Sentetik maddeler ile DNA kesimi

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ÖZET

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$\UÕFD  DULO UDGLNDOHUL LOH ROXúDQ '1$ KDVDUÕ ]Hrine antioksidant ve antimikrobiyal aktiviteleri bilinen Hypericum retusum Aucher, Hypericum scabrum L.,

Hypericum lysimachioides Boiss&Nöe var .lysimachioides, Achillea aleppica D.C. subsp. aleppica, Achillea aleppica D.C. subsp. zederbaueri (Hayek) Hub. -Mor. ve

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Anahtar Kelimeler: '1$ .HVLPL 6HUEHVW 5DGLNDOOHU 5DGLNDO 6|QGUF %DNÕU

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ABSTRACT

The ultimate aim of this thesis was to investigate the effect of different aryl substituted analogues of benzenediazonium tetrafluoroborate on radical reactivity and DNA cleavage ability. The results indicated that cleavage of a DNA duplex from pBluescript M13+ DNA was observed by the different substituted aryl diazonium salts, in the presence of inorganic one-electron donor. Moreover, DNA cleavage was partly affected by different substitute group and DNA strand-scission was also observed without one electron donor in the presence of some tested diazonium salts. Its mechanism involves the generation of the aryl radical that cleaving DNA by hydrogen atom abstraction from deoxyribose sugar.

The protective effect of Hypericum retusum Aucher, Hypericum scabrum L.,

Hypericum lysimachioides Boiss&Nöe var .lysimachioides, Achillea aleppica D.C. subsp. aleppica, Achillea aleppica D.C. subsp. zederbaueri (Hayek) Hub. -Mor. ve

Achillea biebersteinii Afan. plants extracts on DNA cleavage mediated by aryl radical was also investigated using pBluescript M13+ plasmid DNA, as judged by agarose gel electrophoresis. It was found that aryl radical induced DNA strand scission was not prevented by ethanol extracts of Hypericum and Achillea. On the contrary, DNA cleavage was increased in the presence of plant extracts. Therefore, we decided to investigate the DNA cleavage ability of plant extracts alone and also in the presence of copper (II) chloride. It was found that the naturally occuring plant extracts caused strand scission of DNA in the presence of copper ion. The mechanism of the DNA strand scission by plant extracts (in the presence of Cu2+ ion) indicated an involvement of oxygenation of aromatic nucleus, affording catecholic moieties that were proposed to coordinate Cu2+ and subsequently effect the reduction of dioxygen to reactive species, followed by the oxidation of catecholic moiety via the coordinated Cu2+ ion.

Keywords: DNA Cleavage, Free Radical, Radical Scavenger, Copper, Hypericum,

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KISALTMALAR

DNA Deoksiribonükleik asit RNA Ribonükleik asit

A1 Achillea aleppica subsp. aleppica A2 Achillea aleppica subsp. zederbaueri A3 Achillea biebersteinii

H1 Hypericum retusum

H2 Hypericum scabrum H3 Hypericum lysimachioides

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1. 2. DNA’ya Zarar Veren Maddeler Neden Önemlidir?

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Biyolojik aktivite gösterme SRWDQVL\HOLQHVDKLSGR÷DOUQOHULQGR÷DOVHOHNVL\RQ VRQXFX ROXúWX÷XQD LQDQÕOÕU12 'R÷DO UQOHULQ QHGHQ ROGX÷X '1$ KDVDUÕ JHQHOGH

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RODQ GR÷DO UQOHU ED]HQ EHNOHQPHGLN \ROODUOD EL\RORMLN HWNL J|VWHUHELOGLNOHUL LoLQ NRPSOHNV\DúDPVUHFLQLDoÕNODPDNLoLQ\DUDUOÕRODELOLUOHU

.RYDOHQW'1$0RGLILNDV\RQXQXQ*HQHO0HNDQL]PDVÕ

'1$¶QÕQNRYDOHQWPRGLILNDV\RQPHNDQL]PDODUÕLNLNDWHJRULGHVÕQÕIODQGÕUÕOÕU(i) (OHNWURILOOHULQ'1$¶QÕQQNOHRILOLNNÕVÕPODUODUHDNVL\RQX\DGD LL UDGLNDOOHULQ'1$ ile reaksiyonu.

