biologiurad aqtiur nivtierebata sintezis ziritadi mimartulebani prof. sota samsonia iv. javaxisvilis...
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biologiurad aqtiur nivTierebaTa sinTezis
ZiriTadi mimarTulebani
prof. SoTa samsonia
iv. javaxiSvilis saxelobis Tbilisis saxelmwifo universiteti
biologiurad aqtiur nivTierebaTa sinTezis ZiriTadi mimarTulebebia:
– axali qimiuri struqturis, potenciuri biologiuri aqtiurobis mqone naerTebis Seqmna;
– cnobili biologiurad aqtiuri naerTebis qimiuri modifikacia;
– cnobili biologiurad aqtiuri naerTebis struqturuli analogebis miRebis meTodebis damuSaveba da sinTezis racionaluri gzebis Zieba.
1. alizarini (endros fesvebi, Rubia tinktoria). 1868 weli grebe da
libermani, sinTezi antracenidan;
2. vitamini C (askorbinis mJava) – 1928 weli agebulebis dadgena, xolo 1934 weli raixStainis mier misi laboratoriuli sinTezi D-glukozidan da Semdeg sawarmoo sinTezi; 3. 1953 weli, dnm, ormagi spirali – uotsoni da kriki.
korana, dnm-is fragmentis - biologiurad aqtiuri genis sruli sinTezi (nobelis premia);
Oorganuli sinTezis mizani
saqarTvelos samecniero-kvleviTi dawesebulebebi, romlebmac warmoadgines samuSaoebi biologiurad
aqtiuri sinTezuri naerTebis mimarTulebiT:
- javaxiSvilis saxelobis Tbilisis saxelmwifo universiteti - 18
- saqarTvelos teqnikuri universiteti - 8- iovel quTaTelaZis farmakoqimiis instituti - 4 - petre meliqiSvilis fizikuri da organuli qimiis instituti
- 3- saqarTvelos saxelmwifo agraruri universiteti - 1- soxumis saxelmwifo universiteti - 1- niko kecxovelis botanikis instituti - 1
saqarTvelos samecniero-kvleviTi dawesebulebebi, romlebmac warmoadgines samuSaoebi fitoqimiis, mcenareTa dacvis,
analizis, teqnologiis, da farmakologiis mimarTulebiT
- iovel quTaTelaZis farmakoqimiis instituti - 12- Tbilisis saxelmwifo samedicino universiteti - 6- javaxiSvilis saxelobis Tsu - 6- p. meliqiSvilisfizikuri da organuli qimiis inst. - 5- baTumis rusTavelis sax. saxelmwifo universiteti - 3- levan yanCavelis sax. mcenareTa dacvis instituti - 3- niko kecxovelis botanikis instituti - 2- samedicino bioteqnologiis instituti - 2- saqarTvelos agraruri universiteti - 1- durmiSiZis sax. bioqimiis da bioteqnologiis inst. -1
gagrZeleba
- Tbilisis samedicino bioteqnologiis instituti - 1- saqarTvelos mebaReobis, mevenaxeobis da meRvineobis
instituti -1- saqarTvelos maRali teqnologiebis erovnuli centri-1- saqarTvelos teqnikuri universiteti - 1
- Sps “ji-em-pi - 1- a. wereTelis sax. quTaisis saxelmwifo universiteti -1- akad mix. winamZRvriSvilis sax. Kardiologiis inst. -1- a/k rkinigzis e. fifias sax. Klinikuri saavadmyofo -1- samedicino instituti “panacea” -1
samecniero mimarTulebebi
1. aromatuli heterocikluri naerTebi – 9 (Tsu, stu)
2. Sualeduri produqtebi da struqturuli analogebi – 3 (p. meliqiSvilis inst., agraruri uni., Tsu)
3. steroidebis warmoebulebi 3 (farmakoqimiis inst.)4. biodegradirebadi polimeruli masalebi -2 (stu, Tsu)5. adamantanis warmoebulebi – 2 (Tsu)6. naxSirwylebi – 4 (Tsu, p. meliqiSvilis instituti)7. enantiomerebis sinTezi – 1 (farmakoqim. inst., Tsu)8. maTematikuri qimia – 1 (Tsu, soxumis sax. uni.)9. koordinaciuli naerTebi -3 (stu, Tsu, botanikis inst.)
