TY  - JOUR
AU  - Gajić, Mihajlo
AU  - Ilić, Budimir S.
AU  - Bondžić, Bojan
AU  - Džambaski, Zdravko
AU  - Filipović, Ana
AU  - Kocić, Gordana
AU  - Šmelcerović, Andrija
PY  - 2021
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/6939
AB  - Xanthine oxidase (XO) is a versatile metalloflavoprotein enzyme that is best known for its rate-limiting role in the purine degradation pathway. Therapeutic inhibition of XO is based on its role in a variety of diseases that is attributed either to the hyperproduction of uric acid, or the hyperproduction of reactive oxygen species. Herein, we report the assessment of XO inhibitory properties of 24 1,2,3,4-tetrahydroisoquinoline derivatives, among which compound 
16 exhibited IC50 value of 135.72 ± 2.71 µM. The interaction of compound 16 with XO enzyme was simulated using the Site Finder module, molecular docking and molecular dynamics. Molecular modeling suggests that interactions with Met 1038, Gln 1040, Thr 1077, Gln 1194 and Val 1259 are an important factor for inhibitor affinity toward the XO enzyme. Our proposed binding model might be beneficial for the discovery of new active 1,2,3,4-tetrahydroisoquinoline-based inhibitors of XO enzyme.
AB  - Ksantin oksidaza (XO) je metaloflavoproteinski enzim, koji je najpoznatiji po svojoj ulozi ograničavanja brzine razgradnje purinskih nukleotida. Terapijska inhibicija XO zasniva se na njenoj ulozi u brojnim bolestima, koje su povezane bilo sa hiperprodukcijom mokraćne kiseline ili hiperprodukcijom reaktivnih kiseoničnih vrsta. U ovom radu izvršeno je ispitivanje sposobnosti inhibicije XO 24 derivata 1,2,3,4-tetrahidroizohinolina, od kojih je jedinjenje 16 pokazalo IC50 vrednost od 135,72 µM ± 2,71 µM. Interakcija jedinjenja 16 sa XO enzimom simulirana je korišćenjem Site Finder modula molekularnog dokinga i molekularne dinamike. Molekulsko modelovanje ukazuje na to da su interakcije sa Met 1038, Gln 1040, Thr 1077, Gln 1194 i Val 1259 važan faktor postojanja afiniteta inhibitora prema XO enzimu. Naš predloženi model vezivanja mogao bi biti od značaja za razvoj novih aktivnih inhibitora XO zasnovanih na 1,2,3,4-tetrahidroizohinolinskom heterociklusu.
PB  - Acta Medica Medianae
T2  - Acta Medica Medianae
T1  - Xanthine Oxidase Inhibitory Properties of 1,2,3,4–Tetrahydroisoquinoline Derivatives
T1  - Inhibicija ksantin oksidaze derivatima 1,2,3,4-tetrahidroizohinolina
VL  - 60
IS  - 1
SP  - 48
EP  - 55
DO  - 10.5633/amm.2021.0106
ER  - 

