Natural and Semisynthetic Pentacyclic Triterpenes for Chronic Myeloid Leukemia Therapy: Reality, Challenges and Perspectives

Vianna, Débora Renz Barreto; Gotardi, Jessica; Gnoatto, Simone Cristina Baggio; Pilger, Diogo André

doi:10.1002/cmdc.202100038

Cited by 11 publications

(7 citation statements)

References 78 publications

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“…The semisynthetic modifications of pentacyclic triterpenes provide a broad variety of functionalities, from increasing potency and/or selectivity to optimizing pharmacokinetic parameters [ 73 ]. One of the several nitrogen heterocyclic compounds present in nature, the indole ring is often present in plant hormones such as tryptophan and auxins, serotonin or 5-hydroxytryptamine, and melatonin [ 74 ].…”

Section: Discussionmentioning

confidence: 99%

Comparison of In Vitro Antimelanoma and Antimicrobial Activity of 2,3-Indolo-betulinic Acid and Its Glycine Conjugates

Lombrea

Scurtu

Magyari-Pavel

et al. 2023

Plants

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Malignant melanoma is one of the most pressing problems in the developing world. New therapeutic agents that might be effective in treating malignancies that have developed resistance to conventional medications are urgently required. Semisynthesis is an essential method for improving the biological activity and the therapeutic efficacy of natural product precursors. Semisynthetic derivatives of natural compounds are valuable sources of new drug candidates with a variety of pharmacological actions, including anticancer ones. Two novel semisynthetic derivatives of betulinic acid—N-(2,3-indolo-betulinoyl)diglycylglycine (BA1) and N-(2,3-indolo-betulinoyl)glycylglycine (BA2)—were designed and their antiproliferative, cytotoxic, and anti-migratory activity against A375 human melanoma cells was determined in comparison with known N-(2,3-indolo-betulinoyl)glycine (BA3), 2,3-indolo-betulinic acid (BA4) and naturally occurring betulinic acid (BI). A dose-dependent antiproliferative effect with IC50 values that ranged from 5.7 to 19.6 µM was observed in the series of all five compounds including betulinic acid. The novel compounds BA1 (IC50 = 5.7 µM) and BA2 (IC50 = 10.0 µM) were three times and two times more active than the parent cyclic structure B4 and natural BI. Additionally, compounds BA2, BA3, and BA4 possess antibacterial activity against Streptococcus pyogenes ATCC 19615 and Staphylococcus aureus ATCC 25923 with MIC values in the range of 13–16 µg/mL and 26–32 µg/mL, respectively. On the other hand, antifungal activity toward Candida albicans ATCC 10231 and Candida parapsilosis ATCC 22019 was found for compound BA3 with MIC 29 µg/mL. This is the first report of antibacterial and antifungal activity of 2,3-indolo-betulinic acid derivatives and also the first extended report on their anti-melanoma activity, which among others includes data on anti-migratory activity and shows the significance of amino acid side chain on the observed activity. The obtained data justify further research on the anti-melanoma and antimicrobial activity of 2,3-indolo-betulinic acid derivatives.

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Section: Discussionmentioning

confidence: 99%

Comparison of In Vitro Antimelanoma and Antimicrobial Activity of 2,3-Indolo-betulinic Acid and Its Glycine Conjugates

Lombrea

Scurtu

Magyari-Pavel

et al. 2023

Plants

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“…[74,75] Some steroids and terpenes could exert antileukemic activity through various pathways including the activation of mitochondrial apoptosis, whereas some of them are deemed as sensitizing leukemia cells to the chemotherapeutic effects of many cytotoxic agents, primarily by inhibiting efflux pumps, thus reducing leukemia resistance. [76,77] Accordingly, a combination of 1,2,3-triazole with steroid/terpene is a promising strategy to develop novel antileukemic chemotherapeutics.…”

Section: 23-triazole-naphthoquinone Hybridsmentioning

confidence: 99%

Therapeutic potential of 1,2,3‐triazole hybrids for leukemia treatment

Yang¹,

Xuan²,

Li³

et al. 2022

Archiv der Pharmazie

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Leukemia, a hematological malignancy originating from the bone marrow, is the principal cancer of childhood. In recent decades, improved remission rates and survival of patients with leukemia have been achieved due to significant breakthroughs in the treatment. However, chemoresistance and relapse are common, creating an urgent need for the search for novel pharmaceutical interventions. 1,2,3‐Triazole is one of the most fascinating pharmacophores in the discovery of new drugs, and several 1,2,3‐triazole derivatives have already been used in clinics or are under clinical evaluation for the treatment of cancers. In particular, 1,2,3‐triazole hybrids could suppress tumor proliferation, invasion, and metastasis by inhibiting enzymes, proteins, and receptors in cancer cells, revealing their potential as putative antileukemic agents. This review covers the recent advances regarding the 1,2,3‐triazole hybrids with potential antileukemic activity, focusing on the chemical structures, structure–activity relationship, and mechanisms of action, covering articles published from January 2017 to January 2022.

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“…These triterpenoids’ properties, along with previous reports on pentacyclic triterpenes’ action against leukemia cells [ 7 , 12 ], suggested to us the need to assess their effects in chronic and acute myeloid leukemia cells. The present study objective was to evaluate the effect of these metabolites against the K562 and HL60 myeloid leukemia cell lines.…”

Section: Introductionmentioning

confidence: 98%

Apoptotic and Cell Cycle Effects of Triterpenes Isolated from Phoradendron wattii on Leukemia Cell Lines

et al. 2022

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Current antineoplastic agents present multiple disadvantages, driving an ongoing search for new and better compounds. Four lupane-type triterpenes, 3α,24-dihydroxylup-20(29)-en-28-oic acid (1), 3α,23-dihydroxy-30-oxo-lup-20(29)-en-28-oic acid (2), 3α,23-O-isopropylidenyl-3α,23-dihydroxylup-20(29)-en-28-oic acid (3), and 3α,23-dihydroxylup-20(29)-en-28-oic acid (4), previously isolated from Phoradendron wattii, were evaluated on two cell lines of chronic (K562) and acute (HL60) myeloid leukemia. Compounds 1, 2, and 4 decreased cell viability and inhibit proliferation, mainly in K562, and exhibited an apoptotic effect from 24 h of treatment. Of particular interest is compound 2, which caused arrest in active phases (G2/M) of the cell cycle, as shown by in silico study of the CDK1/Cyclin B/Csk2 complex by molecular docking. This compound [3α,23-dihydroxy-30-oxo-lup-20(29)-en-28-oic acid] s a promising candidate for incorporation into cancer treatments and deserves further study.

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Natural and Semisynthetic Pentacyclic Triterpenes for Chronic Myeloid Leukemia Therapy: Reality, Challenges and Perspectives

Cited by 11 publications

References 78 publications

Comparison of In Vitro Antimelanoma and Antimicrobial Activity of 2,3-Indolo-betulinic Acid and Its Glycine Conjugates

Comparison of In Vitro Antimelanoma and Antimicrobial Activity of 2,3-Indolo-betulinic Acid and Its Glycine Conjugates

Therapeutic potential of 1,2,3‐triazole hybrids for leukemia treatment

Apoptotic and Cell Cycle Effects of Triterpenes Isolated from Phoradendron wattii on Leukemia Cell Lines

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