Aantibiotiki CC-1065gamoyofilia obis sokodan. adreamicinze 400-jer meti simsivnis
sawinaarmdego aqtiuroba
NH
N
O
HN
N
H3CO
HNO
OH
OO
O
NNH2
H
NH
N N
O O NH
CH3
CH2Cl CH2Cl
H3C
NH
NH
HN
HN
O
1
2
sqema 1
oligoindoluri alkaloidebi
NH
NCH3
HN
CH3N
NH
NCH3
NH
NCH3
HN
CH3N
NH
NCH3
HN
CH3N
34
sqema 2
piroloindolebi, indoloindolebi, arilindolebi, bisindolebi
1. Samsonia Sh., Targmadze N., Suvorov N. The Chemistry of Pyrroloindoles. Russian Chemical Reviews 1994, v. 63, № 10, pp. 815-832.
2. Samsoniya Sh., Trapaidze M. The chemistry of indoloindoles. Russian Chemical Reviews, 2007, v. 76, №4, pp. 313-326.
3. Samsoniya Sh., Chikvaidze I., Narindoshvili. 2-Phenylindole derivatives. Selected methods for synthesis and modifikation of heterocycles, Kartsev V.G., Ed., Moskow: IBS Press, 2004, vol. 3, pp. 219-559 (Review)
sqema 3
NH
HN
NH
NH
HN
HN
HN
NH
NHHN
N
N
NH
X
NH
NH N
H
NH
X
NH
NN N
N
1 23 4
5 6 7
8
9
16
HN
HN
HN
NH
NH
NH10
1112
NH
Y
13Y = CH2, C2H4
14
NH
NN
Cl
15
N N
O
O
17
piroloindolebi biciklizaciiT (e. fiSeri)
sqema 4
HN
NHNNHN CC
CH3
COOR
H3C
ROOC
H+
1
2 3 4 5
67
NH
COOEt
EtOOC
HN
COOEt
COOEt
HN
HN
COOEt
NH
NH
NH
COOEt
EtOOC
COOEt
HN
NH
HN
HN
HN
NH
NH
NH
89
indoloindolebi biciklizaciiT
NH
HN
NH
HN
HOOC
COOH
NH
HN
ROOC
COOR
NH
HN
NH
HN COOR
COOR
NH
HN
NHNNHN CC
CH3
COOR
H3C
ROOC
H+
1
23 4
5 6 7
sqema 5
bisindolebi biciklizaciiT
NH
NH
×
R R
X
H2N NH2
X
N NH
C-COOEtN
CH3
CEtOOC
CH3
NH
NH
NH
×
X= -,O,CH2,C2H4 CH=CH,C6H4,S,SO2; R=COOEt,COOH
5 6
7 8
sqema 6
sinTezi indolinis safuZvelze
N
COCH3
NH-N C
CH3
COOC2H5
HN
NCOCH3
COOC2H5
HN
NCOCH3
COOC2H5
N
NH
H3COC
COOC2H5
1
2 3
4 N
NH
H3COC
COOC2H5
5
HN
NH
COOH
6
HN
NH 8
NH
NH
COOH
7
NH
NH
9
sqema 7
sinTezi indolinis safuZvelze
N
COCH3
NH-N C
CH3
COOC2H5
NH
N
H3COC
COOC2H5
NH
N
H3COC
COOC2H5
NH
NH
COOH
NH
NH
NH
NH3COC
C2H5OOC
NH
NH3COC
C2H5OOC
10
1112
1314
15 16
sqema 8
asimetriuli bisindolebis sinTezi
NH
NH COOEt
NH COOEt
NH2
H3COC 3) OH-
NH
H3COC
N C
CH3
COOEt
H3COC
NH-N C
CH3
NH COOEt
1 2
3
5
4
NH
NH
6
1) NaNO2/HCl
2) CH3COCH(CH3)COOEt