@article{
author = "Gajić, Mihajlo and Ilić, Budimir S. and Bondžić, Bojan and Džambaski, Zdravko and Filipović, Ana and Kocić, Gordana and Šmelcerović, Andrija",
year = "2021",
abstract = "Xanthine oxidase (XO) is a versatile metalloflavoprotein enzyme that is best known for its rate-limiting role in the purine degradation pathway. Therapeutic inhibition of XO is based on its role in a variety of diseases that is attributed either to the hyperproduction of uric acid, or the hyperproduction of reactive oxygen species. Herein, we report the assessment of XO inhibitory properties of 24 1,2,3,4-tetrahydroisoquinoline derivatives, among which compound 
16 exhibited IC50 value of 135.72 ± 2.71 µM. The interaction of compound 16 with XO enzyme was simulated using the Site Finder module, molecular docking and molecular dynamics. Molecular modeling suggests that interactions with Met 1038, Gln 1040, Thr 1077, Gln 1194 and Val 1259 are an important factor for inhibitor affinity toward the XO enzyme. Our proposed binding model might be beneficial for the discovery of new active 1,2,3,4-tetrahydroisoquinoline-based inhibitors of XO enzyme., Ksantin oksidaza (XO) je metaloflavoproteinski enzim, koji je najpoznatiji po svojoj ulozi ograničavanja brzine razgradnje purinskih nukleotida. Terapijska inhibicija XO zasniva se na njenoj ulozi u brojnim bolestima, koje su povezane bilo sa hiperprodukcijom mokraćne kiseline ili hiperprodukcijom reaktivnih kiseoničnih vrsta. U ovom radu izvršeno je ispitivanje sposobnosti inhibicije XO 24 derivata 1,2,3,4-tetrahidroizohinolina, od kojih je jedinjenje 16 pokazalo IC50 vrednost od 135,72 µM ± 2,71 µM. Interakcija jedinjenja 16 sa XO enzimom simulirana je korišćenjem Site Finder modula molekularnog dokinga i molekularne dinamike. Molekulsko modelovanje ukazuje na to da su interakcije sa Met 1038, Gln 1040, Thr 1077, Gln 1194 i Val 1259 važan faktor postojanja afiniteta inhibitora prema XO enzimu. Naš predloženi model vezivanja mogao bi biti od značaja za razvoj novih aktivnih inhibitora XO zasnovanih na 1,2,3,4-tetrahidroizohinolinskom heterociklusu.",
publisher = "Acta Medica Medianae",
journal = "Acta Medica Medianae",
title = "Xanthine Oxidase Inhibitory Properties of 1,2,3,4–Tetrahydroisoquinoline Derivatives, Inhibicija ksantin oksidaze derivatima 1,2,3,4-tetrahidroizohinolina",
volume = "60",
number = "1",
pages = "48-55",
doi = "10.5633/amm.2021.0106"
}

Gajić, M., Ilić, B. S., Bondžić, B., Džambaski, Z., Filipović, A., Kocić, G.,& Šmelcerović, A.. (2021). Xanthine Oxidase Inhibitory Properties of 1,2,3,4–Tetrahydroisoquinoline Derivatives. in Acta Medica Medianae
Acta Medica Medianae., 60(1), 48-55.
https://doi.org/10.5633/amm.2021.0106

Gajić M, Ilić BS, Bondžić B, Džambaski Z, Filipović A, Kocić G, Šmelcerović A. Xanthine Oxidase Inhibitory Properties of 1,2,3,4–Tetrahydroisoquinoline Derivatives. in Acta Medica Medianae. 2021;60(1):48-55.
doi:10.5633/amm.2021.0106 .

Gajić, Mihajlo, Ilić, Budimir S., Bondžić, Bojan, Džambaski, Zdravko, Filipović, Ana, Kocić, Gordana, Šmelcerović, Andrija, "Xanthine Oxidase Inhibitory Properties of 1,2,3,4–Tetrahydroisoquinoline Derivatives" in Acta Medica Medianae, 60, no. 1 (2021):48-55,
https://doi.org/10.5633/amm.2021.0106 . .

TY  - JOUR
AU  - Gajić, Mihajlo
AU  - Ilić, Budimir S.
AU  - Bondžić, Bojan
AU  - Džambaski, Zdravko
AU  - Kojić, Vesna V.
AU  - Jakimov, Dimitar S.
AU  - Kocić, Gordana
AU  - Šmelcerović, Andrija
PY  - 2021
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/4815
AB  - Herein we report an assessment of 24 1,2,3,4-tetrahydroisoquinoline derivatives for potential DNase I (deoxyribonuclease I) inhibitory properties in vitro. Four of them inhibited DNase I with IC50 values below 200 μM. The most potent was 1-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-one (2) (IC50=134.35±11.38 μM) exhibiting slightly better IC50 value compared to three other active compounds, 2-[2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-1-phenylethan-1-one (15) (IC50=147.51±14.87 μM), 2-[2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]cyclohexan-1-one (18) (IC50=149.07±2.98 μM) and 2-[6,7-dimethoxy-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]cyclohexan-1-one (22) (IC50=148.31±2.96 μM). Cytotoxicity assessment of the active DNase I inhibitors revealed a lack of toxic effects on the healthy cell lines MRC-5. Molecular docking and molecular dynamics simulations suggest that interactions with Glu 39, His 134, Asn 170, Tyr 211, Asp 251 and His 252 are an important factor for inhibitors affinity toward the DNase I. Observed interactions would be beneficial for the discovery of new active 1,2,3,4-tetrahydroisoquinoline-based inhibitors of DNase I, but might also encourage researchers to further explore and utilize potential therapeutic application of DNase I inhibitors, based on a versatile role of DNase I during apoptotic cell death.
PB  - Wiley
T2  - Chemistry and Biodisversity
T1  - 1,2,3,4-Tetrahydroisoquinoline Derivatives as a Novel Deoxyribonuclease I Inhibitors
VL  - 18
IS  - 8
SP  - e2100261
DO  - 10.1002/cbdv.202100261
ER  - 

