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The Synthesis of 2´, 3' - Dideoxynucleozides
Full text linkU radu je ostvarena višefazna transformacija D-ksiloze u pogodno funkcionalizovane derivate koji su kuplovanjem sa siliranim timinom selektivno dali nukleozide sa beta-konfiguracijom na anomernom centru. Takođe, u cilju sinteze nukleozida L-serije, ispitana je mogućnost izomerizacije nekih derivata D-šečera u odgovarajuće L-stereoizomere.Muitistep transformation of D-xylose to suitabte functional derivatives were achieved. Coupling of these derivatives with silylated thymine gave the nucleosides with beta-configuration on anomeric centre. In order to synthesis nucleosides of L-series, the possibility for isomerization of some kinds D-sugar derivatives in corresponding L-stereisomeric compounds, were investigatet, too
The Synthesis of 2´, 3' - Dideoxynucleozides
Full text linkU radu je ostvarena višefazna transformacija D-ksiloze u pogodno funkcionalizovane derivate koji su kuplovanjem sa siliranim timinom selektivno dali nukleozide sa beta-konfiguracijom na anomernom centru. Takođe, u cilju sinteze nukleozida L-serije, ispitana je mogućnost izomerizacije nekih derivata D-šečera u odgovarajuće L-stereoizomere.Muitistep transformation of D-xylose to suitabte functional derivatives were achieved. Coupling of these derivatives with silylated thymine gave the nucleosides with beta-configuration on anomeric centre. In order to synthesis nucleosides of L-series, the possibility for isomerization of some kinds D-sugar derivatives in corresponding L-stereisomeric compounds, were investigatet, too
Defining of lipophilicity, pharmacokinetic parameters and anticancer potential of newly synthesized series of styryl lactones
Full text linkReverzno-faznom tečnom hromatografijom pod visokim pritiskom primenom dva sistema rastvarača ispitano je ponašanje i hromatografska lipofilnost prirodnih stiril laktona 7-(+)- goniofufurona, 7-epi-(+)-goniofufurona, krasalaktona B i C i dvadeset njihovih novosintetizovanih derivata i analoga. U ranijim ispitivanjima pokazalo se da ova jedinjenja imaju veliki biološki potencijal jer pokazuju zapaženu citotoksičnost prema više humanih tumorskih ćelijskih linija. Hromatografsko ponašanje jedinjenja uglavnom je u skladu sa njihovom strukturom. Ustanovljene su linearne veze između hromatografskih retencionih konstanti i većine in silico parametara lipofilnosti. Primenom hemometrijske QSRR analize utvrđeni su veoma dobri multi linearni regresioni prediktivni modeli kvantitativne zavisnosti između eksperimentalno dobijene hromatografske retencione konstante, koja definiše retenciju jedinjenja u čistoj vodi i in silico molekulskih deskriptora odnosno strukture jedinjenja. Lipofilnost jedinjenja ima najveći uticaj na njihove farmakokinetičke, tj. ADME (apsorpcija, distribucija, metabolizam, eliminacija) osobine. Definisani su i statistički potvrđeni najbolji multi linearni regresioni modeli zavisnosti farmakokinetičkih parametara stiril laktona i od drugih molekulskih deskriptora. In vitro citotoksična aktivnost jedinjenja evaluirana je prema četiri nove humane maligne ćelijske linije: kancer prostate (PC3), kancer debelog creva (HT-29), melanom (Hs294T), adenokancer pluća (A549). Najaktivnije novosintetizovano jedinjenje je triciklični 4-fluorocinamatni analog, koji ispoljava nanomolarnu aktivnost (IC50 2,1 nM) prema ćelijama melanoma i aktivniji je preko 2250 puta od komercijalnog antitumorskog agensa doksorubicina (DOX). SAR analizom utvrđena je zavisnost između strukture i biološke aktivnosti jedinjenja. Molekulskim dokingom ispitana je veza stiril laktona i ciljanog proteina značajnog za kancer prostate. Jedinjenja sa visokom inhibitornom aktivnošću prema ćelijama kancera prostate imaju visok doking skor i mogu graditi koordinativno-kovalentnu vezu sa Fe2+jonom prisutnim u aktivnom centru enzima. 