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Novel Triterpenic Acid—Benzotriazole Esters Act as Pro-Apoptotic Antimelanoma Agents

Mioc, Marius, Mioc, Alexandra, Prodea, Alexandra, Milan, Andreea, Balan-Porcarasu, Mihaela, Racoviceanu, Roxana, Ghiulai, Roxana, Iovanescu, Gheorghe, Macasoi, Ioana, Draghici, George, Dehelean, Cristina, Soica, Codruta·2022·International Journal of Molecular Sciences
DOI 10.3390/ijms23179992PMC PMC9456456
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Abstract

Pentacyclic triterpenes, such as betulinic, ursolic, and oleanolic acids are efficient and selective anticancer agents whose underlying mechanisms of action have been widely investigated. The introduction of N-bearing heterocycles (e.g., triazoles) into the structures of natural compounds (particularly pentacyclic triterpenes) has yielded semisynthetic derivatives with increased antiproliferative potential as opposed to unmodified starting compounds. In this work, we report the synthesis and biological assessment of benzotriazole esters of betulinic acid (BA), oleanolic acid (OA), and ursolic acid (UA) (compounds 1–3). The esters were obtained in moderate yields (28–42%). All three compounds showed dose-dependent reductions in cell viability against A375 melanoma cells and no cytotoxic effects against healthy human keratinocytes. The morphology analysis of treated cells showed characteristic apoptotic changes consisting of nuclear shrinkage, condensation, fragmentation, and cellular membrane disruption. rtPCR analysis reinforced the proapoptotic evidence, showing a reduction in anti-apoptotic Bcl-2 expression and upregulation of the pro-apoptotic Bax. High-resolution respirometry studies showed that all three compounds were able to significantly inhibit mitochondrial function. Molecular docking showed that compounds 1–3 showed an increase in binding affinity against Bcl-2 as opposed to BA, OA, and UA and similar binding patterns compared to known Bcl-2 inhibitors.

