Student or educator? Sign up with your school email and get 6 months of Pro free.
CoChat
Sign Up
Cited by 19

The DOI matches its Crossref record.

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
Open this paper in CoChat — free account

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.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3390/ijms23179992

Cites

Statistics

Figures

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

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

No references could be resolved yet.

Research works printed but not linked: 60

  1. Hughes, 2011, Principles of early drug discovery, Br. J. Pharmacol., 162, 1239, 10.1111/j.1476-5381.2010.01127.x · DOI · Paper page
  2. Ghante, 2019, Role of Pentacyclic Triterpenoids in Chemoprevention and Anticancer Treatment: An Overview on Targets and Underling Mechanisms, J. Pharmacopunct., 22, 55, 10.3831/KPI.201.22.007 · DOI
  3. Sung, 2021, Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA, Cancer J. Clin., 71, 209, 10.3322/caac.21660 · DOI · Paper page
  4. Zhong, 2021, Recent progress on betulinic acid and its derivatives as antitumor agents: A mini review, Chin. J. Nat. Med., 19, 641
  5. Ayeleso, T., Matumba, M., and Mukwevho, E. (2017). Oleanolic Acid and Its Derivatives: Biological Activities and Therapeutic Potential in Chronic Diseases. Molecules, 22. · DOI
  6. Mlala, S., Oyedeji, A.O., Gondwe, M., and Oyedeji, O.O. (2019). Ursolic Acid and Its Derivatives as Bioactive Agents. Molecules, 24. · DOI
  7. Dangroo, 2017, A convergent synthesis of novel alkyne–azide cycloaddition congeners of betulinic acid as potent cytotoxic agent, Steroids, 123, 1, 10.1016/j.steroids.2017.04.002 · DOI
  8. Wei, 2015, A library of 1,2,3-triazole-substituted oleanolic acid derivatives as anticancer agents: Design, synthesis, and biological evaluation, Org. Biomol. Chem., 13, 1507, 10.1039/C4OB01605J · DOI
  9. Suman, 2017, Synthesis and cytotoxicity of Baylis-Hillman template derived betulinic acid-triazole conjugates, Tetrahedron, 73, 4214, 10.1016/j.tet.2016.11.056 · DOI
  10. Banerji, 2018, Synthesis of Triazole-Substituted Quinazoline Hybrids for Anticancer Activity and a Lead Compound as the EGFR Blocker and ROS Inducer Agent, ACS Omega, 3, 16134, 10.1021/acsomega.8b01960 · DOI
  11. Chan, 2007, Kinetics of Amide Formation through Carbodiimide/N-Hydroxybenzotriazole (HOBt) Couplings, J. Org. Chem., 72, 8863, 10.1021/jo701558y · DOI
  12. Sheikh, 2010, Mechanistic studies of DCC/HOBt-mediated reaction of 3-phenylpropionic acid with benzyl alcohol and studies on the reactivities of ‘active ester’ and the related derivatives with nucleophiles, Tetrahedron, 66, 7272, 10.1016/j.tet.2010.07.011 · DOI
  13. Demuner, 2015, Hederagenin as a triterpene template for the development of new antitumor compounds, Eur. J. Med. Chem., 105, 57, 10.1016/j.ejmech.2015.10.006 · DOI
  14. Wang, 2019, Synthesis and biological evaluation of novel H6 analogues as drug resistance reversal agents, Eur. J. Med. Chem., 161, 364, 10.1016/j.ejmech.2018.10.033 · DOI
  15. He, 2020, Synthesis and biological evaluation of celastrol derivatives as potential immunosuppressive agents, J. Nat. Prod., 83, 2578, 10.1021/acs.jnatprod.0c00067 · DOI
  16. Wu, 2007, Synthesis, in vitro inhibitory activity towards COX-2 and haemolytic activity of derivatives of Esculentoside, A, Bioorg. Med. Chem. Lett., 17, 6430, 10.1016/j.bmcl.2007.10.006 · DOI
  17. Schwarz, 2014, Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases, Bioorg. Med. Chem., 22, 3370, 10.1016/j.bmc.2014.04.046 · DOI
  18. Ghosh, P., Vidal, C., Dey, S., and Zhang, L. (2020). Mitochondria Targeting as an Effective Strategy for Cancer Therapy. Int. J. Mol. Sci., 21. · DOI
  19. Porporato, 2018, Mitochondrial metabolism and cancer, Cell Res., 28, 265, 10.1038/cr.2017.155 · DOI
  20. Ren, 2019, Natural Product Triterpenoids and Their Semi-Synthetic Derivatives with Potential Anticancer Activity, Planta Med., 85, 802, 10.1055/a-0832-2383 · DOI
  21. Guo, 2021, Application of triazoles in the structural modification of natural products, J. Enzym. Inhib. Med. Chem., 36, 1115, 10.1080/14756366.2021.1890066 · DOI
