Synthesis and Biological Evaluation of New <i>cis</i>-Restricted Triazole Analogues of Combretastatin A-4
The natural products combretastatins A-1 and A-4 are potent antimitotic and vascular-disrupting agents through their binding at the colchicine site in tubulin. However, these compounds suffer from a low water solubility and a tendency to isomerize to the inactive <i>trans</i> stilbenes....
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/30/2/317 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832587828486209536 |
|---|---|
| author | Lidia Prieto Daniel Gaviña Marcos Escolano María Cánovas-Belchí María Sánchez-Roselló Carlos del Pozo Eva Falomir Santiago Díaz-Oltra |
| author_facet | Lidia Prieto Daniel Gaviña Marcos Escolano María Cánovas-Belchí María Sánchez-Roselló Carlos del Pozo Eva Falomir Santiago Díaz-Oltra |
| author_sort | Lidia Prieto |
| collection | DOAJ |
| description | The natural products combretastatins A-1 and A-4 are potent antimitotic and vascular-disrupting agents through their binding at the colchicine site in tubulin. However, these compounds suffer from a low water solubility and a tendency to isomerize to the inactive <i>trans</i> stilbenes. In this study, we have prepared a series of 18 <i>cis</i>-restricted triazole analogues of combretastatin A-4 (CA-4), maintaining, in all cases, the 3,4,5-trimethoxy phenyl ring A, with the aim of investigating the substitution pattern on the B-ring in a systematic way. To this end, cytotoxic activities of the <i>cis</i>-restricted analogues of CA-4 prepared were determined in two tumor cell lines, namely, HT-29 and A-549, as well as in the non-tumor cell line HEK-293, to pre-evaluate the selectivity profile of the compounds for the tumor cell lines. The main conclusion was the essential presence of methoxyl or ethoxyl groups at the <i>para</i> position of the B-ring in order to obtain good antitumor activities. Thus, the more active compounds in our study displayed IC<sub>50</sub> values in the nanomolar range for the tumor cell lines but not for the normal cells. Consequently, these triazole analogues of CA-4 could serve as promising alternatives to the natural product, although further studies about their biological activity are essential in order to fully determine their viability as therapeutic agents in the treatment of cancer. |
| format | Article |
| id | doaj-art-0948ff41430a42c890dc55591fa2aa3e |
| institution | Kabale University |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-0948ff41430a42c890dc55591fa2aa3e2025-01-24T13:43:34ZengMDPI AGMolecules1420-30492025-01-0130231710.3390/molecules30020317Synthesis and Biological Evaluation of New <i>cis</i>-Restricted Triazole Analogues of Combretastatin A-4Lidia Prieto0Daniel Gaviña1Marcos Escolano2María Cánovas-Belchí3María Sánchez-Roselló4Carlos del Pozo5Eva Falomir6Santiago Díaz-Oltra7Department of Organic Chemistry, University of Valencia, E-46100 Burjassot, SpainDepartment of Organic Chemistry, University of Valencia, E-46100 Burjassot, SpainDepartment of Organic Chemistry, University of Valencia, E-46100 Burjassot, SpainDepartment of Organic Chemistry, University of Valencia, E-46100 Burjassot, SpainDepartment of Organic Chemistry, University of Valencia, E-46100 Burjassot, SpainDepartment of Organic Chemistry, University of Valencia, E-46100 Burjassot, SpainDepartment of Organic and Inorganic Chemistry, University Jaume I, E-12071 Castellón, SpainDepartment of Organic Chemistry, University of Valencia, E-46100 Burjassot, SpainThe natural products combretastatins A-1 and A-4 are potent antimitotic and vascular-disrupting agents through their binding at the colchicine site in tubulin. However, these compounds suffer from a low water solubility and a tendency to isomerize to the inactive <i>trans</i> stilbenes. In this study, we have prepared a series of 18 <i>cis</i>-restricted triazole analogues of combretastatin A-4 (CA-4), maintaining, in all cases, the 3,4,5-trimethoxy phenyl ring A, with the aim of investigating the substitution pattern on the B-ring in a systematic way. To this end, cytotoxic activities of the <i>cis</i>-restricted analogues of CA-4 prepared were determined in two tumor cell lines, namely, HT-29 and A-549, as well as in the non-tumor cell line HEK-293, to pre-evaluate the selectivity profile of the compounds for the tumor cell lines. The main conclusion was the essential presence of methoxyl or ethoxyl groups at the <i>para</i> position of the B-ring in order to obtain good antitumor activities. Thus, the more active compounds in our study displayed IC<sub>50</sub> values in the nanomolar range for the tumor cell lines but not for the normal cells. Consequently, these triazole analogues of CA-4 could serve as promising alternatives to the natural product, although further studies about their biological activity are essential in order to fully determine their viability as therapeutic agents in the treatment of cancer.https://www.mdpi.com/1420-3049/30/2/317cancertubulinantimitoticscombretastatin A-4triazolescytotoxicity |
| spellingShingle | Lidia Prieto Daniel Gaviña Marcos Escolano María Cánovas-Belchí María Sánchez-Roselló Carlos del Pozo Eva Falomir Santiago Díaz-Oltra Synthesis and Biological Evaluation of New <i>cis</i>-Restricted Triazole Analogues of Combretastatin A-4 Molecules cancer tubulin antimitotics combretastatin A-4 triazoles cytotoxicity |
| title | Synthesis and Biological Evaluation of New <i>cis</i>-Restricted Triazole Analogues of Combretastatin A-4 |
| title_full | Synthesis and Biological Evaluation of New <i>cis</i>-Restricted Triazole Analogues of Combretastatin A-4 |
| title_fullStr | Synthesis and Biological Evaluation of New <i>cis</i>-Restricted Triazole Analogues of Combretastatin A-4 |
| title_full_unstemmed | Synthesis and Biological Evaluation of New <i>cis</i>-Restricted Triazole Analogues of Combretastatin A-4 |
| title_short | Synthesis and Biological Evaluation of New <i>cis</i>-Restricted Triazole Analogues of Combretastatin A-4 |
| title_sort | synthesis and biological evaluation of new i cis i restricted triazole analogues of combretastatin a 4 |
| topic | cancer tubulin antimitotics combretastatin A-4 triazoles cytotoxicity |
| url | https://www.mdpi.com/1420-3049/30/2/317 |
| work_keys_str_mv | AT lidiaprieto synthesisandbiologicalevaluationofnewicisirestrictedtriazoleanaloguesofcombretastatina4 AT danielgavina synthesisandbiologicalevaluationofnewicisirestrictedtriazoleanaloguesofcombretastatina4 AT marcosescolano synthesisandbiologicalevaluationofnewicisirestrictedtriazoleanaloguesofcombretastatina4 AT mariacanovasbelchi synthesisandbiologicalevaluationofnewicisirestrictedtriazoleanaloguesofcombretastatina4 AT mariasanchezrosello synthesisandbiologicalevaluationofnewicisirestrictedtriazoleanaloguesofcombretastatina4 AT carlosdelpozo synthesisandbiologicalevaluationofnewicisirestrictedtriazoleanaloguesofcombretastatina4 AT evafalomir synthesisandbiologicalevaluationofnewicisirestrictedtriazoleanaloguesofcombretastatina4 AT santiagodiazoltra synthesisandbiologicalevaluationofnewicisirestrictedtriazoleanaloguesofcombretastatina4 |