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Figure 1 Synthesis procedure of BA, OA, and UA-HOBt esters (1–3).
Figure 1 Synthesis procedure of BA, OA, and UA-HOBt esters (1–3).CC BY · PubMed Central
Figure 2 Cell viability of HaCaT and A375 cells after 24 h of treatment with 0.4, 2, 10, 25, and 50 μM of compounds 1 (A), 2 (B), and 3 (C), determined using the Alamar Blue assay. The results are expressed as cell viability percentage (%) normalized to control (100%). The data represent the mean values ± SD of three independent experiments performed in triplicate. The statistical differences vs. the control was determined using one-way ANOVA analysis followed by Tukey’s multiple comparisons post-test (* p < 0.05, ** p < 0.005 and *** p < 0.0001).
Figure 2 Cell viability of HaCaT and A375 cells after 24 h of treatment with 0.4, 2, 10, 25, and 50 μM of compounds 1 (A), 2 (B), and 3 (C), determined using the Alamar Blue assay. The results are expressed as cell viability percentage (%) normalized to control (100%). The data represent the mean values ± SD of three independent experiments performed in triplicate. The statistical differences vs. the control was determined using one-way ANOVA analysis followed by Tukey’s multiple comparisons post-test (* p < 0.05, ** p < 0.005 and *** p < 0.0001).CC BY · PubMed Central
Figure 3 Representative images of the morphological aspects of HaCaT cells after treatment for 24 h with 1, 2 (25 μM), and 3 (50 μM). The scale bar was 100 μm.
Figure 3 Representative images of the morphological aspects of HaCaT cells after treatment for 24 h with 1, 2 (25 μM), and 3 (50 μM). The scale bar was 100 μm.CC BY · PubMed Central
Figure 4 Representative images of the morphological aspects of A375 cells after treatment for 24 h with 1, 2 (25 μM), and 3 (50 μM). The scale bar was 100 μm.
Figure 4 Representative images of the morphological aspects of A375 cells after treatment for 24 h with 1, 2 (25 μM), and 3 (50 μM). The scale bar was 100 μm.CC BY · PubMed Central
Figure 5 Nuclear staining using DAPI in HaCaT cells after treatment with 1, 2, and 3 (10, 25, and 50 μM) for 24 h. The pictures were captured 24 h post-treatment. The staurosporine solution (5 μM) was used as the positive control for apoptotic changes at the nuclear level. The yellow arrows represent signs of apoptosis, such as nuclear shrinkage, condensation, fragmentation, and cellular membrane disruption.
Figure 5 Nuclear staining using DAPI in HaCaT cells after treatment with 1, 2, and 3 (10, 25, and 50 μM) for 24 h. The pictures were captured 24 h post-treatment. The staurosporine solution (5 μM) was used as the positive control for apoptotic changes at the nuclear level. The yellow arrows represent signs of apoptosis, such as nuclear shrinkage, condensation, fragmentation, and cellular membrane disruption.CC BY · PubMed Central
Figure 6 Nuclear staining using DAPI in A375 cells after treatment with 1, 2, and 3 (10, 25, and 50 μM) for 24 h. The pictures were captured 24 h post-treatment. The staurosporine solution (5 μM) was used as the positive control for apoptotic changes at the nuclear level. The yellow arrows represent signs of apoptosis, such as nuclear shrinkage, condensation, fragmentation, and cellular membrane disruption.
Figure 6 Nuclear staining using DAPI in A375 cells after treatment with 1, 2, and 3 (10, 25, and 50 μM) for 24 h. The pictures were captured 24 h post-treatment. The staurosporine solution (5 μM) was used as the positive control for apoptotic changes at the nuclear level. The yellow arrows represent signs of apoptosis, such as nuclear shrinkage, condensation, fragmentation, and cellular membrane disruption.CC BY · PubMed Central
Figure 7 Relative fold change expression in mRNA of Bcl-2 and BAX in A375 cells after stimulation with 1, 2 (25 μM), and 3 (50 μM) for 24 h. The expressions were normalized to 18S and DMSO was used as the control. Data represent the mean values ± SD of three independent experiments. One-way ANOVA with Dunnett’s post-test was applied to determine the statistical differences in rapport with DMSO stimulated cells (* p < 0.05, ** p < 0.01, and *** p < 0.001).
Figure 7 Relative fold change expression in mRNA of Bcl-2 and BAX in A375 cells after stimulation with 1, 2 (25 μM), and 3 (50 μM) for 24 h. The expressions were normalized to 18S and DMSO was used as the control. Data represent the mean values ± SD of three independent experiments. One-way ANOVA with Dunnett’s post-test was applied to determine the statistical differences in rapport with DMSO stimulated cells (* p < 0.05, ** p < 0.01, and *** p < 0.001).CC BY · PubMed Central
Figure 8 Respiration of permeabilized immortalized human keratinocytes (HaCaT) and human melanoma cells (A375) following a 24 h stimulation with 25 μM 1. Data represent the mean ± SD of five individual experiments. Values with p < 0.05 were considered to have statistically significant differences (* p < 0.05, and *** p < 0.01). The respiratory parameters displayed represent the following: Routine—respiration of cells suspended in a substrate-free media, supported by endogenous ADP; State 2CI—mitochondrial respiration in basal conditions driven by CI, OXPHOSCI—active respiration dependent on CI substrates and exogenous ADP; OXPHOSCI+II—maximal active respiration driven by both CI and CII; State 4CI+II—basal respiration dependent on both CI and CII; ETSCI+II—maximal respiratory capacity of the electron transport system in the fully noncoupled state; ETSCII—electron transport system maximal capacity dependent only on CII.