3D-QSAR analizom, koja je izvedena metodama komparativnih polja CoMFA i CoMSIA, formiran je značajan prediktivni model između hemijske strukture i biološke aktivnosti stiril laktona.The behavior and the chromatographic lipophilicity natural styryl lactone 7-(+)- goniofufurone, 7-epi-(+)-goniofufurone, crassalactones B and C and twenty of their newly synthesized derivatives and analogs were examined using reverse-phase high performance liquid chromatography in the two solvent systems. In previous studies it has been shown that these compounds have great biological potential toward several human tumor cell lines. Chromatographic behavior of the compounds is generally in accordance with their structure. The relationships between the chromatographic retention constants and the majority of their in silico lipophilicity parameters are linear. The application of chemometric QSRR analysis determined very good multiple linear regression predictive models of quantitative correlation between experimentally obtained chromatographic retention constant, which determines the retention of the compound in pure water and in silico molecular descriptors, i.e. the structure of the compound. The lipophilicity of the compounds has a major influence on their pharmacokinetics, i.e. ADME (absorption, distribution, metabolism, elimination) properties. The best multi-linear regression models depending on the pharmacokinetic parameters of styryl lactone and other molecular descriptors have been defined and statistically validated. In vitro cytotoxic activity of the compounds was evaluated according to four novel human malignant cell lines: prostate cancer (PC3), colon cancer (HT-29), melanoma (Hs294T), lung adenocarcinom (A549). The most active compound was tricyclic 4-fluorocinnamic analog, which exhibits a nanomolar activity (IC50 2,1 nM) toward melanoma cells. This compound is over 2250 times more active than commercial antitumor agent doxorubicin (DOX). SAR analysis has revealed a correlation between the structure and the biological activity of the compounds. Using the molecular docking the relationship of the styryl lactone and the target protein important for prostate cancer was examined. The compounds with high inhibitory activity against prostate cancer cells have a high docking score and are capable to form a coordinative-covalent bond with a Fe2+ ion present in the active centre of the enzyme. 3DQSAR analysis, which was performed by methods of comparative CoMFA and CoMSIA fields, has formed a good predictive model between chemical structure and biological activity of the styryl lactone
Defining of lipophilicity, pharmacokinetic parameters and anticancer potential of newly synthesized series of styryl lactones
Full text linkReverzno-faznom tečnom hromatografijom pod visokim pritiskom primenom dva sistema rastvarača ispitano je ponašanje i hromatografska lipofilnost prirodnih stiril laktona 7-(+)- goniofufurona, 7-epi-(+)-goniofufurona, krasalaktona B i C i dvadeset njihovih novosintetizovanih derivata i analoga. U ranijim ispitivanjima pokazalo se da ova jedinjenja imaju veliki biološki potencijal jer pokazuju zapaženu citotoksičnost prema više humanih tumorskih ćelijskih linija. Hromatografsko ponašanje jedinjenja uglavnom je u skladu sa njihovom strukturom. Ustanovljene su linearne veze između hromatografskih retencionih konstanti i većine in silico parametara lipofilnosti. Primenom hemometrijske QSRR analize utvrđeni su veoma dobri multi linearni regresioni prediktivni modeli kvantitativne zavisnosti između eksperimentalno dobijene hromatografske retencione konstante, koja definiše retenciju jedinjenja u čistoj vodi i in silico molekulskih deskriptora odnosno strukture jedinjenja. Lipofilnost jedinjenja ima najveći uticaj na njihove farmakokinetičke, tj. ADME (apsorpcija, distribucija, metabolizam, eliminacija) osobine. Definisani su i statistički potvrđeni najbolji multi linearni regresioni modeli zavisnosti farmakokinetičkih parametara stiril laktona i od drugih molekulskih