  22. Zlatskiy, 2020, Comparative Analysis of the Different Dyes’ Potential to Assess Human Normal and Cancer Cell Viability In Vitro under Different D/H Ratios in a Culture Medium, Sci. World J., 2020, 2373021, 10.1155/2020/2373021 · DOI
  23. Knez, 2021, Antiproliferative Activity of Selected Triterpene Acids from Rosemary on Metastatic Melanoma Cell Line WM-266-4, Open Access Maced. J. Med. Sci., 9, 515, 10.3889/oamjms.2021.6176 · DOI
  24. Coricovac, D., Dehelean, C.A., Pinzaru, I., Mioc, A., Aburel, O.-M., Macasoi, I., Draghici, G.A., Petean, C., Soica, C., and Boruga, M. (2021). Assessment of Betulinic Acid Cytotoxicity and Mitochondrial Metabolism Impairment in a Human Melanoma Cell Line. Int. J. Mol. Sci., 22. · DOI · Paper page
  25. Oprean, 2018, Selective in vitro anti-melanoma activity of ursolic and oleanolic acids, Toxicol. Mech. Methods, 28, 148, 10.1080/15376516.2017.1373881 · DOI
  26. Khan, 2016, A novel triazole derivative of betulinic acid induces extrinsic and intrinsic apoptosis in human leukemia HL-60 cells, Eur. J. Med. Chem., 108, 104, 10.1016/j.ejmech.2015.11.018 · DOI
  27. Wang, W., Lei, L., Liu, Z., Wang, H., and Meng, Q. (2019). Design, Synthesis, and Biological Evaluation of Novel Nitrogen Heterocycle-Containing Ursolic Acid Analogs as Antitumor Agents. Molecules, 24. · DOI
  28. Singh, V., Khurana, A., Navik, U., Allawadhi, P., Bharani, K.K., and Weiskirchen, R. (2022). Apoptosis and Pharmacological Therapies for Targeting Thereof for Cancer Therapeutics. Science, 4. · DOI
  29. Vianna, 2021, Natural and Semisynthetic Pentacyclic Triterpenes for Chronic Myeloid Leukemia Therapy: Reality, Challenges and Perspectives, ChemMedChem, 16, 1835, 10.1002/cmdc.202100038 · DOI
  30. Borska, 2017, Anticancer properties of ester derivatives of betulin in human metastatic melanoma cells (Me-45), Cancer Cell Int., 17, 4, 10.1186/s12935-016-0369-3 · DOI
  31. Zhuo, 2017, Novel betulin derivative induces anti-proliferative activity by G2/M phase cell cycle arrest and apoptosis in Huh7 cells, Oncol. Lett., 15, 2097
  32. Gou, 2022, Ursolic Acid Derivative UA232 Promotes Tumor Cell Apoptosis by Inducing Endoplasmic Reticulum Stress and Lysosomal Dysfunction, Int. J. Biol. Sci., 18, 2639, 10.7150/ijbs.67166 · DOI
  33. Rivas, 2016, The oleanolic acid derivative, 3-O-succinyl-28-O-benzyl oleanolate, induces apoptosis in B16–F10 melanoma cells via the mitochondrial apoptotic pathway, RSC Adv., 6, 93590, 10.1039/C6RA18879F · DOI
  34. Park, 2014, Relationships between chemical structures and functions of triterpene glycosides isolated from sea cucumbers, Front. Chem., 2, 77, 10.3389/fchem.2014.00077 · DOI
  35. Malyarenko, T.V., Kicha, A.A., Kalinovsky, A.I., Dmitrenok, P.S., Malyarenko, O.S., Kuzmich, A.S., Stonik, V.A., and Ivanchina, N.V. (2021). New Triterpene Glycosides from the Far Eastern Starfish Solaster pacificus and Their Biological Activity. Biomolecules, 11. · DOI
  36. Dubinin, 2020, Effect of betulin and betulonic acid on isolated rat liver mitochondria and liposomes, Biochim. Biophys. Acta-Biomembr., 1862, 183383, 10.1016/j.bbamem.2020.183383 · DOI
  37. George, 2012, Apoptosis-Induced Cell Death due to Oleanolic Acid in HaCaT Keratinocyte Cells—A Proof-of-Principle Approach for Chemopreventive Drug Development, Asian Pac. J. Cancer Prev., 13, 2015, 10.7314/APJCP.2012.13.5.2015 · DOI
  38. Harmand, 2003, Ursolic acid induces apoptosis through caspase-3 activation and cell cycle arrest in HaCat cells, Int. J. Oncol., 23, 105
  39. Guo, Y., Zhu, H., Weng, M., Wang, C., and Sun, L. (2020). Chemopreventive effect of Betulinic acid via mTOR -Caspases/Bcl2/Bax apoptotic signaling in pancreatic cancer. BMC Complement. Med. Ther., 20. · DOI
  40. Pratheeshkumar, 2011, Oleanolic acid induces Apoptosis by modulating p53, Bax, Bcl-2 and caspase-3 gene expression and regulates the activation of transcription factors and cytokine profile in B16F, J. Environ. Pathol. Toxicol. Oncol., 30, 21, 10.1615/JEnvironPatholToxicolOncol.v30.i1.30 · DOI