(OHNWURILOOHU '1$ \DSÕVÕQGDNL IDUNOÕ QNOHRILOLN NÕVÕPODUOD HWNLOHúHELOLU .LP\DVDO \DSÕODUÕQD ED÷OÕ RODUDN '1$¶QÕQ EHOOL QNOHRILOLN NÕVÕPODUÕQD VHOHNWLYLWH gösterirler. DNA’da guaninin N-7, N-3 ve exosiklik N2 amino grubu ile adeninin N-7 ve N-NÕVÕPODUÕGR÷DOUQOHUOHHQoRNPRGLILNDV\RQDX÷UD\DQNÕVÕPODUGÕU17-20 ùHNLO 

(17)

ùHNLOWatson–&ULFNED]oLIWLYHúHNHUIRVIDWRPXUJDVÕ ùHNLO$ED]LNE|OJHROXúXPXYH'1$NHVLPL O N N N NH O NH2 RO RO O N N N NH O NH2 RO RO E E+ + N N N NH O NH2 E O RO RO H2 O O RO RO OH OH RO RO O OH RO RO O + (1) + N N O O CH3 H R N N N N N H H R N N O N H H R N N N N O N H H H R 1 2 3 5 6 7 3 8 9 Büyük Oluk Küçük Oluk A-T G-C Büyük Oluk Küçük Oluk 5 3 1 2 3 1 6 8 9 R=DNA Zinciri O B O P O O O O H O B O H -B=DNA Baz 3' C5 ' C4' C3' C2 ' C1'

(18)

3ULQ NDOÕQWÕODUÕQÕQ 1-7 ya da N-3 pozisyonundan elektrofilik modifikasyonu JOLNR]LGLNED÷ÕQ]D\ÕIODPDVÕ\ODVRQXoODQÕU%XQXQVRQXQGDDED]LNE|OJH 1 ROXúXUYH Q|WUDO úDUWODUGD EX E|OJHOHU KLGUROL]OHQHUHN '1$ NHVLPL JHUoHNOHúLU21-25 ùHNLO  

'1$ ED]ODUÕQGDNL H[RVLNOLN D]RW YH NDUERQLO RNVLMHQOHUL \D GD '1$ RPXUJDVÕQGDNL IRVIDW  RNVLMHQOHUL LOH HOHNWURILN  WUOHUL  UHDNVL\RQX  JHQHOOLNOH NDUDUOÕ UQOHU ROXúWXUXU26-28

%D]Õ UDGLNDO WUOHUL '1$ LOH GH÷LúLN SR]LV\RQODUGD HWNLOHúLUOHU '1$¶QÕQ UDGLNDOOHU WDUDIÕQGDQ KDVDUD X÷UDWÕOPDVÕQGD HQ |QHPOL \RO GHoksiribozdan hidrojen DWRPX NRSDUÕOPDVÕGÕU29-31 'HRNVLULER] úHNHULQGHQ KLGURMHQ DWRPX NRSDUÕOPDVÕ úHNHU

IRVIDW RPXUJDVÕQÕQ NÕUÕOPDVÕQD VHEHS ROXU30-31 ùHNLO   ùHNHU IRVIDW RPXUJDVÕQD

HWNLPH\HHNRODUDNED]ÕUDGLNDOOHUGH'1$ED]ODUÕ\ODHWNLOHúLUOHU32-35 Bu reaksiyonlar

úHNHU IRVIDW RPXUJDVÕQÕQ NÕUÕOPDVÕQD VHEHS ROPD]ODU IDNDW '1$ \DSÕVÕQGDNL PRGLILNDV\RQODUEL\RORMLNRODUDN|QHPOLGLUOHU6SHVLILNELUED÷ODQPDROPDGÕ÷Õ]DPDQ '1$NHVLPLJHQHOGHNoNGL]LOHUOH\DGDED]|]JQO÷\OHPH\GDQDJHOLU36 Bunun DNVLQHDONLOOH\LFLDMDQODUOD'1$NHVLPLELUYH\DGDKDID]OD'1$ED]ÕLoLQVHOHNWLYLWH gösterir. ùHNLO'1$úHNHULQGHQKLGURMHQDWRPXNRSDUÕOPDVÕ 55¶ '1$RPXUJDVÕ O2

.

