Synthesis and antiproliferative activity of (5R)-cleistenolide and analogues Scientific paper

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Sándor Farkas
Goran Benedeković
https://orcid.org/0000-0002-4752-7569
Slađana M. Stanisavljević
https://orcid.org/0000-0002-4766-9137
Bojana M. Srećo Zelenović
https://orcid.org/0000-0003-0216-2583
Mirjana Popsavin
https://orcid.org/0000-0002-0924-1041
Velimir Popsavin
https://orcid.org/0000-0001-9910-2987
Dimitar Jakimov
https://orcid.org/0000-0002-1747-4718

Abstract

(5R)-Cleistenolide and a few related analogues have been synthesized starting from d-glucose. The key steps of the synthesis included a Z-selective Wittig olefination and an intramolecular Mitsunobu reaction with an inversion of configuration at the C-5 position. In vitro antiproliferative activity of syn­thesized compounds was tested on a panel of eight human tumour cells and against a single normal cell line (MRC-5). The majority of tested compounds showed strong antiproliferative effects on certain human tumour cells and all of them showed negligible toxicity to normal foetal lung fibroblasts (MRC-5). The most active compound obtained in this work is lactone 5, which in MDA-MB 231 cell culture showed the same activity as doxorubicin (IC50 0.09 µM). Strong antiproliferative activities of analogues 2, 5 and 6 were recorded in the K562 cell line (IC50 0.21, 0.34 and 0.33 µM, respectively), in which they showed very similar activities to doxorubicin (IC50 0.25 µM). A performed SAR study revealed that a change in the stereochemistry at the C-5 position may increase the activity of resulting stereoisomers.

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How to Cite
[1]
S. Farkas, “Synthesis and antiproliferative activity of (5R)-cleistenolide and analogues: Scientific paper”, J. Serb. Chem. Soc., vol. 88, no. 7-8, pp. 705–713, Jun. 2023.
Section
Organic Chemistry
Author Biographies

Sándor Farkas, University of Novi Sad, Faculty of Sciences, Novi Sad, Serbia

Department of Chemistry, Biochemistry and Environmental Protection

Goran Benedeković, University of Novi Sad, Faculty of Sciences, Novi Sad, Serbia

Department of Chemistry, Biochemistry and Environmental Protection

Slađana M. Stanisavljević, University of Novi Sad, Faculty of Sciences, Novi Sad, Serbia

Department of Chemistry, Biochemistry and Environmental Protection

Bojana M. Srećo Zelenović, University of Novi Sad, Faculty of Sciences, Novi Sad, Serbia

Department of Chemistry, Biochemistry and Environmental Protection

Mirjana Popsavin, University of Novi Sad, Faculty of Sciences, Novi Sad, Serbia

Department of Chemistry, Biochemistry and Environmental Protection

Dimitar Jakimov, University of Novi Sad, Faculty of Medicine, Novi Sad, Serbia

Oncology Institute of Vojvodina

References

S. Samwel, S. J. M. Mdachi, M. H. H. Nkunya, B. N. Irungu, M. J. Moshi, B. Moulton, B. Luisi, Nat. Prod. Commun. 2 (2007) 737 (https://doi.org/10.1177/1934578X0700200706)

M. H. H. Nkunya, Pure Appl. Chem. 77 (2005) 1943 (https://doi.org/10.1351/pac200577111943)

F. Pereira, A. M. Madureira, S. Sancha, S. Mulhovo, X. Luo, A. Duarte, M. J. U. Ferreira, J. Ethnopharm. 178 (2016) 180 (https://doi.org/10.1016/j.jep.2015.12.009)

R. Verzár, G. Petri, J. Ethnopharmacol. 19 (1987) 67 (https://doi.org/10.1016/0378-8741(87)90137-1)

G. Benedeković, M. Popsavin, N. S. Radulović, Z. Stojanović-Radić, S. Farkas, J. Francuz, V. Popsavin, Bioorg. Chem. 106 (2021) 104491 (https://doi.org/10.1016/j.bioorg.2020.104491)

G. Benedeković, I. Kovačević, M. Popsavin, J. Francuz, V. Kojić, G. Bogdanović, V. Popsavin, Bioorg. Med. Chem. Lett. 26 (2016) 3318 (https://doi.org/10.1016/j.bmcl.2016.05.044)

G. Benedeković, M. Popsavin, I. Kovačević, V. Kojić, M. Rodić, V. Popsavin, Eur. J. Med. Chem. 202 (2020) 112597 (https://doi.org/10.1016/j.ejmech.2020.112597)

G. Benedeković, M. Popsavin, I. Kovačević, V. Kojić, J. Kesić, S. Farkas, V. Popsavin, Tetrahedron 96 (2021) 132385 (https://doi.org/10.1016/j.tet.2021.132385)

S. S. Nyandoro, G. Maeda, J. J. E. Munissi, A. Gruhonjic, P. A. Fitzpatrick, S. Lindblad, S. Duffy, J. Pelletier, F. Pan, R. Puttreddy, V. M. Avery, M. Erdélyi, Molecules 24 (2019) 2746 (https://doi.org/10.3390/molecules24152746)

P. S. Mahajan, R. G. Gonnade, S. B. Mhaske, Eur. J. Org. Chem. 2014 (2014) 8049 (http://dx.doi.org/10.1002/ejoc.201403123)

D. A. Scudiero, R. H. Shoemaker, K. D. Paull, A. Monks, S. Tierney, T. H. Nofziger, M. J. Currens, D. Seniff, M. R. Boyd, Cancer Res. 48 (1988) 4827 (https://cancerres.aacrjournals.org/content/48/17/4827)

A. Nakayama, H. Sato, S. Nagano, S. Karanjit, H. Imagawa, K. Namba, Chem. Pharm. Bull. 67 (2019) 953 (http://dx.doi.org/10.1248/cpb.c18-00948)

Selectivity Index (SI) is calculated as follows: SI = IC50 of normal cell line (MRC-

-5)/IC50 of cancer cell line. SI values greater than 2 are considered as a satisfactory selectivity (see ref. 14)

M. I. Ahmad, S. Dixit, R. Konwar, P. G. Vasdev, A. K. Yadav, S. Tripathi, M. M. Gupta, A. Sharma, A. Gupta, Bioorg. Med. Chem. Lett. 27 (2017) 5040 (https://doi.org/10.1016/j.bmcl.2017.09.060).

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