Antitumor activity of newly synthesized oxo and ethylidene derivatives of bile acids and their amides and oxazolines

Bjedov, Srđan; Jakimov, Dimitar; Pilipović, Ana; Poša, Mihalj; Sakač, Marija N.

doi:10.1016/j.steroids.2017.01.008

Cited by 11 publications

(7 citation statements)

References 25 publications

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“…Next, compounds 2b-2k were prepared by the addition of Grignard reagent on the C-7 carbonyl group. The addition proceeded exclusively from the β-side of the steroid skeleton to form a new equatorial C-C bond, as reported by other groups (Une et al, 1989;Bjedov et al, 2017). The stereochemistry at C-7 was assigned and confirmed by several ROESY NMR experiments.…”

Section: Library Synthesissupporting

confidence: 73%

(E)-7-Ethylidene-lithocholic Acid (7-ELCA) Is a Potent Dual Farnesoid X Receptor (FXR) Antagonist and GPBAR1 Agonist Inhibiting FXR-Induced Gene Expression in Hepatocytes and Stimulating Glucagon-like Peptide-1 Secretion From Enteroendocrine Cells

et al. 2021

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Bile acids (BAs) are key signaling steroidal molecules that regulate glucose, lipid, and energy homeostasis via interactions with the farnesoid X receptor (FXR) and G-protein bile acid receptor 1 (GPBAR1). Extensive medicinal chemistry modifications of the BA scaffold led to the discovery of potent selective or dual FXR and GPBAR1 agonists. Herein, we discovered 7-ethylidene-lithocholic acid (7-ELCA) as a novel combined FXR antagonist/GPBAR1 agonist (IC50 = 15 μM/EC50 = 26 nM) with no off-target activation in a library of 7-alkyl substituted derivatives of BAs. 7-ELCA significantly suppressed the effect of the FXR agonist obeticholic acid in BSEP and SHP regulation in human hepatocytes. Importantly, 7-ELCA significantly stimulated the production of glucagon-like peptide-1 (GLP-1), an incretin with insulinotropic effect in postprandial glucose utilization, in intestinal enteroendocrine cells. We can suggest that 7-ELCA may be a prospective approach to the treatment of type II diabetes as the dual modulation of GPBAR1 and FXR has been supposed to be effective in the synergistic regulation of glucose homeostasis in the intestine.

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Section: Library Synthesissupporting

confidence: 73%

(E)-7-Ethylidene-lithocholic Acid (7-ELCA) Is a Potent Dual Farnesoid X Receptor (FXR) Antagonist and GPBAR1 Agonist Inhibiting FXR-Induced Gene Expression in Hepatocytes and Stimulating Glucagon-like Peptide-1 Secretion From Enteroendocrine Cells

et al. 2021

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“…Pharmaceuticals 2021, 14, x FOR PEER REVIEW 2 of 30 tives exhibit various biological activities. Many of these compounds are proteasome regulators [9,10], activate the vitamin D receptor, and enhance the interaction between cholecalciferols and the receptor [11][12][13], exhibit inhibitory activity toward DNA polymerases β (pol β) [14], and also have antibacterial [15] and antitumor effects [16][17][18][19][20][21][22].…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Anticancer Activity of Hybrid Molecules Based on Lithocholic and (5Z,9Z)-Tetradeca-5,9-dienedioic Acids Linked via Mono(di,tri,tetra)ethylene Glycol and α,ω-Diaminoalkane Units

et al. 2021

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For the first time, hybrid molecules were synthesized on the basis of lithocholic and (5Z,9Z)-1,14-tetradeca-5,9-dienedicarboxylic acids, obtained in two stages using the homo-cyclomagnesiation reaction of 2-(hepta-5,6-diene-1-yloxy)tetrahydro-2H-pyran at the key stage. The resulting hybrid molecules containing 5Z,9Z-dienoic acids are of interest as novel synthetic biologically active precursors to create modern drugs for the treatment of human oncological diseases. The synthesized hybrid molecules were found to exhibit extremely high in vitro inhibitory activity against human topoisomerase I, which is 2–4 times higher than that of camptothecin, a known topoisomerase I inhibitor. Using flow cytometry and fluorescence microscopy, it was first shown that these new molecules are efficient apoptosis inducers in HeLa, U937, Jurkat, K562, and Hek293 cell cultures. In addition, the results of investigations into the effect of the synthesized acids on mitochondria and studies of possible DNA damage in Jurkat tumor cells are also presented.

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“…Our previous work showed that bile acids could interact with certain drug molecules and improve their biological activity [10,11]. To evade the membranolytic action of natural bile acids, derivatives with altered hydrophobicity are being studied [12][13][14]. The tetrazole moiety can be found in many biologically active compounds, and monosubstituted tetrazole is being used in medicinal chemistry as a bioisostere of carboxylic acid [15] because it increases the lipophilicity and metabolic stability of the molecule [16].…”

Section: Introductionmentioning

confidence: 99%

“…Our previous work showed that bile acids could interact with certain drug molecules and improve their biological activity [ 10 – 11 ]. To evade the membranolytic action of natural bile acids, derivatives with altered hydrophobicity are being studied [ 12 – 14 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of new bile acid-fused tetrazoles using the Schmidt reaction

Škorić¹,

Klisurić²,

Jakimov³

et al. 2021

Beilstein J. Org. Chem.

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A practical and high-yielding Schmidt reaction for the synthesis of fused tetrazoles from bile acid precursors was developed. Mild reaction conditions using TMSN3 instead of hydrazoic acid as an azide source produced good yields of the desired tetrazoles. These conditions could be applied to other steroidal precursors. Additionally, an improved methodology for the synthesis of different ketone and enone precursors from cholic acid, deoxycholic acid, and chenodeoxycholic acid was established. Newly obtained tetrazole derivatives were characterized by NMR and X-ray diffraction spectroscopy. In a number of cases, preliminary antiproliferative tests of new compounds showed strong and selective activity towards certain tumor cell lines.

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Antitumor activity of newly synthesized oxo and ethylidene derivatives of bile acids and their amides and oxazolines

Cited by 11 publications

References 25 publications

(E)-7-Ethylidene-lithocholic Acid (7-ELCA) Is a Potent Dual Farnesoid X Receptor (FXR) Antagonist and GPBAR1 Agonist Inhibiting FXR-Induced Gene Expression in Hepatocytes and Stimulating Glucagon-like Peptide-1 Secretion From Enteroendocrine Cells

(E)-7-Ethylidene-lithocholic Acid (7-ELCA) Is a Potent Dual Farnesoid X Receptor (FXR) Antagonist and GPBAR1 Agonist Inhibiting FXR-Induced Gene Expression in Hepatocytes and Stimulating Glucagon-like Peptide-1 Secretion From Enteroendocrine Cells

Synthesis and Anticancer Activity of Hybrid Molecules Based on Lithocholic and (5Z,9Z)-Tetradeca-5,9-dienedioic Acids Linked via Mono(di,tri,tetra)ethylene Glycol and α,ω-Diaminoalkane Units

Synthesis of new bile acid-fused tetrazoles using the Schmidt reaction

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