O O O H B OR' R + RH RO O B OR' RO O B OR' RO RO O B HO-O OR' O O B O RO -OR' O O RO B O Criegee Yeniden Düzenlenmesi +

(19)

'1$øOH(WNLOHúHQøODoODU

'1$ LOH HWNLOHúHQ LODoODUÕ o DQD EDúOÕN DOWÕQGD WRSOD\DELOLUL] '1$µGDNL ED] oLIWOHULDUDVÕQDJLUHUHN.-KHOLNV\DSÕ\ÕER]DQLQWHUNDODW|UOHU'1$ED]ODUÕ\ODNRYDOHQW RODUDNED÷ODQDQDONLOOH\LFLDMDQODUYHUDGLNDOROXúWXUDUDN'1$SROLQNOHRWLG]LQFLULQGH NHVLPHQHGHQRODQ'1$]LQFLULQLNÕUDQODU10

'1$øQWHUNDODW|UOHUL

Düz, genellikle aromatik ya da heteroaromatik moleküller .-KHOLNV\DSÕGDNLED] oLIWOHUL DUDVÕQD JLUHUHN '1$¶ \D ED÷ODQÕUODU YH ED] oLIWOHUL\OH NPHOHQLUOHU øQWHUNDODV\RQGDHWNLQRODQNXYYHWOHU\NWUDQVIHUNXYYHWOHULGLUIDNDWKLGURMHQED÷ODUÕYH HOHNWURVWDWLN NXYYHWOHU GH NDUDUOÕOÕNWD URO R\QDUODU37

 øON RODUDN  \ÕOÕQGD /HUPDQ WDUDIÕQGDQDoÕNODQDQLQWHUNDODV\RQLODFÕQKHOLNVLQHNVHQLQHULMLWELUúHNLOGHGLNRODUDN NRYDOHQWROPD\DQED÷ODQPDVÕGÕU38 Bu da baz çiftleriniQGúH\RODUDND\UÕOPDVÕQDVHEHS

ROXU GROD\ÕVÕ\OD úHNHU IRVIDW RPXUJDVÕ ENOU YH KHOLNVLQ \DSÕVÕ ER]XOXU *|UQúH J|UH LQWHUNDODV\RQJoOH LOJLOLGLU %D]oLIOHULLOHLQWHUNDODW|UPROHNODUDVÕQGDNLYDQ GHU :DDOV NXYYHWOHUL ELUELUOHUL\OH NPHOHQPLú ED] oLIWOHUL DUDVÕQGDNL YDQ GHU :DDOV kuvvetleri’nden daha güçlüdür.39

ùHNLO Etidyum bromürün B-DNA’ya interkalasyonu. N+

N

H2 NH2

C2H5 Br

(20)

øQWHUNDODV\RQ :DWVRQ-&ULFN KLGURMHQ ED÷ODUÕQÕ NÕUPD] KHOLNV \DSÕ\Õ GHIRUPH HGHU'LUHN'1$KDVDUÕQDVHEHSROPD]KHOLNV\DSÕGDNRQIRUPDV\RQGH÷LúLNOL÷LQH\RO açar.

'1$LQWHUNDODW|UOHULQLoJUXEDD\ÕUDELOLUL]Akridinler (2), aktinomisinler (3) ve anthrasiklinler (4).10

(2) Amsacrine, R=R’=H (3) Actinomycin D, R=R’= D-Val

(4) Adriamycin, X=OH

1. 4. 2. Alkilleyici Ajanlar

'1$ DONLOOH\LFLOHUL LOH LQWHUNDODW|UOHUL DUDVÕQGDNL IDUN ED÷ODQPD úHNLOOHULGLU '1$LQWHUNDODW|UOHUL'1$LOHNRYDOHQWROPD\DQED÷ODUODED÷ODQÕUNHQDONLOOH\LFLDMDQODU NRYDOHQWED÷ODUODED÷ODQÕUODU.DQVHUNHPRWHUDSLVLQGHNXOODQÕODQHQ|QHPOLDONLOOHyici DMDQODU D]RW KDUGDOODUÕ HWLOHQLPLQOHU PHWDQRVOIRQLN DVLW HVWHUOHUL YH SODWLQ komplekleridir.10 N R R' HN NHSO2CH3 MeO L-Pro R' L-Thr O L-MeVal Sar L-Pro R' L-Thr O L-MeVal Sar O CH3 CH3 O N O O O O O OMe OH X O OH O H NH3 OH C H3

(21)