2,5'-bi s-1H-i ndol i
sqema 9
sqema 10
N2Cl
+NH-N C
CH2 NO2
NH
NO2
NH-N C
CH3
COOEt
CH3COCH
COOEt
NO2
COOEt
COOEt
NH
COOEt NH
NH
R
R
NH-NH2
NH
COOEt
R=COOEt,COOH,H
8
10 11
12 13
7 9
3,5'-bis-1H-i ndol i
CH2
izomeruli triindoluri sistemebi
NH-NH2
NH
COOEt
NH-N
NH
COOEt
CCH3
NH
NHCOOEt
NH
R
H3COC
NH
R
NH
COOEt
NH
NH
NH
11 14
1516
sqema 11
NH2
H3COC
1) NaNO2/HCl2) CH3COCH(CH2-C6H4-NO2)COOEt3) OH-
NH
H3COC
N C
CH2-C6H4-NO2
COOEt
NH
NO2
COOEt
H3COC NH-N=C
NH
COOEt
H3COCCH3
NH
NHCOOEt
H3COCNH-NH2 NH-N
COOEt NH
NHCOOEt COOEt
CCH3
NH N
HNHCOOEt COOEt
NH N
HNH
COOEt
1718
1920
21 22
sqema 12
benzopiroloindolis sinTezi
OH
OH
H2N-NH2NH
NH
NH2
NH2
CH3COCOOEt
NH
NH
N
N
C
CH3
COOEt
C
CH3
COOEt
H+NH
HN
COOEt
EtOOC
NHHN
COOH
HOOC
NHHN
OH-
34
5 6
to
1 2
sqema 13
dihidroindolizinuri fotoqromebi
N
N
N
N
NN
N
N
MeO2C
CO2Me
NN
CO2Me
CO2MeMeO2C
MeO2C
N
NCO2Me
CO2Me
CO2Me
CO2Me
N
NCO2Me
CO2Me
MeO2C CO2Me
+
4
5
6
1
2
3
sqema 14
bis-spiroqromenebisqema 15
N
N
NN
N
N
NN OO R1
R2
R1
R2
NNO OR2
R1
R2
R1
NN
O
O
O2N
NO2
C
O H
OH
R
1
2
36
5a-c
4 a-c
a R1 = NO2, R2 = H; b R1 = R2 = NO2; c R1 = R2 = Br
aril- da diarilindolebi
N
R
R'
N
R
R'
R''80-105°C
PPANH2 R"
CO
Me
+1 2 3
R=H,Me; R'=H,Cl,Br,OMe,Ph;
R''=H,Br,OMe,Ph,CH2Ph, CH2CH2Ph,NO2,NH2,NH-Ac,NHC(S)NH2
sqema 16
indoloindolis molekuluri diagrama (qvantur-qimiuri gaTvlebi)
N
N
3.932 (1.014)
4.074 (1.098)
4.001 (1.032)
3.997 (1.001)
3.932 (1.014)
4.074 (1.098)
4.001 (1.032)
3.997 (1.001)
0.92
6
0.91
7
0.92
6
5.16
6 (1
.759
)
sqema 17
eleqtrofiluri Canacvleba
NHHN
R R
NHHN
R R
NHHN
R
HN NH
R
NHHN
2
1
3
45 R=Ac,CHO, CH2NMe2, N=N-Ar
sqema 18
eleqtrofiluri Canacvlebasqema 19
NH
HN
R
R
NH
HN
NHHN
NHHN
NHHN
R
R
R
R=CHO, CH2N(CH3)2, N=N-Ar, Ac
5 6
7
8
9
anomaluri reaqciebi
NH
N
R
N
CO2EtNH
NH2
CO2Et
Cl-
NH
NH
Cl
EtO2C
CO2Et
Me C CH
CH3
CO2Et
NH
N
R
R''
N
Me
R'OOC
CO2Et
NaNO2 / HCl
1
2, 3
2 R = H; 3 R = Cl; 4 R = R'' = H, R' = Et; 5 R = Cl, R' = Et, R'' = H; 6 R = Cl, R' = R'' = H; 7 R = Cl, R' = R'' = Et
8
+
45 oC
8%
in ethanol, refluxed 25h
1.
2.
