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Synthesis, characterization and biological activity of steroidal hydrazone derivatives

dc.contributor.advisorSladić, Dušan
dc.contributor.otherKrstić, Natalija
dc.contributor.otherAnđelković, Katarina
dc.contributor.otherNovaković, Irena
dc.contributor.otherMatić, Ivana
dc.creatorŽivković, Marijana
dc.date.accessioned2020-02-25T11:34:36Z
dc.date.available2020-02-25T11:34:36Z
dc.date.issued2019
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=7090
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:20739/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=51729935
dc.identifier.urihttp://nardus.mpn.gov.rs/123456789/11807
dc.identifier.urihttps://cer.ihtm.bg.ac.rs/handle/123456789/3424
dc.description.abstractU potrazi za biološki aktivnim jedinjenjima, počev od progesterona i 3-okso-α,β-nezasićenih androstenskih steroida, u okviru ove disertacije sintetisano je i potpunookarakterisano pedeset novih derivata steroidnih hidrazona, od kojih po jedanaesttiosemikarbazona, tijadiazolina i semikarbazona, dvanaest tiazolidin-4-ona i petkarbazatnih estara.Po prvi put je urađena detaljna analiza stereohemije steroidnih hidrazona u položajimaC-3/17 androstenskih, odnosno C-3/20 progesteronskih derivata. Struktura istereohemija potvrđene su rezultatima rendgenske strukturne analize za tijadiazolin 7a,prvo okarakterisano steroidno jedinjenje koje sadrži šestočlani ugljenični prstenkondenzovan sa spiro-tijadiazolinskim prstenom, i tiazolidinon 9b-E, prvi steroidniderivat sa poznatom konfiguracijom dvostruke veze u položaju C-3 hidrazonotiazolidin-4-onskog fragmenta.Sintetisana jedinjenja su ispoljila najjaču citotoksičnost prema HeLa ćelijamaadenokarcinoma cerviksa i prema K562 ćelijama hronične mijeloidne leukemije, a posvojoj aktivnosti istakli su se tiosemikarbazoni 2a, 2b, 2c i 2f, tijadiazolini 8a i 8e itiazolidin-4-oni 9a i 10a. Pritom su koeficijenti selektivnosti u antikancerskom dejstvuprema malignim ćelijama u odnosu na normalne humane PBMC, kako na nestimulisanetako i na mitogenom stimulisane, bili daleko veći od vrednosti 2,5 što ova jedinjenjasvrstava u potencijalne kandidate za in vivo ispitivanja. Sumporni derivati bili su dalekoaktivniji od kiseoničnih. Najaktivniji derivati indukovali su apoptozu posredstvomkaspaza-3, -8 i -9 i inhibirali angiogezu in vitro zbog čega se smatra da posedujuznačajan antikancerski potencijal.sr
dc.description.abstractSearching for biologically active compounds, within this doctoraldissertation fifty new steroidal hydrazone derivatives, of which 11 thiosemicarbazones,11 thiadiazolines, 12 thiazolidin-4-ones, 11 semicarbazones and 5 carbazate esters, weresynthesized starting with progesterone and 3-oxo-α,β-unsaturated androstene steroids,and fully characterized.For the first time, detailed stereochemistry analyses of steroidal hydrazones in the C-3/17 positions of androstene derivatives, or C-3/20 positions of progesterone derivativeswas done. Structure and stereochemistry were confirmed by the results of X-rayanalyses for thiadiazoline 7a, the first characterized steroid compound that contains sixmemberedcarbon ring condensed with the spiro-thiadiazoline ring, and thiazolidinone9b-E, the first steroidal derivative with known configuration of double bond in C-3position of the hydrazono-thiazolidin-4-one fragment.Synthesised compounds manifested the best cytotoxicity towards HeLa cervixadenocarcinoma cells, and K562 cells of chronic myeloide leukemia, the best activitybeing showed by thiosemicarbazones 2a, 2b, 2c and 2f, thiadiazolines 8a and 8e, andthiazolidin-4-ones 9a and 10a. All of these compounds exhibited considerably higherintensities of cytotoxic action against malignant cells when compared with normalhuman PBMC, both resting and mitogen-stimulated, with coefficient of selectivityhigher than 2.5, which makes these compounds potential candidates for in vivoexperiments. Sulfur derivatives were much more active than oxygen derivatives. Themost active derivatives induced apoptosis mediated by caspase-3, -8 and -9, and theyinhibited angiogenesis in vitro, because of what they are considered to have significantanticancer potential.en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Хемијски факултетsr
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/172053/RS//
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/172055/RS//
dc.rightsopenAccess
dc.rights.urihttps://creativecommons.org/licenses/by-nc-sa/4.0/
dc.sourceУниверзитет у Београдуsr
dc.subjectoxo-αsr
dc.subject3-okso-αen
dc.subjectβ-unsaturated steroidssr
dc.subjecthydrazonessr
dc.subjectthiosemi/semi-carbazonessr
dc.subjectthiadiazolinessr
dc.subjectthiazolidin-4-onessr
dc.subjectcarbazate esterssr
dc.subjectcytotoxicitysr
dc.subjectapoptosissr
dc.subjectangiogenesissr
dc.subjectantimicrobial activitysr
dc.subjectβ-nezasićeni steroidien
dc.subjecthidrazonien
dc.subjecttiosemi/semi-karbazonien
dc.subjecttijadiazolinien
dc.subjecttiazolidin-4-onien
dc.subjectkarbazatni estrien
dc.subjectcitotoksičnosten
dc.subjectapoptozaen
dc.subjectangiogenezaen
dc.subjectantimikrobna aktivnosten
dc.titleSinteza, karakterizacija i biološka aktivnost derivata steroidnih hidrazonasr
dc.title.alternativeSynthesis, characterization and biological activity of steroidal hydrazone derivativesen
dc.typedoctoralThesisen
dc.rights.licenseBY-NC-SA
dcterms.abstractСладић, Душан; Матић, Ивана; Aнђелковић, Катарина; Новаковић, Ирена; Крстић, Наталија; Живковић, Маријана; Синтеза, карактеризација и биолошка активност деривата стероидних хидразона; Синтеза, карактеризација и биолошка активност деривата стероидних хидразона;
dc.identifier.rcubhttps://hdl.handle.net/21.15107/rcub_nardus_11807
dc.identifier.fulltexthttps://cer.ihtm.bg.ac.rs/bitstream/id/16126/Disertacija.pdf
dc.identifier.fulltexthttps://cer.ihtm.bg.ac.rs/bitstream/id/16127/IzvestajKomisije21599.pdf
dc.type.versionpublishedVersion


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