biologiurad aqtiur nivTierebaTa sinTezis

ZiriTadi mimarTulebani

prof. SoTa samsonia

iv. javaxiSvilis saxelobis Tbilisis saxelmwifo universiteti

shota.samsonia@tsu.ge

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!