Figure 8 Respiration of permeabilized immortalized human keratinocytes (HaCaT) and human melanoma cells (A375) following a 24 h stimulation with 25 μM 1. Data represent the mean ± SD of five individual experiments. Values with p < 0.05 were considered to have statistically significant differences (* p < 0.05, and *** p < 0.01). The respiratory parameters displayed represent the following: Routine—respiration of cells suspended in a substrate-free media, supported by endogenous ADP; State 2CI—mitochondrial respiration in basal conditions driven by CI, OXPHOSCI—active respiration dependent on CI substrates and exogenous ADP; OXPHOSCI+II—maximal active respiration driven by both CI and CII; State 4CI+II—basal respiration dependent on both CI and CII; ETSCI+II—maximal respiratory capacity of the electron transport system in the fully noncoupled state; ETSCII—electron transport system maximal capacity dependent only on CII.CC BY · PubMed Central
Figure 9 Respiration of permeabilized immortalized human keratinocytes (HaCaT) and human melanoma cells (A375) following 24 h stimulation with 25 μM 2. Data represent the mean ± SD of five individual experiments. Values with p < 0.05 were considered to have statistically significant differences (* p < 0.05, ** p < 0.01, and *** p < 0.01). The respiratory parameters displayed represent the following: Routine—respiration of cells suspended in a substrate-free media, supported by endogenous ADP; State 2CI –mitochondrial respiration in basal conditions driven by CI, OXPHOSCI—active respiration dependent on CI substrates and exogenous ADP; OXPHOSCI+II—maximal active respiration driven by both CI and CII; State 4CI+II—basal respiration dependent on both CI and CII; ETSCI+II—maximal respiratory capacity of the electron transport system in the fully noncoupled state; ETSCII—electron transport system maximal capacity dependent only on CII.
Figure 9 Respiration of permeabilized immortalized human keratinocytes (HaCaT) and human melanoma cells (A375) following 24 h stimulation with 25 μM 2. Data represent the mean ± SD of five individual experiments. Values with p < 0.05 were considered to have statistically significant differences (* p < 0.05, ** p < 0.01, and *** p < 0.01). The respiratory parameters displayed represent the following: Routine—respiration of cells suspended in a substrate-free media, supported by endogenous ADP; State 2CI –mitochondrial respiration in basal conditions driven by CI, OXPHOSCI—active respiration dependent on CI substrates and exogenous ADP; OXPHOSCI+II—maximal active respiration driven by both CI and CII; State 4CI+II—basal respiration dependent on both CI and CII; ETSCI+II—maximal respiratory capacity of the electron transport system in the fully noncoupled state; ETSCII—electron transport system maximal capacity dependent only on CII.CC BY · PubMed Central
Figure 10 Respiration of permeabilized immortalized human keratinocytes (HaCaT) and human melanoma cells (A375) following 24 h of stimulation with 50 μM 3. Data represent the mean ± SD of five individual experiments. Values with p < 0.05 were considered to have statistically significant differences (* p < 0.05, ** p < 0.01, and *** p < 0.01). The respiratory parameters displayed represent the following: Routine—respiration of cells suspended in a substrate-free media, supported by endogenous ADP; State 2CI—mitochondrial respiration in basal conditions driven by CI, OXPHOSCI—active respiration dependent on CI substrates and exogenous ADP; OXPHOSCI+II—maximal active respiration driven by both CI and CII; State 4CI+II—basal respiration dependent on both CI and CII; ETSCI+II—maximal respiratory capacity of the electron transport system in the fully noncoupled state; ETSCII—electron transport system maximal capacity dependent only on CII.
Figure 10 Respiration of permeabilized immortalized human keratinocytes (HaCaT) and human melanoma cells (A375) following 24 h of stimulation with 50 μM 3. Data represent the mean ± SD of five individual experiments. Values with p < 0.05 were considered to have statistically significant differences (* p < 0.05, ** p < 0.01, and *** p < 0.01). The respiratory parameters displayed represent the following: Routine—respiration of cells suspended in a substrate-free media, supported by endogenous ADP; State 2CI—mitochondrial respiration in basal conditions driven by CI, OXPHOSCI—active respiration dependent on CI substrates and exogenous ADP; OXPHOSCI+II—maximal active respiration driven by both CI and CII; State 4CI+II—basal respiration dependent on both CI and CII; ETSCI+II—maximal respiratory capacity of the electron transport system in the fully noncoupled state; ETSCII—electron transport system maximal capacity dependent only on CII.CC BY · PubMed Central
Figure 11 Structure of Bcl-2 (2W3L) in complex with compounds 1 (orange), 2 (blue), and 3 (green); HB interactions are depicted as green dotted lines, hydrophobic interactions as purple dotted lines, and electrostatic interactions as orange dotted lines; interacting amino acids are shown as dark gray sticks.
Figure 11 Structure of Bcl-2 (2W3L) in complex with compounds 1 (orange), 2 (blue), and 3 (green); HB interactions are depicted as green dotted lines, hydrophobic interactions as purple dotted lines, and electrostatic interactions as orange dotted lines; interacting amino acids are shown as dark gray sticks.CC BY · PubMed Central

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Cited by

Metadata

Authors
Mioc, M., Mioc, A., Prodea, A., Milan, A., Balan-Porcarasu, M., Racoviceanu, R., Ghiulai, R., Iovanescu, G., Macasoi, I., Draghici, G., Dehelean, C., & Soica, C.
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2022-09-01
Volume
23
Issue
17
Pages
9992
ISSN
1422-0067
DOI
10.3390/ijms23179992
PMC
PMC9456456
Cited by
19
References
0
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
Romanian UEFISCDI (PN-III-P1-1.1-PD-2019-1078)

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