Synthesis and structure of novel phenothiazine derivatives, and compound prioritization via in silico target search and screening for cytotoxic and cholinesterase modulatory activities in liver cancer cells and in vivo in zebrafish

buir.contributor.authorYaman, Murat
buir.contributor.authorKorkmaz, Büşra
buir.contributor.authorBayazeid, Ömer
buir.contributor.authorGüneş, Damla
buir.contributor.authorTiryaki, Rafed Said
buir.contributor.authorKonu, Özlen
buir.contributor.orcidYaman, Murat|0000-0001-6773-6811
buir.contributor.orcidBayazeid, Ömer|0000-0002-2638-8475
buir.contributor.orcidKonu, Özlen|0000-0002-6223-5329
dc.citation.epage30614
dc.citation.issueNumber28
dc.citation.spage30594
dc.citation.volumeNumber9
dc.contributor.authorKisla, Mehmet Murat
dc.contributor.authorYaman, Murat
dc.contributor.authorZengin Karadayi,Fikriye
dc.contributor.authorKorkmaz, Büşra
dc.contributor.authorBayazeid, Ömer
dc.contributor.authorKumar, Amrish
dc.contributor.authorPeravali, Ravindra
dc.contributor.authorGüneş, Damla
dc.contributor.authorTiryaki, Rafed Said
dc.contributor.authorGelinci, Emine
dc.contributor.authorÇakan Akdoğan, Gülçin
dc.contributor.authorAteş Alagöz, Zeynep
dc.contributor.authorKonu, Özlen
dc.date.accessioned2025-03-01T13:31:09Z
dc.date.available2025-03-01T13:31:09Z
dc.date.issued2024-06-03
dc.departmentDepartment of Molecular Biology and Genetics
dc.description
dc.description.abstractPhenothiazines (PTZ) are antipsychotics known to modulate a variety of neurotransmitter activities that include dopaminergic and cholinergic signaling and have been identified as potential anticancer agents in vitro. However, it is important to also test whether a highly cytotoxic, repurposed, or novel PTZ has low toxicity and neuromodulatory activity in vivo using vertebrate model organisms, such as zebrafish. In this study, we synthesized novel phenothiazines and screened them in vitro in liver cancer and in vivo in zebrafish embryos/larvae. The syntheses of several intermediate PTZ 10-yl acyl chlorides were followed by elemental analysis and determination of 1H NMR and 13C NMR mass (ESI+) spectra of a large number of novel PTZ 10-carboxamides. Cytotoxicities of 28 PTZ derivatives (1–28) screened against Hep3B and SkHep1 liver cancer cell lines revealed five intermediate and five novel leads along with trifluoperazine (TFP), prochlorperazine (PCP), and perphenazine, which are relatively more cytotoxic than the basic PTZ core. Overall, the derivatives were more cytotoxic to Hep3B than SkHep1 cells. Moreover, in silico target screening identified cholinesterases as some of the commonest targets of the screened phenothiazines. Interestingly, molecular docking studies with acetylcholinesterase (AChE) and butyrylcholinesterase proteins showed that the most cytotoxic compounds 1, 3, PCP, and TFP behaved similar to Huprin W in their amino acid interactions with the AChE protein. The highly cytotoxic intermediate PTZ derivative 1 exhibited a relatively lower toxicity profile than those of 2 and 3 during the zebrafish development. It also modulated in vivo the cholinesterase activity in a dose-dependent manner while significantly increasing the total cholinesterase activity and/or ACHE mRNA levels, independent of the liver cancer cell type. Our screen also identified novel phenothiazines, i.e., 8 and 10, with significant cytotoxic and cholinesterase modulatory effects in liver cancer cells; yet both compounds had low levels of toxicity in zebrafish. Moreover, they modulated the cholinesterase activity or expression of ACHE in a cancer cell line-specific manner, and compound 10 significantly inhibited the cholinesterase activity in zebrafish. Accordingly, using a successful combination of in silico, in vitro, and in vivo approaches, we identified several lead anticancer and cholinesterase modulatory PTZ derivatives for future research.
dc.identifier.doi10.1021/acsomega.3c06532
dc.identifier.issn2470-1343
dc.identifier.urihttps://hdl.handle.net/11693/117034
dc.language.isoEnglish
dc.publisherAmerican Chemical Society
dc.relation.isversionofhttps://dx.doi.org/10.1021/acsomega.3c06532
dc.rightsCC BY 4.0 (Attribution 4.0 International Deed)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.source.titleACS Omega
dc.subjectCells
dc.subjectPeptides and proteins
dc.subjectReaction products
dc.subjectToxicity
dc.subjectZebrafish
dc.titleSynthesis and structure of novel phenothiazine derivatives, and compound prioritization via in silico target search and screening for cytotoxic and cholinesterase modulatory activities in liver cancer cells and in vivo in zebrafish
dc.typeArticle

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