deskriptora. In vitro citotoksična aktivnost jedinjenja evaluirana je prema četiri nove humane maligne ćelijske linije: kancer prostate (PC3), kancer debelog creva (HT-29), melanom (Hs294T), adenokancer pluća (A549). Najaktivnije novosintetizovano jedinjenje je triciklični 4-fluorocinamatni analog, koji ispoljava nanomolarnu aktivnost (IC50 2,1 nM) prema ćelijama melanoma i aktivniji je preko 2250 puta od komercijalnog antitumorskog agensa doksorubicina (DOX). SAR analizom utvrđena je zavisnost između strukture i biološke aktivnosti jedinjenja. Molekulskim dokingom ispitana je veza stiril laktona i ciljanog proteina značajnog za kancer prostate. Jedinjenja sa visokom inhibitornom aktivnošću prema ćelijama kancera prostate imaju visok doking skor i mogu graditi koordinativno-kovalentnu vezu sa Fe2+jonom prisutnim u aktivnom centru enzima. 3D-QSAR analizom, koja je izvedena metodama komparativnih polja CoMFA i CoMSIA, formiran je značajan prediktivni model između hemijske strukture i biološke aktivnosti stiril laktona.The behavior and the chromatographic lipophilicity natural styryl lactone 7-(+)- goniofufurone, 7-epi-(+)-goniofufurone, crassalactones B and C and twenty of their newly synthesized derivatives and analogs were examined using reverse-phase high performance liquid chromatography in the two solvent systems. In previous studies it has been shown that these compounds have great biological potential toward several human tumor cell lines. Chromatographic behavior of the compounds is generally in accordance with their structure. The relationships between the chromatographic retention constants and the majority of their in silico lipophilicity parameters are linear. The application of chemometric QSRR analysis determined very good multiple linear regression predictive models of quantitative correlation between experimentally obtained chromatographic retention constant, which determines the retention of the compound in pure water and in silico molecular descriptors, i.e. the structure of the compound. The lipophilicity of the compounds has a major influence on their pharmacokinetics, i.e. ADME (absorption, distribution, metabolism, elimination) properties. The best multi-linear regression models depending on the pharmacokinetic parameters of styryl lactone and other molecular descriptors have been defined and statistically validated. In vitro cytotoxic activity of the compounds was evaluated according to four novel human malignant cell lines: prostate cancer (PC3), colon cancer (HT-29), melanoma (Hs294T), lung adenocarcinom (A549). The most active compound was tricyclic 4-fluorocinnamic analog, which exhibits a nanomolar activity (IC50 2,1 nM) toward melanoma cells. This compound is over 2250 times more active than commercial antitumor agent doxorubicin (DOX). SAR analysis has revealed a correlation between the structure and the biological activity of the compounds. Using the molecular docking the relationship of the styryl lactone and the target protein important for prostate cancer was examined. The compounds with high inhibitory activity against prostate cancer cells have a high docking score and are capable to form a coordinative-covalent bond with a Fe2+ ion present in the active centre of the enzyme. 3DQSAR analysis, which was performed by methods of comparative CoMFA and CoMSIA fields, has formed a good predictive model between chemical structure and biological activity of the styryl lactone
Design, synthesis and antiproliferative activity of (+)-protulactone A and itsanalogues
