New phosphate derivatives of betulin as anticancer agents: Synthesis, crystal structure, and molecular docking study

Chrobak, Elwira; Kadela-Tomanek, Monika; Bębenek, Ewa; Marciniec, Krzysztof; Wietrzyk, Joanna; Trynda, Justyna; Pawełczak, Bartosz; Kusz, Joachim; Kasperczyk, Janusz; Chodurek, Ewa; Paduszyński, Piotr; Boryczka, Stanisław

doi:10.1016/j.bioorg.2019.03.060

Cited by 27 publications

(31 citation statements)

References 48 publications

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“…The literature review shows that the presence of an alkynyl moiety in a compound molecule may favorably influence its antitumor activity [ 12 , 13 , 14 ]. This is also confirmed by the studies conducted earlier by our team [ 15 , 16 , 17 , 18 , 19 ]. It, therefore, seemed interesting to obtain new betulin derivatives containing diethylphosphate group in position C30, and an alkynyl substituent in position C3 and/or C28 ( Figure 1 ).…”

Section: Introductionsupporting

confidence: 91%

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Molecular Structure, In Vitro Anticancer Study and Molecular Docking of New Phosphate Derivatives of Betulin

et al. 2021

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A series of 30-diethylphosphate derivatives of betulin were synthesized and evaluated for their in vitro cytotoxic activity against human cancer cell lines, such as amelanotic melanoma (C-32), glioblastoma (SNB-19), and two lines of breast cancer (T47D, MDA-MB-231). The molecular structure and activities of the new compounds were also compared with their 29-phosphonate analogs. Compounds 7a and 7b showed the highest activity against C-32 and SNB-19 cell lines. The IC50 values for 7a were 2.15 and 0.91 μM, and, for 7b, they were 0.76 and 0.8 μM for the C-32 and SNB-19 lines, respectively. The most potent compounds, 7a and 7b, were tested for their effects on markers of apoptosis, such as H3, TP53, BAX, and BCL-2. For the whole series of phosphate derivatives, a lipophilicity study was performed, and the ADME parameters were calculated. The most active products were docked to the active site of the EGFR protein. The relative binding affinity of selected phosphate betulin derivatives toward EGFR was compared with standard erlotinib on the basis of ChemScore and KDEEP score. Positively, all derivatives docked inside the cavity and showed significant interactions. Moreover, a molecular dynamics study also reveals that ligands 7a,b form stable complexes and the plateau phase started after 7 ns.

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Section: Introductionsupporting

confidence: 91%

“…According to our previous article on 3-substituted derivatives of betulin as potential EGFR inhibitors [ 19 ], molecular modeling was carried out to predict the possible mode of action of the newly synthesized compounds 7a and 7b . EGFR structure was obtained from PDB (PDB ID: 1M17).…”

Section: Resultsmentioning

confidence: 99%

Molecular Structure, In Vitro Anticancer Study and Molecular Docking of New Phosphate Derivatives of Betulin

et al. 2021

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“…Two of the compounds obtained, namely 3-diethoxyphosphoryl-28propyloylbetulin and 3-diethoxyphosphorylbetulinic acid, showed higher activity against the melanoma cell line compared to betulin. Additionally, 3-diethoxyphosphoryl-28-propyloylbetulin turned out to be more effective than cisplatin used as the reference compound [54]. Another study showed the effectiveness of amides derived from betulinic acid and platonic acid.…”

Section: Effect On Angiogenesismentioning

confidence: 97%

“…1). To a large extent, their results have proved to be promising and have shown the therapeutic efficacy of this substance [43][44][45][46][47][48][49][50][51][52][53][54][55].…”

Section: Effect On Angiogenesismentioning

confidence: 99%

Anti-cancer effect of betulin and its derivatives, with particular emphasis on the treatment of melanoma

Cabaj¹,

Bąk²,

Wróblewska-Łuczka³

2021

J Pre Clin Clin Res.

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Introduction. Neoplastic diseases are a common cause of death, especially in developed countries. Various methods are used in cancer therapy including natural substances. Terpenes and terpenoids play a special role, including betulin and betulinic acid with the pentacyclic structure of lupane. They have a wide range of pharmacological activity, among which anti-cancer activity attracts the greatest attention. Abbreviated description of the state of knowledge. The review discusses the pharmacological effects of betulin and its derivatives on tumours, and focuses on the potential of its application in the treatment of melanoma. The review study also presents future prospects for the use of this natural substance. Betulin and its derivatives have the ability to influence the processes of apoptosis, angiogenesis and autophagy. Additionally, they have the ability to sensitize, increasing the sensitivity to commonly used methods of cancer treatment. To-date, numerous studies have been carried out on the synthesis of betulinic acid derivatives, which would show greater polarity and activity compared to the starting compound. Due to their greater bioavailability, the modified compounds showed a stronger anti-tumour effect. Conclusion.The results of the above-mentioned studies confirm the anti-cancer properties of betulin. Regarding melanoma, betulin shows significant therapeutic efficacy. This gives new perspectives for the treatment of the most dangerous skin cancer.

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“…These compounds, as well as their derivatives, have a broad spectrum of biological activity, including anticancer, antiviral, antimalarial, antibacterial, anti-inflammatory and hepatoprotective effects [2,3,4]. However, betulin derivatives inhibiting the HIV-1 replication were described for the first time in 1994 and included betulinic acid (half maximal effective concentration (EC 50 ) = 1.6 μM, therapeutic index (TI) = 9.3) and dihydrobetulin (EC 50 = 0.9 µM, TI = 14) [5].…”

Section: Introductionmentioning

confidence: 99%

New Phosphorus Analogs of Bevirimat: Synthesis, Evaluation of Anti-HIV-1 Activity and Molecular Docking Study

Chrobak

Marciniec

Dąbrowska

et al. 2019

IJMS

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Since the beginning of the human immunodeficiency virus (HIV) epidemic, many groups of drugs characterized by diverse mechanisms of action have been developed, which can suppress HIV viremia. 3-O-(3′,3′-Dimethylsuccinyl) betulinic acid, known as bevirimat (BVM), was the first compound in the class of HIV maturation inhibitors. In the present work, phosphate and phosphonate derivatives of 3-carboxyacylbetulinic acid were synthesized and evaluated for anti-HIV-1 activity. In vitro studies showed that 30-diethylphosphonate analog of BVM (compound 14a) has comparable effects to BVM (half maximal inhibitory concentrations (IC50) equal to 0.02 μM and 0.03 μM, respectively) and is also more selective (selectivity indices: 3450 and 967, respectively). To investigate the possible mechanism of antiviral effect of 14a, molecular docking was carried out on the C-terminal domain (CTD) of HIV-1 capsid (CA)–spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1, which was described as a molecular target for maturation inhibitors. Compared with interactions between BVM and the protein, an increased number of strong interactions between ligand 14a and protein, generated by the phosphonate group, was observed.

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New phosphate derivatives of betulin as anticancer agents: Synthesis, crystal structure, and molecular docking study

Cited by 27 publications

References 48 publications

Molecular Structure, In Vitro Anticancer Study and Molecular Docking of New Phosphate Derivatives of Betulin

Molecular Structure, In Vitro Anticancer Study and Molecular Docking of New Phosphate Derivatives of Betulin

Anti-cancer effect of betulin and its derivatives, with particular emphasis on the treatment of melanoma

New Phosphorus Analogs of Bevirimat: Synthesis, Evaluation of Anti-HIV-1 Activity and Molecular Docking Study

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