Access to New Cytotoxic Triterpene and Steroidal Acid-TEMPO Conjugates by Ugi Multicomponent-Reactions
Multicomponent reactions, especially the Ugi-four component reaction (U-4CR), provide powerful protocols to efficiently access compounds having potent biological and pharmacological effects. Thus, a diverse library of betulinic acid (BA), fusidic acid (FA), cholic acid (CA) conjugates with TEMPO (ni...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/13/7125 |
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| author | Haider N. Sultani Ibrahim Morgan Hidayat Hussain Andreas H. Roos Haleh H. Haeri Goran N. Kaluđerović Dariush Hinderberger Bernhard Westermann |
| author_facet | Haider N. Sultani Ibrahim Morgan Hidayat Hussain Andreas H. Roos Haleh H. Haeri Goran N. Kaluđerović Dariush Hinderberger Bernhard Westermann |
| author_sort | Haider N. Sultani |
| collection | DOAJ |
| description | Multicomponent reactions, especially the Ugi-four component reaction (U-4CR), provide powerful protocols to efficiently access compounds having potent biological and pharmacological effects. Thus, a diverse library of betulinic acid (BA), fusidic acid (FA), cholic acid (CA) conjugates with TEMPO (nitroxide) have been prepared using this approach, which also makes them applicable in electron paramagnetic resonance (EPR) spectroscopy. Moreover, convertible amide modified spin-labelled fusidic acid derivatives were selected for post-Ugi modification utilizing a wide range of reaction conditions which kept the paramagnetic center intact. The nitroxide labelled betulinic acid analogue <b>6</b> possesses cytotoxic effects towards two investigated cell lines: prostate cancer PC3 (IC<sub>50</sub> 7.4 ± 0.7 μM) and colon cancer HT29 (IC<sub>50</sub> 9.0 ± 0.4 μM). Notably, spin-labelled fusidic acid derivative <b>8</b> acts strongly against these two cancer cell lines (PC3: IC<sub>50</sub> 6.0 ± 1.1 μM; HT29: IC<sub>50</sub> 7.4 ± 0.6 μM). Additionally, another fusidic acid analogue <b>9</b> was also found to be active towards HT29 with IC<sub>50</sub> 7.0 ± 0.3 μM (CV). Studies on the mode of action revealed that compound <b>8</b> increased the level of caspase-3 significantly which clearly indicates induction of apoptosis by activation of the caspase pathway. Furthermore, the exclusive mitochondria targeting of compound <b>18</b> was successfully achieved, since mitochondria are the major source of ROS generation. |
| first_indexed | 2024-03-10T09:52:22Z |
| format | Article |
| id | doaj.art-f544868874524751b3fb49517be02510 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T09:52:22Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f544868874524751b3fb49517be025102023-11-22T02:40:34ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-07-012213712510.3390/ijms22137125Access to New Cytotoxic Triterpene and Steroidal Acid-TEMPO Conjugates by Ugi Multicomponent-ReactionsHaider N. Sultani0Ibrahim Morgan1Hidayat Hussain2Andreas H. Roos3Haleh H. Haeri4Goran N. Kaluđerović5Dariush Hinderberger6Bernhard Westermann7Department of Bioorganic Chemistry, Leibniz-Institute of Plant Biochemistry, Weinberg 3, 06120 Halle, GermanyDepartment of Bioorganic Chemistry, Leibniz-Institute of Plant Biochemistry, Weinberg 3, 06120 Halle, GermanyDepartment of Bioorganic Chemistry, Leibniz-Institute of Plant Biochemistry, Weinberg 3, 06120 Halle, GermanyPhysical Chemistry—Complex Self-Organizing Systems, Institute of Chemistry, Martin Luther University Halle-Wittenberg, von-Danckelmann-Platz 4, 06120 Halle, GermanyPhysical Chemistry—Complex Self-Organizing