4,
25%
5-7
KOH (in ethanol)0-5 oC
H2SO4
O
sqema 20
Ddeformilireba
sqema 21
N
R
R''
R'
HO
N
R
R''
R'
NH
XH
O
CO2Et
a R=Me; R'=Ph, R''=H; b R=H, R'=Ph, R''=H; c R=H, R'=C6H4CH2Ph, R'' = H;
d R=H, R'=C6H4CH2CH2Ph, R'' = H; e R =H, R' = CO2Et, R'' = Me;
polyatomic alcohols
100-150°C
1a-f 2 a-f
X=CH2 or O R'' =f R = H, R' = CO2Et,
1,7-migracia
N
CH2
C6H5
R
NH
R
CH2
C6H5
1
R= Me, CO2Et, Ar; Ar=C6H5,C6H4-NO2,C6H4-Br, C6H4-OMe, C6H4-Ph, C6H4-CH2-Ph
100-1500CPPA
2
sqema 22
savaraudo meqanizmi
NH
R
H
+
N
CH2
R
N
CH2
H
+ RN
CH2
H
R
N
R
H
+I
IVV
IIIII
+H+
-H+
sqema 23
1. narTi 5-is 4’-amino- da 4’-Tioureidonawarmebi – maRali citosta- tikuri da antimikrobuli aqtiuroba;
2. monoazonaerTebi 8,9 R=H,Cl– maRali tuberkulostatikuri moqmedeba;
3. formilwarmoebulebi 5, 6 R=H, R=R=CHO – maRali tuberkulosta- tikuri da maRali aqtiuroba fitopaTogenuri baqteriebis
mimarT;4. graminis bisanalogebis hidroqloridebi 10 R4=H; 11 R4=COOEt,
10, 11 R5=R6=CH2N(CH3)2 – maRali simsivnis sawinaaRmdego aqtiur- oba;
5. azonaerTi 14 AAr= p-C6H4-Cl – tuberkulostatikuri aqtiuroba da maRali aqtiuroba fitopaTogenuri baqteriebis mimarT;
- Самсония Ш.А., Трапаидзе М.В., Купрашвили Н.А. Хим.-Фарм. Журнал, 2009, 43, 2, 23-25- Самсония Ш.А., Чикваидзе И.Ш., Каджришвили Д.О., Таргамадзе Н.Л. ХГС, 2010, в
печати, рег. №151-08 (Tsu)
HN
NH
N=N R
2-4, 7-9
N
R
R'
X
5
24
• Самсония Ш.А., Медведев Г.А., Машковский М.Д. и др. Синтез и фармакологическая активность некоторых пирролоиндольных и бисиндольных четвертичных аммониевых солей. Химико-Фармацевтический Журнал, 1982, № 11, с.55-58.
• Чикваидзе И.Ш., Медведев Б.А., Самсония Ш.А., Машковский М.Д., Суворов Н.Н. синтез и фармакологическая активность бис-индольных аммониевых солей. Химико-Фармацевтический Журнал, 1980, №5, с. 36-39.
NH
NH
×
R R
R=COOEt,H; X=CH2,CH2-CH2,O,SO2; y=CH3SO4, I
(H3C)3NH2C CH2N(CH3)3
2Y
R
R
R=COOEt,H; y=CH3SO4, I
CH2N(CH3)3
(H3C)3NH2C
2YNH
HN
kurares msgavsi aqtiuroba (Tsu)
25
benzimidazol- da benzotriazolSemcveli heterocikluri sistemebi benzoTiofenis, benzofuranisa da
karbazolis safuZvelze (stu)
• sadac X= O, S, N; R= amino, alkil, arilalkili, qlorfenil, aminofenil, hidroqsifenil, qlormeTili, da a.S.