No full textU doktorskoj disertaciji ostvarena je totalna sinteza i detaljna karakterizacija tri prirodna proizvoda: novi sintetski pristup za (+)-protulakton A (13), kao i prve totalne sinteze za (+)-asperilakton C (16) i (+)-asperilakton B (46). (+)- Protulakton A (13) i (+)-asperilakton C (16) su sintetizovani iz D-galaktoze, pri čemu su razvijena dva pristupa za njihovu sintezu, dok je (+)-asperilakton B (46) sintetizovan iz D-glukoze. Osim prirodnih proizvoda, sintetizovano je 38 strukturnih analoga, uključujući hibridne molekule i njihove analoge. Struktura i stereohemija sva 3 prirodna proizvoda potvrđena je rendgenskom strukturnom analizom, prvi put od njihove izolacije. Dodatno, revidirana je i stereohemija za dva prirodna molekula: (+)-asperilakton B (46) i C (16). Nakon sinteze, istražena je antiproliferativna aktivnost svih jedinjenja na deset malignih i jednoj zdravoj ćelijskoj liniji, a ispitana je antimikrobna aktivnost prirodnog proizvoda (+)-protulaktona A (13). Analizirana je i veza između strukture i antiproliferativne aktivnosti (SAR), koja je ukazala na strukturne osobine značajne za biološku aktivnost ovog tipa jedinjenja.In the doctoral dissertation, total synthesis and detailed characterization of three natural products were achieved: a new synthetic approach to (+)- protulactone A (13) and the first total syntheses of (+)-asperilactone C (16) and (+)-asperilactone B (46). Both (+)-protulactone A (13) and (+)- asperilactone C (16) were synthesized from D-galactose using two approaches, while (+)-asperilactone B (46) was synthesized from D-glucose. Additionally, 38 structural analogues were synthesized, including hybrid molecules. The structure and stereochemistry of all three natural products were confirmed by X-ray crystallographic analysis for the first time since their isolation. Moreover, the stereochemistry of two natural molecules, (+)- asperilactone B (46) and C (16), was revised. Following synthesis, antiproliferative activity of all compounds was investigated on ten malignant and one normal cell line; and antimicrobial activity of natural product (+)- protulactone A (13) was examined. The relationship between structure and antiproliferative activity (SAR) was also analyzed, which indicated significant structural features for the biological activity of this type of compound
Natural styryl-lactones, their derivatives and analogues as potential antitumour agents: Design, synthesis and a SAR study
Full text linkU radu je ostvarena sinteza četiri prirodna proizvoda, goniobutenolida A i B, krasalaktona D i 3-deoksi-kardiobutanolida i 32 derivata i analoga polazeći iz D-glukoze. Sinteza prirodnog stiril-laktona, kardiobutanolida i njegova 4 derivata je izvedena polazeći iz D-ksiloze. Ispitan je uticaj sintetizovanih jedinjenja na inhibiciju rasta 10 tumorskih i jedne zdrave ćelijske linije. Uspostavljene su i korelacije izmedju strukture i antiproliferativne aktivnosti (SAR) i ispitan je mehanzam antitumorskog dejstva.Synthesis of four natural products: goniobutenolide A and B, crassalactone D, 3-deoxy-cardiobutanolide and their 32 analogues and derivatives is accomplished starting from D-glucose. Synthesis of natural styryl lactone cardiobutanolide and its four derivatives is achieved starting from D-xylose. Synthesized natural lactones, their analogues and derivatives were evaluated for their antiproliferative activity against ten malignant cell lines as well as against a single normal cell line. Influence of functional groups on antitumour activity was established by correlating structures of synthesized compounds with their biological activity (SAR). Also, mechanism of antitumour action was investigated
Novel isosteres and bioisosteres of natural styryl lactones: design,synthesis and antiproliferative activity
Full text linkU radu su ostvarene višefazne sinteze većeg broja analoga prirodnih stiril-laktona (+)-goniofufurona i 7-epi-(+)-goniofufurona polazeći iz D-glukoze. Ispitana je in vitro citotoksičnost sintetizovanih analoga prema devet malignih i jednoj zdravoj ćelijskoj liniji. Uspostavljeni su korelacioni odnosi izmedju strukture i antiproliferati vne aktivnosti sintetizovanih proizvoda, pored toga uradjeni su i dodatni biološki testovi koji se odnose na dokazivanje mehanizma citotoksičnog dejstva pomenutih stiril-laktona i analoga.Multistep synthesis of a number of natural styryl lactones goniofufurone and 7-epi-goniofufurone analogues was achieved starting f rom D-glucose. In vitro cytotoxicity of newly synthetized analogues against nine human tumour cell lines and against a single normal cell line was evaluated. Structure-activity relationships were established for both natural products and analogues. Some additional biological tests related to the cell mechanisms underlying the cytotoxicity of the mentioned styryl lactones and analogues, were also carried out
