Tropinone-Derived Alkaloids As Potent Anticancer Agents: Synthesis, Tyrosinase Inhibition, Mechanism of Action, DFT Calculation, and Molecular Docking Studies

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2020 Dec 2

PMID 33260768

Citations 12

Authors

Katarzyna Piechowska

Magdalena Mizerska-Kowalska

Barbara Zdzisinska

Joanna Cytarska

Angelika Baranowska-Laczkowska

Karol Jaroch

Kamil Luczykowski

Wojciech Plazinski

Barbara Bojko

Stefan Kruszewski

Konrad Misiura

Krzysztof Z Laczkowski

Affiliations

Soon will be listed here.

Abstract

A new series of hybrid compounds with tropinone and thiazole rings in the structure was designed and synthesized as potential anticancer agents. They were tested against human multiple myeloma (RPMI 8226), lung carcinoma (A549), breast adenocarcinoma (MDA-MB-231), and mouse skin melanoma (B16-F10) cell lines. Toxicity was tested on human normal skin fibroblasts (HSF) and normal colon fibroblasts (CCD-18Co). The growth inhibition mechanism of the most active derivative was analyzed through investigation of its effect on the distribution of cell cycle phases and ability to induce apoptosis and necrosis in RPMI 8226 and A549 cancer cells. The tyrosinase inhibitory potential was assessed, followed by molecular docking studies. Compounds show high anticancer activity against MDA-MB-231 and B16-F10 cell lines with IC values of 1.51-3.03 µM. Moreover, the cytotoxic activity of the investigated compounds against HSF and CCD-18Co cells was 8-70 times lower than against the cancer cells or no toxicity was shown in our tests, with derivative being particularly successful. The mechanism of action of compound in RPMI 8226 cell was shown to be through induction of cell death through apoptosis. The derivatives show ability to inhibit the tyrosinase activity with a mixed mechanism of inhibition. The final molecular docking results showed for IC distinct correlation with experiment.

Citing Articles

Design, synthesis, molecular docking and anticancer activity evaluation of methyl salicylate based thiazoles as PTP1B inhibitors.

Kolodziej-Sobczak D, Sobczak L, Plazinski W, Slawinska-Brych A, Mizerska-Kowalska M, Holub K Sci Rep. 2025; 15(1):4892.

PMID: 39929933 PMC: 11811031. DOI: 10.1038/s41598-025-88038-9.

Theoretical Investigation of Electric Polarizability in Porphyrin-Zinc and Porphyrin-Zinc-Thiazole Complexes Using Small Property-Oriented Basis Sets.

Kuziemski A, Laczkowski K, Baranowska-Laczkowska A Int J Mol Sci. 2024; 25(20).

PMID: 39456825 PMC: 11507248. DOI: 10.3390/ijms252011044.

Synthesis of Carbazole-Thiazole Dyes via One-Pot Tricomponent Reaction: Exploring Photophysical Properties, Tyrosinase Inhibition, and Molecular Docking.

Krawczyk P, Jedrzejewska B, Cytarska J, Seklecka K, Laczkowski K Sensors (Basel). 2024; 24(19).

PMID: 39409408 PMC: 11479044. DOI: 10.3390/s24196368.

Synthesis of Carborane-Thiazole Conjugates as Tyrosinase and 11β-Hydroxysteroid Dehydrogenase Inhibitors: Antiproliferative Activity and Molecular Docking Studies.

Donarska B, Cytarska J, Kolodziej-Sobczak D, Studzinska R, Kupczyk D, Baranowska-Laczkowska A Molecules. 2024; 29(19).

PMID: 39407644 PMC: 11477717. DOI: 10.3390/molecules29194716.

Recent development of azole-sulfonamide hybrids with the anticancer potential.

Zhao C, Liu Y, Cui Z Future Med Chem. 2024; 16(12):1267-1281.

PMID: 38989985 PMC: 11244697. DOI: 10.1080/17568919.2024.2351291.

References

Konno S, Thanigaimalai P, Yamamoto T, Nakada K, Kakiuchi R, Takayama K . Design and synthesis of new tripeptide-type SARS-CoV 3CL protease inhibitors containing an electrophilic arylketone moiety. Bioorg Med Chem. 2012; 21(2):412-24. PMC: 7127713. DOI: 10.1016/j.bmc.2012.11.017. View

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

Kohnen-Johannsen K, Kayser O . Tropane Alkaloids: Chemistry, Pharmacology, Biosynthesis and Production. Molecules. 2019; 24(4). PMC: 6412926. DOI: 10.3390/molecules24040796. View

Lino C, Goncalves de Souza I, Borelli B, Matos T, Santos Teixeira I, Ramos J . Synthesis, molecular modeling studies and evaluation of antifungal activity of a novel series of thiazole derivatives. Eur J Med Chem. 2018; 151:248-260. DOI: 10.1016/j.ejmech.2018.03.083. View

Piechowska K, Switalska M, Cytarska J, Jaroch K, Luczykowski K, Chalupka J . Discovery of tropinone-thiazole derivatives as potent caspase 3/7 activators, and noncompetitive tyrosinase inhibitors with high antiproliferative activity: Rational design, one-pot tricomponent synthesis, and lipophilicity determination. Eur J Med Chem. 2019; 175:162-171. DOI: 10.1016/j.ejmech.2019.05.006. View