$]RW+DUGDOODUÕ

6OIUKDUGDOÕ,YH,,'Q\DVDYDúODUÕQGDNXOODQÕOPÕúoRNWRNVLNVLQLUJD]ÕGÕU, 'Q\D 6DYDúÕQGD VOIU KDUGDOÕ\OD |Oen askerlerin otopsileri sonucu lökopeni GúN EH\D] NDQ KFUHVL  NHPLN LOL÷L aplazi, OHQI GRNXODUÕQGD ER]XQPD YH JDVWURLQWHVWLQDO VLVWHPGH OVHU VDSWDQPÕúWÕU %X OH]\RQODU VOIU KDUGDOODUÕQÕQ KÕ]OÕ E|OQHQ KFUHOHUH HWNLOL ROGX÷X VRQXFXQD J|WUPú YH DQWLWP|U HWNLOHUL RODELOHFH÷L GúQOPú  \ÕOÕQGD VOIU KDUGDOÕ LQVDQODUGD WP|U KFUHVLQH HQMHNWH HGLOPLú40

 IDNDW EX LúOHPLQ VLVWHPDWLNNXOODQÕPLoLQoRNWRNVLNROGX÷XDUWD\DoÕNPÕúWÕU*LOOPDQYHGL÷HUNLP\DFÕODU daha az toksik olan azot hardallaUÕQÕQDQWLWP|UHWNLVLQLLQFHOHPLúOHU\ÕOÕQGDD]RW KDUGDOÕQÕQ NOLQLN GHQHPHOHUL EDúODPÕúWÕU dDOÕúPD ,, 'Q\D VDYDúÕ VUHVLQFH GHYDP HWPLúWLU $]RW KDUGDOODUÕQÕQ  \ÕOÕQGDQ EHUL NDQVHU WHGDYLVLQGH NXOODQÕOGÕ÷Õ bilinmektedir.41%XoDOÕúPDPRGHUQNDQVHUNHPRWHUDSLVLQLQEDúODQJÕFÕROPXúWXU

6OIUKDUGDOÕ $]RWKDUGDOÕ

5RVV¶D J|UH EL\RORMLN DONLOOH\LFL DMDQODU IL]\RORMLN NRúXOODUGD S+  0 C,

VXOXo|]HOWL KLGURMHQDWRPX\ODDONLOJUXEXQXQ\HULQLGH÷LúWLUHELOHQPROHNOOHUGLU'1$ için en iyiUHDNWLIRODQQNOHRILOLNNÕVÕPODU1-7 guanin > 3 adenin > 1 adenin > N-VLWR]LQVÕUDODPDVÕGÕU42

$]RW KDUGDOODUÕ ELIRQNVL\RQHO DONLOOH\LFL DMDQODUGÕU \DQL LNL WDQH HOHNWURILOLN NÕVÕPODUÕ YDUGÕU '1$ ED]ODUÕQÕ ]LQFLU LoL YH\D ]LQFLUOHU DUDVÕ ED÷OD\DEilirler. Azot KDUGDOODUÕQÕQ DONLODV\RQX úHNLO¶GDJ|VWHULOPLúWLU$]RWKDUGDOODUÕNRPúXLNL'1$ ]LQFLUL DUDVÕQD JLUHUHN LNL JXDQLQ ED]ÕQÕ 1-7 pozisyonundan alkilleyerek iki zinciri ELUELULQHED÷OD\DELOLUOHU10 ùHNLO 

Cl S Cl Cl N Cl

(22)

ùHNLO Azot hardallaUÕ\ODDONLODV\RQ ùHNLO$]RWKDUGDOODUÕQÕQQHGHQROGX÷XoDSUD]ED÷ODQPD N R Cl N R Nu1 Cl N R Nu1 Cl Cl Nu1 N R Nu2 -Nu2 N R Nu1 + -+ + N N N N H O N H2 N CH3 O O P O O O O P O O O N N N NH O NH2 O O P O O O O P O O O + -

(23)

-'L÷HU$ONLOOH\LFL$MDQODU

'L÷HUDONLOOH\LFLDMDQODU etileniminler (5), metanosülfonik asit esterleri (6), azot ND\QDNOÕODU 7) ve platin kompleksleridir (8).10

(5) (6)

(7) (8)