26
aqtiuri anTrapiridonuli naerTebi – axali fluorescentuli markerebi (stu)
27
Sualeduri produqtebi da struqturuli analogebi
• 3-hidroqsi-2-eTil-6-meTilpiridinis hidroqloridisa da suqcinitis, Sesa-bamisad, sisxlis gamaTxelebelis - emoqsipinisa da tvinSi sisxlis mimoq-cevis regulatoris – meqsadolis sinTezis aqtiuri sawyisis 2-propio-nil-5-meTilfuranis (87%) furanidan miRebis gaumjobesebuli meTodi. (Микадзе И.И., Алавидзе Т.Г. и др. Известия НАН Грузии, 2009, 2, 35, 254-256);
• yurZnis Wiis, aRmosavleTis qliavis, vaSlis nayofWamias, arafarda parkmx- veviasa da mbeWdavi qerqiWamias sqesis feromonebis racionaluri sinTe-zis gzebi. mwerebSi kanis cvlis damamuxruWebeli iuvenaluri hormonis analogebis sinTezi (fenoqsikarbi). blok-sintonebis gamoyeneba qrizante- mis mJavas nawarmebis – piretroidebis sinTezSi (Цицаги М.В., Церодзе Н.П. и др. GEN, 2002, 2. 86-87). P/p. meliqiSvilis instituti/;
• antimikrobuli, baqteriostatikuri da baqtericiduli preparatis tri-oninis – 3’ 4’, 5-tribromsalicilanilidis analogis ГЗ-048 miRebis meTo-dis gaumjobeseba (86%). dadgenilia preparatis maRali anthelminTuri moqmedeba “heqsiqolTan” da meTilinTan” SedarebiT. gentamicinTan Seda-rebiT amJRavnebs maRal aqtiurobas sxvadasxva mikroorganizmebis mi-marT (Зурабишвиди В., Гоголашвили И.Н. и др. Известия аграрной науки, 2006, 4, 3, 77-83). /Tsu/
28
steroidebis warmoebulebi(farmakoqimiis instituti)
• steroiduli sapogeninis tigogeninis miRebis meTodi mowode-buli iqna farmakoqimiis institutis mier (Кемертелидзе Э.П., Пхеидзе Т.А. Хим.-Фарм. Журнал, 1972, 44).
• mowodebulia 3-adiolis sinTezis gamartivebuli sqema: tigo- genini gadayavT pregnenolonis acetatSi, Semdgom epiandroste- ronis acetatSi da Semdgomi aRdgeniT 5-androstan-3,17-dio-lSi (Сообщ. АН Грузинской ССР, 1988, 132, 3, 537; Сб. науч. Тр. ВНИХФИ им. С. Орджоникидзе, 1982, 10, 83).
• mowodebulia 5-ketosteroidebis izonikotinoilhidrazonebis miRebis meTodi. naCvenebia sinTezirebuli naerTebis maRali antituberkulozuri aqtiuroba (Chemistry of Natural Compounds, 2009, 45, 3, 389-91).
• tigogeninis safuZvelze sinTezirebulia antituberkulozuri aqtiurobis mqone 5-androstanis rigis najeri da ujeri А birTvis mqone aminosteroidi.
29
Bbiodegradirebadi polimeruli masalebi
• ganxorcielebulia wamlis gadamtani axali biodegradirebadi mikrokonteinerebis sinTezi bis-azalaqtonebis safuZvelze. naC-venebia micelebis gamoyenebis SesaZlebloba wamlebis nanokon-teinerebad gamoyenebis mizniT (Acta Polymerica, 1985, 36, 1, 29-38; J.Polym. Sci.: Part A: Polym. Chem., 1999, 37, 4, 391-407). /stu, Tsu/;
• miRebulia wyalSi xsnadi, biodegradirebadi, axali klasis po-likationebi polifunqciuri aminomJava L-argininis safuZvelze. isini gacilebiT nakleb toksikurni arian vidre genoTerapiaSi amJamad gamoyenebuli cnobili sinTezuri polikationebi poli-eTileniminiP(PEI), poli-L-lizini(PLL) da poliarginini(Poly-Arg). L-arginiis safuZvelze miRebuli polikationebi dnm-Tan war-moqmnian stabilur nanokompleqsebs 200-250nm zomiT, romlebic perspeqtiuli da efeqturi reagentebia ujredis transfeqciis-Tvis (stu, Tsu).
30
Aadamantanis warmoebulebi
• mowodebulia 2-(1-adamantil)benzimidazolebis miRebis meTodi da dadgenilia sinTezis optomaluri pirobebi. 5(6)-(1-adaman-til)benzimidazolebisaTvis gamovlenilia antimikrobuli da anthelminTuri aqtiuroba. lipofiluri bunebis adamantanis fragmenti xels uwyobs heterocikluri fragmentis Seyvanas ujredSi (ХГС, 1997, 12, 1646-1649; ХГС, 2008, 8, 1172-11). /Tsu/;
• aminoadamantanis, adamantan-1-karbonmJavasa da p-aminobenzois mJavas nawarmebis biologiuri aqtiurobis farTo speqtridan gamomdinare damuSavebulia adamantanis rigis p-aminobenzoisa da p-aminoacetofenonis nawarmebis miRebis meTodebi. miRebulia agreTve N-adamantil-p-aminobenzois mJavas nitrirebis produq- tebi, xolo misi qloranhidridis urTierTqmedebiT aminoadaman- tanis hidroqloridTan – Sesabamisi benzamidebi (Tsu).
