A set of fifteen triterpenoid pyrazines and pyridines was prepared from parent triterpenoid 3-oxoderivatives (betulonic acid, dihydrobetulonic acid, oleanonic acid, moronic acid, ursonic acid, heterobetulonic acid, and allobetulone). Cytotoxicity of all compounds was tested in eight cancer and two non-cancer cell lines. Evaluation of the structure-activity relationships revealed that the triterpenoid core determined whether the final molecule is active or not, while the heterocycle is able to increase the activity and modulate the specificity. Five compounds (1b, 1c, 2b, 2c, and 8) were found to be preferentially and highly cytotoxic (IC50 ≈ 1 μM) against leukemic cancer cell lines (CCRF-CEM, K562, CEM-DNR, or K562-TAX). Surprisingly, compounds 1c, 2b, and 2c are 10-fold more active in multidrug-resistant leukemia cells (CEM-DNR and K562-TAX) than in their non-resistant analogs (CCRF-CEM and K562). Pharmacological parameters were measured for the most promising candidates and two types of prodrugs were synthesized: 1) Sugar-containing conjugates, most of which had improved cell penetration and retained high cytotoxicity in the CCRF-CEM cell line, unfortunately, they lost the selectivity against resistant cells. 2) Medoxomil derivatives, among which compounds 26-28 gained activities of IC50 0.026-0.043 μM against K562 cells. Compounds 1b, 8, 21, 22, 23, and 24 were selected for the evaluation of the mechanism of action based on their highest cytotoxicity against CCRF-CEM cell line. Several experiments showed that the majority of them cause apoptosis via the mitochondrial pathway. Compounds 1b, 8, and 21 inhibit growth and disintegrate spheroid cultures of HCT116 and HeLa cells, which would be important for the treatment of solid tumors. In summary, compounds 1b, 1c, 2b, 2c, 24, and 26-28 are highly and selectively cytotoxic against cancer cell lines and were selected for future in vivo tests and further development of anticancer drugs.

Czech Advanced Technologies and Research Institute Institute of Molecular and Translational Medicine Palacký University Olomouc Křížkovského 511 8 77900 Olomouc Czech Republic

Czech Technical University Prague Faculty of Nuclear Sciences and Physical Engineering Břehová 7 115 19 Prague 1 Czech Republic

Department of Organic Chemistry Faculty of Science Palacký University Olomouc 17 Listopadu 1192 12 771 46 Olomouc Czech Republic

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacký University Olomouc Hněvotínská 1333 5 779 00 Olomouc Czech Republic

000      

00000naa a2200000 a 4500

001      

bmc22032248

003      

CZ-PrNML

005      

20230131151436.0

007      

ta

008      

230120s2022 fr f 000 0|eng||

009      

AR

024    7_

$a 10.1016/j.ejmech.2022.114777 $2 doi

035    __

$a (PubMed)36174412

040    __

$a ABA008 $b cze $d ABA008 $e AACR2

041    0_

$a eng

044    __

$a fr

100    1_

$a Hodoň, Jiří $u Department of Organic Chemistry, Faculty of Science, Palacký University Olomouc, 17. Listopadu 1192/12, 771 46, Olomouc, Czech Republic

245    10

$a Triterpenoid pyrazines and pyridines - Synthesis, cytotoxicity, mechanism of action, preparation of prodrugs / $c J. Hodoň, I. Frydrych, Z. Trhlíková, J. Pokorný, L. Borková, S. Benická, M. Vlk, B. Lišková, A. Kubíčková, M. Medvedíková, M. Pisár, J. Šarek, V. Das, A. Ligasová, K. Koberna, P. Džubák, M. Hajdúch, M. Urban

520    9_

$a A set of fifteen triterpenoid pyrazines and pyridines was prepared from parent triterpenoid 3-oxoderivatives (betulonic acid, dihydrobetulonic acid, oleanonic acid, moronic acid, ursonic acid, heterobetulonic acid, and allobetulone). Cytotoxicity of all compounds was tested in eight cancer and two non-cancer cell lines. Evaluation of the structure-activity relationships revealed that the triterpenoid core determined whether the final molecule is active or not, while the heterocycle is able to increase the activity and modulate the specificity. Five compounds (1b, 1c, 2b, 2c, and 8) were found to be preferentially and highly cytotoxic (IC50 ≈ 1 μM) against leukemic cancer cell lines (CCRF-CEM, K562, CEM-DNR, or K562-TAX). Surprisingly, compounds 1c, 2b, and 2c are 10-fold more active in multidrug-resistant leukemia cells (CEM-DNR and K562-TAX) than in their non-resistant analogs (CCRF-CEM and K562). Pharmacological parameters were measured for the most promising candidates and two types of prodrugs were synthesized: 1) Sugar-containing conjugates, most of which had improved cell penetration and retained high cytotoxicity in the CCRF-CEM cell line, unfortunately, they lost the selectivity against resistant cells. 2) Medoxomil derivatives, among which compounds 26-28 gained activities of IC50 0.026-0.043 μM against K562 cells. Compounds 1b, 8, 21, 22, 23, and 24 were selected for the evaluation of the mechanism of action based on their highest cytotoxicity against CCRF-CEM cell line. Several experiments showed that the majority of them cause apoptosis via the mitochondrial pathway. Compounds 1b, 8, and 21 inhibit growth and disintegrate spheroid cultures of HCT116 and HeLa cells, which would be important for the treatment of solid tumors. In summary, compounds 1b, 1c, 2b, 2c, 24, and 26-28 are highly and selectively cytotoxic against cancer cell lines and were selected for future in vivo tests and further development of anticancer drugs.

