivatives containing fluorine atoms have excellent biological activity, among which trifluoromethoxy compounds show the strongest ability. Preliminary work in our laboratory exhibited that n-heptyl containing proguanil derivatives on one alkyl chain side have better biological activity than those with a shorter carbon chain. However, the relationship between the length of the carbon chain and the activity of the compounds is unknown. In this study, we synthesized 10 new trifluoromethoxy-containing proguanil derivatives with various carbon chain lengths. The phenyl side is fixed as the trifluoromethoxy group with change of carbon chain length in alkyl chain side. It was found that the anti-cancer abilities of <b>5C</b>–<b>8C</b> with n-pentyl to n-octyl groups was significantly better than that of proguanil in the five human cancer cell lines. The colony formation assay demonstrated that <b>6C</b>–<b>8C</b> at 0.5 to 1.0 μM significantly inhibited the colony formation of human cancer cell lines, much stronger than that of proguanil. Pharmacologically, <b>8C</b> activates AMPK, leading to inactivation of the mTOR/p70S6K/4EBP1 pathway. Thus, these novel compounds have a great potential for developing new anti-cancer candidates.https://www.mdpi.com/1420-3049/26/19/5775biguanideanti-cancertrifluoromethoxyAMPK |
| spellingShingle | Simeng Xu Yufang Cao Yu Luo Di Xiao Wei Wang Zhiren Wang Xiaoping Yang Synthesis, Anti-Proliferative Evaluation and Mechanism of 4-Trifluoro Methoxy Proguanil Derivatives with Various Carbon Chain Length Molecules biguanide anti-cancer trifluoromethoxy AMPK |
| title | Synthesis, Anti-Proliferative Evaluation and Mechanism of 4-Trifluoro Methoxy Proguanil Derivatives with Various Carbon Chain Length |
| title_full | Synthesis, Anti-Proliferative Evaluation and Mechanism of 4-Trifluoro Methoxy Proguanil Derivatives with Various Carbon Chain Length |
| title_fullStr | Synthesis, Anti-Proliferative Evaluation and Mechanism of 4-Trifluoro Methoxy Proguanil Derivatives with Various Carbon Chain Length |
| title_full_unstemmed | Synthesis, Anti-Proliferative Evaluation and Mechanism of 4-Trifluoro Methoxy Proguanil Derivatives with Various Carbon Chain Length |
| title_short | Synthesis, Anti-Proliferative Evaluation and Mechanism of 4-Trifluoro Methoxy Proguanil Derivatives with Various Carbon Chain Length |
| title_sort | synthesis anti proliferative evaluation and mechanism of 4 trifluoro methoxy proguanil derivatives with various carbon chain length |
| topic | biguanide anti-cancer trifluoromethoxy AMPK |
| url | https://www.mdpi.com/1420-3049/26/19/5775 |
| work_keys_str_mv | AT simengxu synthesisantiproliferativeevaluationandmechanismof4trifluoromethoxyproguanilderivativeswithvariouscarbonchainlength AT yufangcao synthesisantiproliferativeevaluationandmechanismof4trifluoromethoxyproguanilderivativeswithvariouscarbonchainlength AT yuluo synthesisantiproliferativeevaluationandmechanismof4trifluoromethoxyproguanilderivativeswithvariouscarbonchainlength AT dixiao synthesisantiproliferativeevaluationandmechanismof4trifluoromethoxyproguanilderivativeswithvariouscarbonchainlength AT weiwang synthesisantiproliferativeevaluationandmechanismof4trifluoromethoxyproguanilderivativeswithvariouscarbonchainlength AT zhirenwang synthesisantiproliferativeevaluationandmechanismof4trifluoromethoxyproguanilderivativeswithvariouscarbonchainlength AT xiaopingyang synthesisantiproliferativeevaluationandmechanismof4trifluoromethoxyproguanilderivativeswithvariouscarbonchainlength |