'1$=LQFLULQL.ÕUDQODU

'1$ LOH HWNLOHúHQ LODoODUÕQ ED]ÕODUÕ EDúWD '1$ LQWHUNDODW|UOHUL JLEL ED]ODUÕQ DUDVÕQD JLUHUOHU GDKD VRQUD X\JXQ NRúXOODUGD UDGLNDOOHUL ROXúWXUXUODU %X UDGLNDOOHULQ '1$LOHHWNLOHúLPL'1$]LQFLULQLQNÕUÕOPDVÕQDVHEHSROXU

1. 4. 3. 1. Antrasiklin Antitümör Antibiyotikleri

'1$ LQWHNDODW|UOHUL RODQ DQWUDVLNOLQOHU D\QÕ ]DPDQGD RNVLMHQH ED÷OÕ '1$ KDVDUÕQDGDQHGHQROXUODU43 N N O R NHR' O H3N Pt Cl Cl H3N N N N N N N CH3O2SO-(CH2) -OSOn 2CH3

(24)

Doxorubicin, X = OH 1. 4. 3. 2. Bleomycin

%OHRP\FLQ\ÕOÕQGDStreptomyces verticillus’WDQL]ROHHGLOPLúELUDQWLWP|U DQWLEL\RWL÷LGLU44,45

Bleomycin

%OHRP\FLQGH SLULPLGLQ -DPLQRDODQLQ YH -hidroksiimidazol Fe(II) ile DNA NHVLP HWNLVL RODQ NDUDUOÕ ELU NRPSOHNV ROXúWXUXU 105  YH KLGURGLQDPLN oDOÕúPDODU \DSÕGDNL ELWKLD]ROXQ LQWHUNDODV\RQ HWNLVL ROGX÷XQX IDNDW EX LQWHUNDODV\RQXQ NODVLN LQWHUNDODW|UOHU HWLG\XP EURPU YE  NDGDU HWNLVL ROPDGÕ÷ÕQÕ J|VWHUPLúWLU46,47 %D]Õ

oDOÕúPDODU ELWKLD]ROXQ WDP LQWHUNDOHWH ROPDGÕ÷ÕQÕ IDNDW '1$ \DSÕVÕQGDNL ROXNODUD ED÷ODQGÕ÷ÕQÕ J|VWHUPLúWLU48,49 <DSÕGDNL VOIRQ\XP L\RQXQXQ IRVIDW JUXEX LOH

O O O OMe OH X O OH O H NH3 OH C H3 N N H N NH2 O N H2 CH3 O N H N H O H O O OH O H OH O O OH OH OH O O NH2 H NH2 O NH2 H H H H NH S N CH3 H O N O NH S N O Me2 S O H CH3 CH3 H O H + H N NH

(25)

HOHNWURVWDWLN RODUDN HWNLOHúPH RODVÕOÕ÷Õ YDUGÕU50 *OLNR] PDQQR] LVH EOHRPLFLQLQ ED]Õ

kanser hücrelerinde selektif olarak birikiminden sorumlu olabilirler, fakat DNA kesiminde rol almazlar.

Bleomycin-Fe II Kompleksi

DNA kesim ürünlerinin incelenmesiyle, kesimin genellikle DNA zincirinin 3' XFXQGDNL SULQ QNOHRWLGLQH ED÷OÕ RODQ SULPLGLQ QNOHRWLQLQ  NDUERQ DWRPXQGDQ KLGURMHQNRSDUÕOPDVÕ\ODJHUoHNOHúWL÷LDQODúÕOPÕúWÕU51

1. 4. 3. 3. Enediyen Antibiyotikleri

 \ÕOÕQGD L]ROH HGLOHQ QHRFDU]LQRVWDWLQ52 GÕúÕQGDNL HQHGL\HQ DQWLEL\RWLNOHUL

esperamicin,53 calicheamisin,54 ve dynemicin A55 ¶OHULQ VRQODUÕQD GR÷UX oHúLWOL PLNURRUJDQL]PDODUGDQL]ROHHGLOPLúOHUGLU<DSÕODUÕQGDHQD]ELUoLIWED÷YHLNLoOED÷ EXOXQGXUGXNODUÕ LoLQ HQHGL\HQ DQWLWP|U DQWLEL\RWLNOHUL RODUDN DQÕOÕUODU %X WU moleküller DNA zincirinde küçük olukta interkalasyon yaparlar daha sonra SR veya 1$'3+JUXSODUÕ\ODDNWLYHHGLOHUHN'1$]LQFLULQLNHVHQUDGLNDOOHULQLROXúWXUXUOar.