650    _2

$a lidé $7 D006801

650    12

$a prekurzory léčiv $x farmakologie $7 D011355

650    _2

$a pyraziny $x farmakologie $7 D011719

650    _2

$a membránový potenciál mitochondrií $7 D053078

650    12

$a antitumorózní látky fytogenní $x farmakologie $7 D000972

650    _2

$a HeLa buňky $7 D006367

650    _2

$a chemorezistence $7 D019008

650    _2

$a nádorové buněčné linie $7 D045744

650    12

$a triterpeny $x farmakologie $7 D014315

650    12

$a antitumorózní látky $x farmakologie $7 D000970

650    _2

$a pyridiny $x farmakologie $7 D011725

655    _2

$a časopisecké články $7 D016428

700    1_

$a Frydrych, Ivo $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 1333/5, 779 00, Olomouc, Czech Republic

700    1_

$a Trhlíková, Zdeňka $u Department of Organic Chemistry, Faculty of Science, Palacký University Olomouc, 17. Listopadu 1192/12, 771 46, Olomouc, Czech Republic

700    1_

$a Pokorný, Jan $u Department of Organic Chemistry, Faculty of Science, Palacký University Olomouc, 17. Listopadu 1192/12, 771 46, Olomouc, Czech Republic

700    1_

$a Borková, Lucie $u Department of Organic Chemistry, Faculty of Science, Palacký University Olomouc, 17. Listopadu 1192/12, 771 46, Olomouc, Czech Republic

700    1_

$a Benická, Sandra $u Department of Organic Chemistry, Faculty of Science, Palacký University Olomouc, 17. Listopadu 1192/12, 771 46, Olomouc, Czech Republic

700    1_

$a Vlk, Martin $u Czech Technical University in Prague, Faculty of Nuclear Sciences and Physical Engineering, Břehová 7, 115 19, Prague 1, Czech Republic

700    1_

$a Lišková, Barbora $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 1333/5, 779 00, Olomouc, Czech Republic

700    1_

$a Kubíčková, Agáta $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 1333/5, 779 00, Olomouc, Czech Republic; Czech Advanced Technologies and Research Institute (CATRIN), Institute of Molecular and Translational Medicine, Palacký University Olomouc, Křížkovského 511/8, 77900, Olomouc, Czech Republic

700    1_

$a Medvedíková, Martina $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 1333/5, 779 00, Olomouc, Czech Republic

700    1_

$a Pisár, Martin $u Department of Organic Chemistry, Faculty of Science, Palacký University Olomouc, 17. Listopadu 1192/12, 771 46, Olomouc, Czech Republic

700    1_

$a Šarek, Jan $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 1333/5, 779 00, Olomouc, Czech Republic

700    1_

$a Das, Viswanath $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 1333/5, 779 00, Olomouc, Czech Republic; Czech Advanced Technologies and Research Institute (CATRIN), Institute of Molecular and Translational Medicine, Palacký University Olomouc, Křížkovského 511/8, 77900, Olomouc, Czech Republic

700    1_

$a Ligasová, Anna $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 1333/5, 779 00, Olomouc, Czech Republic

700    1_

$a Koberna, Karel $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 1333/5, 779 00, Olomouc, Czech Republic

700    1_

$a Džubák, Petr $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 1333/5, 779 00, Olomouc, Czech Republic

700    1_

$a Hajdúch, Marián $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 1333/5, 779 00, Olomouc, Czech Republic

700    1_

$a Urban, Milan $u Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 1333/5, 779 00, Olomouc, Czech Republic. Electronic address: milan.urban@upol.cz

773    0_

$w MED00001628 $t European journal of medicinal chemistry $x 1768-3254 $g Roč. 243, č. - (2022), s. 114777

856    41

$u https://pubmed.ncbi.nlm.nih.gov/36174412 $y Pubmed

910    __

$a ABA008 $b sig $c sign $y p $z 0

990    __

$a 20230120 $b ABA008

991    __

$a 20230131151432 $b ABA008

999    __

$a ok $b bmc $g 1891165 $s 1183583

BAS    __

$a 3

BAS    __

$a PreBMC-MEDLINE

BMC    __

$a 2022 $b 243 $c - $d 114777 $e 20220923 $i 1768-3254 $m European journal of medicinal chemistry $n Eur J Med Chem $x MED00001628

LZP    __

$a Pubmed-20230120