Synthesis and biomedicinal investigation of novel styryl lactone and antitumor agent tiazofurin bioisosteres
Full text linkU ovom radu prikazana je sinteza 11 tiazolnih izostera goniofufurona (1-11), 4 konformaciono kruta analoga goniofufurona (12-15) i jednog butadiolnog derivata tiazofurina (16). Takođe, izvršeno je ispitivanje i poređenje bioloških aktivnosti sintetisanih analoga sa sa aktivnošću i selektivnošću kako GF i TF tako i doksorubicina, jedinjenja širokog spektra dejstva (DOX). Hiralni prekursor novosintetisanih jedinjenja 1-15 bila je D-glukoza, a jedinjenja 16 D-arabinoza.A multistep synthesis of 11 novel thiazole isosteres of goniofufurone (1-11), 4 novel conformationally constrained isosteres of goniofufurone (12-15), as well as one butanediole derivative of tiazofurin (16) has been achieved. In vitro cytotoxicity of newly synthetized derivatives has been evaluated and compared with the cytotoxicities of goniofufurone, tiazofurin and doxorubicin
Design, synthesis and antiproliferative activity of (+)-protulactone A and itsanalogues
Full text linkU doktorskoj disertaciji ostvarena je totalna sinteza i detaljna karakterizacija tri prirodna proizvoda: novi sintetski pristup za (+)-protulakton A (13), kao i prve totalne sinteze za (+)-asperilakton C (16) i (+)-asperilakton B (46). (+)- Protulakton A (13) i (+)-asperilakton C (16) su sintetizovani iz D-galaktoze, pri čemu su razvijena dva pristupa za njihovu sintezu, dok je (+)-asperilakton B (46) sintetizovan iz D-glukoze. Osim prirodnih proizvoda, sintetizovano je 38 strukturnih analoga, uključujući hibridne molekule i njihove analoge. Struktura i stereohemija sva 3 prirodna proizvoda potvrđena je rendgenskom strukturnom analizom, prvi put od njihove izolacije. Dodatno, revidirana je i stereohemija za dva prirodna molekula: (+)-asperilakton B (46) i C (16). Nakon sinteze, istražena je antiproliferativna aktivnost svih jedinjenja na deset malignih i jednoj zdravoj ćelijskoj liniji, a ispitana je antimikrobna aktivnost prirodnog proizvoda (+)-protulaktona A (13). Analizirana je i veza između strukture i antiproliferativne aktivnosti (SAR), koja je ukazala na strukturne osobine značajne za biološku aktivnost ovog tipa jedinjenja.In the doctoral dissertation, total synthesis and detailed characterization of three natural products were achieved: a new synthetic approach to (+)- protulactone A (13) and the first total syntheses of (+)-asperilactone C (16) and (+)-asperilactone B (46). Both (+)-protulactone A (13) and (+)- asperilactone C (16) were synthesized from D-galactose using two approaches, while (+)-asperilactone B (46) was synthesized from D-glucose. Additionally, 38 structural analogues were synthesized, including hybrid molecules. The structure and stereochemistry of all three natural products were confirmed by X-ray crystallographic analysis for the first time since their isolation. Moreover, the stereochemistry of two natural molecules, (+)- asperilactone B (46) and C (16), was revised. Following synthesis, antiproliferative activity of all compounds was investigated on ten malignant and one normal cell line; and antimicrobial activity of natural product (+)- protulactone A (13) was examined. The relationship between structure and antiproliferative activity (SAR) was also analyzed, which indicated significant structural features for the biological activity of this type of compound
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