1. 4. 3. 3. 1. Neocarzinostatin

\ÕOÕQGD Sterptomyces carzinostaticus’WDQL]ROHHGLOPLúWLU52 Bilinen en eski

HQHGL\HQDQWLEL\RWL÷LGLU=LQRVWDWLQRODUDNGDELOLQLU567L\ROWDUDIÕQGDQDNWLYHHGLOHUHN

Bergman, yeniden düzenlenmesiyle diradikal ROXúWXUXU 2NVLMHQ YDUOÕ÷ÕQGD LNL IDUNOÕ PHNDQL]PDLOH'1$NHVLPLJHUoHNOHúLU57-58 H NH S N CH3 O N H O NH S N O Me2S O H CH3 CH3 NH N N N H2 O H NH2 N N H2 O N H2 CH3 N H O H O-Seker O O H H + ' Fe N N H O2

(26)

Neocarzinostatin

ùHNLO Neocarzinostatinin tiyol ile aktivasyonu

O C H3 O H OH NHCH3 CH3 CH3O OH O O O O O O O O C H3 O H OH NHCH3 O O O O O O Me OH O MeO SR -O C H3 O H OH NHCH3 Me OH O O MeO

. .

O O OH O O SR O C H3 O H OH NHCH3 Me OH O O MeO Bergman yeniden düzenlenmesi O O O O

.

.

.

(27)

ùHNLO$NWLYHHGLOPLúQHRFDU]LQRVWDWLQYHGL÷HUHQHGL\HQDQWLEL\RWLNOHULWDUDIÕQGDQ DNA keVLPPHNDQL]PDVÕ

1. 4. 3. 3. 2. Esperamicin ve Calicheamicin

(VSHUDPLFLQ YH FDOLFKHDPLVLQ DQWLWP|U DQWLEL\RWL÷LGLUOHU (VSHUDPLFLQ

Actinomadura verrucosospora, calicheamicin ise Micromonospora echinospora ssp. calichensis toprak örneklerinden izole ediOPLúOHUGLU54,60,61 Neocarzinostatin gibi

GLUDGLNDOROXúWXUDUDN'1$NHVLPLQHVHEHSROXUODU59 O B PO OP

.

O2 O B PO OP O-O

.

ROO

.

O B PO O OP O B OP O OH PO

..

+e, +H- + veya +RSH, -RS

.

PO H O PO H O DNA Kesimi O+ B OP O B OP OO

.

..

O B OP

.

+ H O2 O OP H -O B Baz OP H H O O + HO H O + PO -O

.

2 -O2 DNA Kesimi

(28)

Esperamicin Calicheamicins O O O CH3 O H O NH OMe MeO O C H3 MeS OH O NHCH(CH3)2 OMe O O O C H3 NH O NHCO2CH3 CH3SSS O H O H O C H2 MeO O C H3 S OH O NHCH2CH3 OMe O O O C H3 NH O NHCO2CH3 CH3SSS O H O H O OH O H C H3 MeO O CH3 I OMe OMe

(29)

1. 4. 3. 3. 3. Dynemicin A

 \ÕOÕQGD Micromonospora chersina’dan izole edilen dynemicin hem enediyen hem de antracyclinH DQWLEL\RWLNOHULQLQ \DSÕVDO RODUDN NRPELQDV\RQXGXU55

<DSÕVÕQGDNLDQWUDTXLQRQXQ'1$GXEOHNVLDUDVÕQDJLUHUHNLQWHUNDODV\RQDVHEHSROGX÷X WDKPLQ HGLOPHNWHGLU 'DKD VRQUD QHRFDU]LQRVWDWLQ JLEL GLUDGLNDO ROXúWXUDUDN '1$ úHNHULQGHQKLGURMHQDWRPXNRSDUDUDN'1A kesimine sebep olurlar.

