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

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

doi:10.1016/j.bioorg.2019.03.060

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

Bioorg Chem. 2019 Jun:87:613-628. doi: 10.1016/j.bioorg.2019.03.060. Epub 2019 Mar 22.

Affiliations

¹ Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Organic Chemistry, 4 Jagiellońska Str., 41-200 Sosnowiec, Poland. Electronic address: echrobak@sum.edu.pl.
² Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Organic Chemistry, 4 Jagiellońska Str., 41-200 Sosnowiec, Poland.
³ Polish Academy of Sciences, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Department of Experimental Oncology, 12 R.Weigla Str., 53-114 Wrocław, Poland.
⁴ Rainbow Pharmacy, 25 Jana Matejki Str., 43-600 Jaworzno, Poland.
⁵ University of Silesia, Institute of Physics, 1 75Pułku Piechoty Str., 41 500 Chorzów, Poland.
⁶ Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Biopharmacy, 8 Jedności Str., 41-200 Sosnowiec, Poland; Centre of Polymer and Carbon Materials, Polish Academy of Sciences, 34 Curie-Sklodowska Str., 41-819 Zabrze, Poland.
⁷ Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Biopharmacy, 8 Jedności Str., 41-200 Sosnowiec, Poland.

PMID: 30947097
DOI: 10.1016/j.bioorg.2019.03.060

Abstract

Betulin derivatives exhibit an antiproliferative activity and have been tested for many cancer cell lines. This paper describes a new series of 3-phosphate derivatives of betulin bearing different substituents at C28 position. The synthesized compounds were tested in vitro for their antiproliferative effect against human leukemia (MV-4-11 and CCRF/CEM), lung carcinoma (A549), prostate cancer (DU 145), melanoma (Hs 294T) cell lines, and murine leukemia P388. To explore the possible mechanism of anticancer activity for the most in vitro active compounds (4, 5, 7 and 8) and betulin, molecular docking was performed to the binding sites of potential anticancer targets, described for the various triterpene derivatives, including topoisomerase I and II, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGFR), transcription factor NF-κB, anti-apoptotic protein Bcl-2 and peroxisome proliferator-activated receptor (PPARγ). According to the results of the docking, the best fit to the binding pocket of PPARγ was shown by compound 4.

Keywords: Anticancer; Betulin; Crystal structure; Molecular docking; Phosphate.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Density Functional Theory
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation*
Molecular Structure
Phosphates / chemical synthesis
Phosphates / chemistry
Phosphates / pharmacology*
Structure-Activity Relationship
Triterpenes / chemical synthesis
Triterpenes / chemistry
Triterpenes / pharmacology*
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Phosphates
Triterpenes
betulin