Sinteza, karakterizacija i biološka aktivnost derivata steroidnih hidrazona
Synthesis, characterization and biological activity of steroidal hydrazone derivatives
Authors
Živković, Marijana
Contributors
Sladić, Dušan
Krstić, Natalija

Anđelković, Katarina

Novaković, Irena

Matić, Ivana

Doctoral thesis (Published version)
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U 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 mijeloi...dne 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.
Searching 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.
Keywords:
oxo-α / 3-okso-α / β-unsaturated steroids / hydrazones / thiosemi/semi-carbazones / thiadiazolines / thiazolidin-4-ones / carbazate esters / cytotoxicity / apoptosis / angiogenesis / antimicrobial activity / β-nezasićeni steroidi / hidrazoni / tiosemi/semi-karbazoni / tijadiazolini / tiazolidin-4-oni / karbazatni estri / citotoksičnost / apoptoza / angiogeneza / antimikrobna aktivnostSource:
Универзитет у Београду, 2019Publisher:
- Универзитет у Београду, Хемијски факултет
Funding / projects:
- Natural products of wild, cultivated and edible plants: structure and bioactivity determination (RS-172053)
- Interactions of natural products, their derivatives and coordination compounds with proteins and nucleic acids (RS-172055)
URI
http://eteze.bg.ac.rs/application/showtheses?thesesId=7090https://fedorabg.bg.ac.rs/fedora/get/o:20739/bdef:Content/download
http://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=51729935
http://nardus.mpn.gov.rs/123456789/11807
https://cer.ihtm.bg.ac.rs/handle/123456789/3424
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Institution/Community
IHTMTY - THES AU - Živković, Marijana PY - 2019 UR - http://eteze.bg.ac.rs/application/showtheses?thesesId=7090 UR - https://fedorabg.bg.ac.rs/fedora/get/o:20739/bdef:Content/download UR - http://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=51729935 UR - http://nardus.mpn.gov.rs/123456789/11807 UR - https://cer.ihtm.bg.ac.rs/handle/123456789/3424 AB - U 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. AB - Searching 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. PB - Универзитет у Београду, Хемијски факултет T2 - Универзитет у Београду T1 - Sinteza, karakterizacija i biološka aktivnost derivata steroidnih hidrazona UR - https://hdl.handle.net/21.15107/rcub_nardus_11807 ER -
@phdthesis{ author = "Živković, Marijana", year = "2019", abstract = "U 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., Searching 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.", publisher = "Универзитет у Београду, Хемијски факултет", journal = "Универзитет у Београду", title = "Sinteza, karakterizacija i biološka aktivnost derivata steroidnih hidrazona", url = "https://hdl.handle.net/21.15107/rcub_nardus_11807" }
Živković, M.. (2019). Sinteza, karakterizacija i biološka aktivnost derivata steroidnih hidrazona. in Универзитет у Београду Универзитет у Београду, Хемијски факултет.. https://hdl.handle.net/21.15107/rcub_nardus_11807
Živković M. Sinteza, karakterizacija i biološka aktivnost derivata steroidnih hidrazona. in Универзитет у Београду. 2019;. https://hdl.handle.net/21.15107/rcub_nardus_11807 .
Živković, Marijana, "Sinteza, karakterizacija i biološka aktivnost derivata steroidnih hidrazona" in Универзитет у Београду (2019), https://hdl.handle.net/21.15107/rcub_nardus_11807 .