Systems, Institute of Chemistry, Martin Luther University Halle-Wittenberg, von-Danckelmann-Platz 4, 06120 Halle, GermanyDepartment of Bioorganic Chemistry, Leibniz-Institute of Plant Biochemistry, Weinberg 3, 06120 Halle, GermanyPhysical Chemistry—Complex Self-Organizing Systems, Institute of Chemistry, Martin Luther University Halle-Wittenberg, von-Danckelmann-Platz 4, 06120 Halle, GermanyDepartment of Bioorganic Chemistry, Leibniz-Institute of Plant Biochemistry, Weinberg 3, 06120 Halle, GermanyMulticomponent reactions, especially the Ugi-four component reaction (U-4CR), provide powerful protocols to efficiently access compounds having potent biological and pharmacological effects. Thus, a diverse library of betulinic acid (BA), fusidic acid (FA), cholic acid (CA) conjugates with TEMPO (nitroxide) have been prepared using this approach, which also makes them applicable in electron paramagnetic resonance (EPR) spectroscopy. Moreover, convertible amide modified spin-labelled fusidic acid derivatives were selected for post-Ugi modification utilizing a wide range of reaction conditions which kept the paramagnetic center intact. The nitroxide labelled betulinic acid analogue <b>6</b> possesses cytotoxic effects towards two investigated cell lines: prostate cancer PC3 (IC<sub>50</sub> 7.4 ± 0.7 μM) and colon cancer HT29 (IC<sub>50</sub> 9.0 ± 0.4 μM). Notably, spin-labelled fusidic acid derivative <b>8</b> acts strongly against these two cancer cell lines (PC3: IC<sub>50</sub> 6.0 ± 1.1 μM; HT29: IC<sub>50</sub> 7.4 ± 0.6 μM). Additionally, another fusidic acid analogue <b>9</b> was also found to be active towards HT29 with IC<sub>50</sub> 7.0 ± 0.3 μM (CV). Studies on the mode of action revealed that compound <b>8</b> increased the level of caspase-3 significantly which clearly indicates induction of apoptosis by activation of the caspase pathway. Furthermore, the exclusive mitochondria targeting of compound <b>18</b> was successfully achieved, since mitochondria are the major source of ROS generation.https://www.mdpi.com/1422-0067/22/13/7125multi-component reactionfusidic acidTEMPO-conjugateelectron paramagnetic resonance (EPR) spectroscopycaspase-3 |
| spellingShingle | Haider N. Sultani Ibrahim Morgan Hidayat Hussain Andreas H. Roos Haleh H. Haeri Goran N. Kaluđerović Dariush Hinderberger Bernhard Westermann Access to New Cytotoxic Triterpene and Steroidal Acid-TEMPO Conjugates by Ugi Multicomponent-Reactions International Journal of Molecular Sciences multi-component reaction fusidic acid TEMPO-conjugate electron paramagnetic resonance (EPR) spectroscopy caspase-3 |
| title | Access to New Cytotoxic Triterpene and Steroidal Acid-TEMPO Conjugates by Ugi Multicomponent-Reactions |
| title_full | Access to New Cytotoxic Triterpene and Steroidal Acid-TEMPO Conjugates by Ugi Multicomponent-Reactions |
| title_fullStr | Access to New Cytotoxic Triterpene and Steroidal Acid-TEMPO Conjugates by Ugi Multicomponent-Reactions |
| title_full_unstemmed | Access to New Cytotoxic Triterpene and Steroidal Acid-TEMPO Conjugates by Ugi Multicomponent-Reactions |
| title_short | Access to New Cytotoxic Triterpene and Steroidal Acid-TEMPO Conjugates by Ugi Multicomponent-Reactions |
| title_sort | access to new cytotoxic triterpene and steroidal acid tempo conjugates by ugi multicomponent reactions |
| topic | multi-component reaction fusidic acid TEMPO-conjugate electron paramagnetic resonance (EPR) spectroscopy caspase-3 |
| url | https://www.mdpi.com/1422-0067/22/13/7125 |
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