  41. Kim, 2011, Induction of apoptotic cell death by ursolic acid through mitochondrial death pathway and extrinsic death receptor pathway in MDA-MB-231 cells, Arch. Pharmacal Res., 34, 1363, 10.1007/s12272-011-0817-5 · DOI
  42. Mioc, M., Milan, A., Malița, D., Mioc, A., Prodea, A., Racoviceanu, R., Ghiulai, R., Cristea, A., Căruntu, F., and Șoica, C. (2022). Recent Advances Regarding the Molecular Mechanisms of Triterpenic Acids: A Review (Part I). Int. J. Mol. Sci., 23. · DOI
  43. Klein, 2020, Role of Mitochondria in Cancer Immune Evasion and Potential Therapeutic Approaches, Front. Immunol., 11, 573326, 10.3389/fimmu.2020.573326 · DOI
  44. Viale, 2015, Tumors and Mitochondrial Respiration: A Neglected Connection, Cancer Res., 75, 3687, 10.1158/0008-5472.CAN-15-0491 · DOI
  45. Prestegarden, 2019, Inhibition of mitochondrial respiration prevents BRAF-mutant melanoma brain metastasis, Acta Neuropathol. Commun., 7, 55, 10.1186/s40478-019-0712-8 · DOI
  46. Kumar, 2021, Mitochondrial oxidative phosphorylation in cutaneous melanoma, Br. J. Cancer, 124, 115, 10.1038/s41416-020-01159-y · DOI
  47. Danese, 2017, Calcium regulates cell death in cancer: Roles of the mitochondria and mitochondria-associated membranes (MAMs), Biochim. Biophys. Acta-Bioenerg., 1858, 615, 10.1016/j.bbabio.2017.01.003 · DOI
  48. Konopleva, 2013, Mitochondrial Uncoupling and the Reprograming of Intermediary Metabolism in Leukemia Cells, Front. Oncol., 3, 67
  49. Brookes, 2005, Mitochondrial H+ leak and ROS generation: An odd couple, Free Radic. Biol. Med., 38, 12, 10.1016/j.freeradbiomed.2004.10.016 · DOI · Paper page
  50. Ling, 2022, Triterpenoids as Reactive Oxygen Species Modulators of Cell Fate, Chem. Res. Toxicol., 35, 569, 10.1021/acs.chemrestox.1c00428 · DOI
  51. Brand, 2011, Assessing mitochondrial dysfunction in cells, Biochem. J., 435, 297, 10.1042/BJ20110162 · DOI
  52. Pinzi, L., and Rastelli, G. (2019). Molecular Docking: Shifting Paradigms in Drug Discovery. Int. J. Mol. Sci., 20. · DOI
  53. Bruncko, 2007, Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL, J. Med. Chem., 50, 641, 10.1021/jm061152t · DOI
  54. Porter, 2009, Tetrahydroisoquinoline amide substituted phenyl pyrazoles as selective Bcl-2 inhibitors, Bioorg. Med. Chem. Lett., 19, 230, 10.1016/j.bmcl.2008.10.113 · DOI
  55. Petrus, 2017, Assessment of Mitochondrial Respiration in Human Platelets, Rev. Chim., 68, 768, 10.37358/RC.17.4.5549 · DOI
  56. Pesta, D., and Gnaiger, E. (2012). High-Resolution Respirometry: OXPHOS Protocols for Human Cells and Permeabilized Fibers from Small Biopsies of Human Muscle. Mitochondrial Bioenergetic, Humana Press. · DOI
  57. Kazakova, O., Mioc, A., Smirnova, I., Baikova, I., Voicu, A., Vlaia, L., Macașoi, I., Mioc, M., Drăghici, G., and Avram, Ş. (2021). Novel Synthesized N-Ethyl-Piperazinyl-Amides of C2-Substituted Oleanonic and Ursonic Acids Exhibit Cytotoxic Effects through Apoptotic Cell Death Regulation. Int. J. Mol. Sci., 22. · DOI
  58. Kazakova, O., Șoica, C., Babaev, M., Petrova, A., Khusnutdinova, E., Poptsov, A., Macașoi, I., Drăghici, G., Avram, Ș., and Vlaia, L. (2021). 3-Pyridinylidene Derivatives of Chemically Modified Lupane and Ursane Triterpenes as Promising Anticancer Agents by Targeting Apoptosis. Int. J. Mol. Sci., 22. · DOI
  59. Berman, 2000, The Protein Data Bank, Nucleic Acids Res., 28, 235, 10.1093/nar/28.1.235 · DOI · Paper page
  60. Trott, 2009, AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading, J. Comput. Chem., 31, 455, 10.1002/jcc.21334 · DOI · Paper page

Cited by

See all 19

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)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: Novel Triterpenic Acid—Benzotriazole Esters Act as Pro-Apoptotic Antimelanoma Agents. https://app.cochat.ai/papers/10.3390/ijms23179992
The paper
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. (2022). Novel Triterpenic Acid—Benzotriazole Esters Act as Pro-Apoptotic Antimelanoma Agents. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms23179992

Data sources

Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.