Molecules 2014, 19(2), 2061-2076; doi:10.3390/molecules19022061
Anticancer and Multidrug Resistance-Reversal Effects of Solanidine Analogs Synthetized from Pregnadienolone Acetate
István Zupkó 1,*
, Judit Molnár 1, Borbála Réthy 1, Renáta Minorics 1, Éva Frank 2, János Wölfling 2, Joseph Molnár 3, Imre Ocsovszki 4, Zeki Topcu 5, Tamás Bitó 6 and László G. Puskás 7,8
, Judit Molnár 1, Borbála Réthy 1, Renáta Minorics 1, Éva Frank 2, János Wölfling 2, Joseph Molnár 3, Imre Ocsovszki 4, Zeki Topcu 5, Tamás Bitó 6 and László G. Puskás 7,81
Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6, Szeged 6720, Hungary
2
Department of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged 6720, Hungary
3
Institute of Microbiology and Immunology, University of Szeged, Dóm tér 10, Szeged 6720, Hungary
4
Department of Biochemistry, University of Szeged, Dóm tér 9, Szeged 6720, Hungary
5
Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Ege University, Bornova, Izmir 35100, Turkey
6
Department of Obstetrics and Gynaecology, University of Szeged, Semmelweis u. 1, Szeged 6725, Hungary
7
Laboratory of Functional Genomics, Institute of Genetics, Biological Research Center, Hungarian Academy of Sciences, Temesvári krt. 62, Szeged 6726, Hungary
8
Avidin Ltd., Alsókikötő sor 11, Szeged 6726, Hungary
*
Author to whom correspondence should be addressed.
Received: 9 December 2013 / Revised: 29 January 2014 / Accepted: 6 February 2014 / Published: 17 February 2014
(This article belongs to the Special Issue Bioactivity-focused Semi-synthesis in Drug Discovery)
Abstract
A set of solanidine analogs with antiproliferative properties were recently synthetized from pregnadienolone acetate, which occurs in Nature. The aim of the present study was an in vitro characterization of their antiproliferative action and an investigation of their multidrug resistance-reversal activity on cancer cells. Six of the compounds elicited the accumulation of a hypodiploid population of HeLa cells, indicating their apoptosis-inducing character, and another one caused cell cycle arrest at the G2/M phase. The most effective agents inhibited the activity of topoisomerase I, as evidenced by plasmid supercoil relaxation assays. One of the most potent analogs down-regulated the expression of cell-cycle related genes at the mRNA level, including tumor necrosis factor alpha and S-phase kinase-associated protein 2, and induced growth arrest and DNA damage protein 45 alpha. Some of the investigated compounds inhibited the ABCB1 transporter and caused rhodamine-123 accumulation in murine lymphoma cells transfected by human MDR1 gene, expressing the efflux pump (L5178). One of the most active agents in this aspect potentiated the antiproliferative action of doxorubicin without substantial intrinsic cytostatic capacity. The current results indicate that the modified solanidine skeleton is a suitable substrate for the rational design and synthesis of further innovative drug candidates with anticancer activities. View Full-TextKeywords:
solanidine analog; anticancer action; efflux pump
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Zupkó, I.; Molnár, J.; Réthy, B.; Minorics, R.; Frank, É.; Wölfling, J.; Molnár, J.; Ocsovszki, I.; Topcu, Z.; Bitó, T.; Puskás, L.G. Anticancer and Multidrug Resistance-Reversal Effects of Solanidine Analogs Synthetized from Pregnadienolone Acetate. Molecules 2014, 19, 2061-2076.
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