@article{
author = "Gajić, Mihajlo and Ilić, Budimir S. and Bondžić, Bojan and Džambaski, Zdravko and Kojić, Vesna V. and Jakimov, Dimitar S. and Kocić, Gordana and Šmelcerović, Andrija",
year = "2021",
abstract = "Herein we report an assessment of 24 1,2,3,4-tetrahydroisoquinoline derivatives for potential DNase I (deoxyribonuclease I) inhibitory properties in vitro. Four of them inhibited DNase I with IC50 values below 200 μM. The most potent was 1-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-one (2) (IC50=134.35±11.38 μM) exhibiting slightly better IC50 value compared to three other active compounds, 2-[2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-1-phenylethan-1-one (15) (IC50=147.51±14.87 μM), 2-[2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]cyclohexan-1-one (18) (IC50=149.07±2.98 μM) and 2-[6,7-dimethoxy-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]cyclohexan-1-one (22) (IC50=148.31±2.96 μM). Cytotoxicity assessment of the active DNase I inhibitors revealed a lack of toxic effects on the healthy cell lines MRC-5. Molecular docking and molecular dynamics simulations suggest that interactions with Glu 39, His 134, Asn 170, Tyr 211, Asp 251 and His 252 are an important factor for inhibitors affinity toward the DNase I. Observed interactions would be beneficial for the discovery of new active 1,2,3,4-tetrahydroisoquinoline-based inhibitors of DNase I, but might also encourage researchers to further explore and utilize potential therapeutic application of DNase I inhibitors, based on a versatile role of DNase I during apoptotic cell death.",
publisher = "Wiley",
journal = "Chemistry and Biodisversity",
title = "1,2,3,4-Tetrahydroisoquinoline Derivatives as a Novel Deoxyribonuclease I Inhibitors",
volume = "18",
number = "8",
pages = "e2100261",
doi = "10.1002/cbdv.202100261"
}

Gajić, M., Ilić, B. S., Bondžić, B., Džambaski, Z., Kojić, V. V., Jakimov, D. S., Kocić, G.,& Šmelcerović, A.. (2021). 1,2,3,4-Tetrahydroisoquinoline Derivatives as a Novel Deoxyribonuclease I Inhibitors. in Chemistry and Biodisversity
Wiley., 18(8), e2100261.
https://doi.org/10.1002/cbdv.202100261

Gajić M, Ilić BS, Bondžić B, Džambaski Z, Kojić VV, Jakimov DS, Kocić G, Šmelcerović A. 1,2,3,4-Tetrahydroisoquinoline Derivatives as a Novel Deoxyribonuclease I Inhibitors. in Chemistry and Biodisversity. 2021;18(8):e2100261.
doi:10.1002/cbdv.202100261 .

Gajić, Mihajlo, Ilić, Budimir S., Bondžić, Bojan, Džambaski, Zdravko, Kojić, Vesna V., Jakimov, Dimitar S., Kocić, Gordana, Šmelcerović, Andrija, "1,2,3,4-Tetrahydroisoquinoline Derivatives as a Novel Deoxyribonuclease I Inhibitors" in Chemistry and Biodisversity, 18, no. 8 (2021):e2100261,
https://doi.org/10.1002/cbdv.202100261 . .