Mizerska-Kowalska M, Kreczko-Kurzawa J, Zdzisinska B, Czerwonka A, Slawinska-Brych A, Mackiewicz Z . Neutral endopeptidase (NEP) inhibitors - thiorphan, sialorphin, and its derivatives exert anti-proliferative activity towards colorectal cancer cells in vitro. Chem Biol Interact. 2019; 307:105-115. DOI: 10.1016/j.cbi.2019.04.033. View

Trott O, Olson A . AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2009; 31(2):455-61. PMC: 3041641. DOI: 10.1002/jcc.21334. View

Bedewitz M, Jones A, DAuria J, Barry C . Tropinone synthesis via an atypical polyketide synthase and P450-mediated cyclization. Nat Commun. 2018; 9(1):5281. PMC: 6290073. DOI: 10.1038/s41467-018-07671-3. View

Falzone L, Salomone S, Libra M . Evolution of Cancer Pharmacological Treatments at the Turn of the Third Millennium. Front Pharmacol. 2018; 9:1300. PMC: 6243123. DOI: 10.3389/fphar.2018.01300. View

10.

Grozav A, Gaina L, Pileczki V, Crisan O, Silaghi-Dumitrescu L, Therrien B . The synthesis and antiproliferative activities of new arylidene-hydrazinyl-thiazole derivatives. Int J Mol Sci. 2014; 15(12):22059-72. PMC: 4284694. DOI: 10.3390/ijms151222059. View

11.

Buitrago E, Hardre R, Haudecoeur R, Jamet H, Belle C, Boumendjel A . Are Human Tyrosinase and Related Proteins Suitable Targets for Melanoma Therapy?. Curr Top Med Chem. 2016; 16(27):3033-3047. DOI: 10.2174/1568026616666160216160112. View

12.

George R, Samir N, Ayoub I, Shalaby E, Demitri N, Wink M . Synthesis, antiproliferative activity and 2D-QSAR study of some 8-alkyl-2,4-bisbenzylidene-3-nortropinones. Future Med Chem. 2018; 10(24):2815-2833. DOI: 10.4155/fmc-2018-0205. View

13.

Pinto V, Bergantim R, Caires H, Seca H, Guimaraes J, Vasconcelos M . Multiple Myeloma: Available Therapies and Causes of Drug Resistance. Cancers (Basel). 2020; 12(2). PMC: 7072128. DOI: 10.3390/cancers12020407. View

14.

Slawinska-Brych A, Zdzisinska B, Mizerska-Dudka M, Kandefer-Szerszen M . Induction of apoptosis in multiple myeloma cells by a statin-thalidomide combination can be enhanced by p38 MAPK inhibition. Leuk Res. 2013; 37(5):586-94. DOI: 10.1016/j.leukres.2013.01.022. View

15.

Laczkowski K, Misiura K, Switalska M, Wietrzyk J, Laczkowska A, Fernandez B . Synthesis and in vitro antiproliferative activity of thiazole-based nitrogen mustards: the hydrogen bonding interaction between model systems and nucleobases. Anticancer Agents Med Chem. 2014; 14(9):1271-81. DOI: 10.2174/1871520614666140723115347. View

16.

Rosada B, Bekier A, Cytarska J, Plazinski W, Zavyalova O, Sikora A . Benzo[b]thiophene-thiazoles as potent anti-Toxoplasma gondii agents: Design, synthesis, tyrosinase/tyrosine hydroxylase inhibitors, molecular docking study, and antioxidant activity. Eur J Med Chem. 2019; 184:111765. DOI: 10.1016/j.ejmech.2019.111765. View

17.

Laczkowski K, Biernasiuk A, Baranowska-Laczkowska A, Zielinska S, Salat K, Furgala A . Synthesis, antimicrobial and anticonvulsant screening of small library of tetrahydro-2H-thiopyran-4-yl based thiazoles and selenazoles. J Enzyme Inhib Med Chem. 2016; 31(sup2):24-39. DOI: 10.1080/14756366.2016.1186020. View

18.

Sayed A, Gomha S, Taher E, Muhammad Z, El-Seedi H, Gaber H . One-Pot Synthesis of Novel Thiazoles as Potential Anti-Cancer Agents. Drug Des Devel Ther. 2020; 14:1363-1375. PMC: 7138620. DOI: 10.2147/DDDT.S221263. View

19.

Dhakal B, DSouza A, Chhabra S, Hari P . Multiple myeloma and COVID-19. Leukemia. 2020; 34(7):1961-1963. DOI: 10.1038/s41375-020-0879-9. View

20.

Saeed A, Mahesar P, Ali Channar P, Abbas Q, Larik F, Hassan M . Synthesis, molecular docking studies of coumarinyl-pyrazolinyl substituted thiazoles as non-competitive inhibitors of mushroom tyrosinase. Bioorg Chem. 2017; 74:187-196. DOI: 10.1016/j.bioorg.2017.08.002. View