31
naxSirwylebi
• D-glukozisa da D-galaqtozis zogierTi warmoebulebis urTi- erTqmedebiT 4,4,8,8-tetrameTil-2,3,6,7-dibenzo-9-oqsabiciklo(3,3,1)- (3,3,1)nonan-1-amino(alkilamino)-5-olTan (5-hidroqsi-dibenz-oqsabi- ciklononani), vercxlis karbonatis Tanaobisas miRebulia Sesa- bamisi heterociklebis Semcveli -glikozidebis rigi (Tsu);
• damuSavebulia selenglukozis, selengalaqtozisa da maTi sili-ciumisa da dariSxanis Semcveli warmoebulebis miRebis meTodi. naCvenebia maTi SerCeviTi biociduri moqmedeba (Tsu);
• izomeruli aminofenolebis N-glikozilireba homomorfuli al-dozebiT – D-manoziTa da L-ramnoziT. (r. kublaSvili, N-gliko-zidebi mailardis reaqciaSi, Tsu, 2009, 210 gv). Seswavlilia nare-vebis izomeruli da anomeruli Sedgeniloba (Tsu);
• sinTezirebulia N-karboqsifenil-L-arabinozilaminebi da Seswav-lilia miRebuli N-glikozidebis anomeruli Sedgeniloba (Tsu, petre meliqiSvilis fizikuri da organuli qimiis instituti)
32
Eenantiomerebis sinTezi
• mcenare SYMPHYTUM ASPERUM AND S.CAUCASICUM-dan gamoyofi- li biologiurad aqtiuri polieTeris struqturuli rgolis Sesabamisi 3-(3,4-dihidroqsifenil)-glicerinis mJavas enantiose- leqtiuri sinTezi (farmakoqimiis instituti, Tsu);
reaqciis meqanizmis kvantur-qimiuri modelireba
• kvanturi qimiis araempiriuli Tanamedrove meTodis _ simkvri-vis funqcionalis Teoriis ((DFT) gamoyenebiT, agebulia pepti-duri bmebis warmoqmnis meqanizmis modeli. modelis mixedviT adgili aqvs wylis gamoyofas da peptiduri bmis warmoqmnas. gadajgufebas safuZvlad udevs muxtis ganawileba moreagire molekulebSi. sakvlevi obieqtebia: valini, alanini, asparginis mJava, da glicini (Tsu, soxumis universiteti).
33
Kkoordinaciuli naerTebi
• potenciuri biologiuri aqtiurobis mqone nivTierebebis Ziebis mizniT miRebulia koordinaciuli naerTebi adamantanis N,N-dia-cilhidrazidebisa da Cu(II), Fe(II) safuZvelze (Tsu);
• orTo(L’)- da meta(L)nitrobenzoilhidrazinTan kobaltisa da rkinis sulfatebis koordinaciuli naerTebis sinTezi. miRebu-li naerTebi sxvadasxva intensivobiT avlenen baqtericidul da aqtinomicidur Tvisebebs test-mikroorganizmebis mimarT: Agro-bacterium tumefaciens, Xanthomonas campestris, Pectobacterium aroideae, Nocar-diopsis dassonvillei.
(stu, Tbilisis botanikuri baRisa da botanikis institutis mikrobiologiis ganyofilebis mikroorganizmTa muzeumi);
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• 20 wevriani makrocikluri poliazomeTinuri naerTebis (Sifis fuZeebis) mdgradi metalkompleqsebi orvalentovani Ni, Co, Cu qloridebTan da sulfatebTan;
• SesaZlebelia mdgradi kompleqsebis miReba fermWer saRebrebis Tanaobisas, (stu).
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madloba
• konferenciis yvela monawiles
• prof. nokoloz suvorovi moskovis mendeleevis saxelobis qimiur-teqnologiuri universiteti
• prof. hainc diuri da prof. uli kacmaieri, saarlandis universiteti • Tsu qimiis departamenti
• “DFG” proeqti (1996-2000); “GNSF” grantebi (2005, 2007-2010, 2009-2012)
• Tsu TanamSromlebi
• prof. e. elizbaraSvili
gmadlobT yuradRebisaTvis!