Dynemicin A

1. 5. Karbon Merkezli Radikal Metabolitleri

Karbon merkezli radikaller normal metabolizmada yüksek konsantrasyonlarda ROXúPD]ODU61

Oksidatif stress62 ve karbonhidrat63 ya da amino asit64,65PHWDEROL]PDVÕQÕ etkiOH\HQ JHQHWLN G]HQVL]OLNOHU JLEL SDWRORMLN GXUXPODUGD ROXúXUODU 6RQXoWD NDUERQ merkezli radikaller karbontetraklorür,66,67 hidrazin türevleri,68 nitroalkanlar,69,70 etanol71,72, diazoquinonlar73,74 ve organik hidroperoksitler75,76JLELoHúLWOLNLP\DVDOODUÕQ PHWRELOL]PDVÕVRQXFXED]ÕJHQRWRNVLN|]HOOLNOHUHED÷OÕRODUDNROXúXUODU 7DEOR  3ROLVLNOLN DURPDWLN KLGURNDUERQODUÕQ DURPDWLN NDW\RQ UDGLNDOOHULQH G|QúPHVL VHUEHVW radikal ara ürünlerine güzel bir örnek olarak verilebilinir.

Karbon merkezli radLNDOOHU PROHNOHU RNVLMHQ LOH oRN KÕ]OÕ HWNLOHúHUHN DONLO UDGLNDOLQGHQGDKDUHDNWLIELRPROHNOOHURODQSHURNVLWUDGLNDOLJLELUQOHUROXúWXUXUODU77

.LP\DVDO NDQVHURMHQOHUOH LOJLOL ELUoRN oDOÕúPD '1$¶\D NRYDOHQW ED÷ODQPDQÕQ kanserojenlerin alkildiazonyuP L\RQODUÕ \D GD HSRNVLWOHU JLEL HOHNWURILOLN DUD UQOHUL DNWLYH HGHUHN L\RQLN PHNDQL]PD LOH ROGX÷X \|QQGHGLU78,79(ùHNLO ) Karbon

PHUNH]OLUDGLNDOOHULQ'1$LOHHWNLOHúHQUHDNWLIWUOHUROGX÷XELOLQLU80 N H O OH O CH3 CH3 O O O OH OH

(30)

ùHNLOAlkil radikali ile DNA hasarÕ-dimetil hidrazin ile DNA baz ürünlerinin ROXúXPX CH3-N-N-CH3 Metabolizma C H3 N N + CH 3

.

Gua-DNA N N N N H O N H2 R CH3 N N N N H O N H2 R CH3 H N N N N H O N H2 R N-MeGua-DNA7 . + N N N N N H2 R OMe N N N N H O N H2 R CH3 O-MeGua-DNA6 C-MeGua-DNA8 H H

(31)

Xenobiotik Serbest Radikal Metabolit Genotoksik Özellik CCl4 Hidrazinler Triklorometil Alkil, Aril ÜCCl3 RÜArÜ Hepatokanserojen81 Mutajen,kanserojen Etanol .-hidroksietil H3C- ÜCHOH Teratojen

2-Nitropropan .-hidroksiizopropil (H3C)2ÜCOH Mutajen

Hepatokanserojen81 Diazoquinonlar Peroksitler .-hidroksifenil alkil, peroksil, alkoksil ÜArOH RÜROOÜ ROÜ Mutajen74,75 Kanserojen82,83 Promoter75,76

PAHa Aril katyonu Ar+-ÜCH Kanserojen84

Tablo 1. 1. *HQHWRNVLN ;HQRELRWLNOHUGHQ ROXúDQ NDUERQ PHUNH]OL VHUEHVW UDGLNDO metabolitleri.

aPolisiklik aromatik hidrokarbonlar

Alkil radikalleri hidroksil radikalinden daha az reaktiftirler. Hem alkil radikali KHP GH KLGURNVLO UDGLNDOL '1$ úHNHULQGHQ KLGUojen atomu kopararak ya da DNA ED]ODUÕ\ODHWNLOHúHUHN]LQFLUNHVLPLQH\DGDDONLODV\RQDVHEHSROXUODU85

ùHNLO

ùHNLO.DUERQPHUNH]OLUDGLNDOPHWDEROLWOHULLOHROXúDQ'1$PRGLILNDV\RQúHPDVÕ DNA + R

.

Pürin baz modifikasyonu

Fosfodiester bag kesimi N N N N H O N H2 R N N N HN NH2 R ( 8 - alkil pürin)

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/LWHUDWU WDUDPDVÕ o \|QGH JHUoHNOHúWLULOGL $ULO UDGLNDOOHUL YH '1$ NHVLPL '1$NHVLPLQLQ|QOHQPHVLYHELWNLHNVWUDNWODUÕLOH'1$NHVLPL

gQFHNLoDOÕúPDODUGDDULOUDGLNDOOHULQLQ'1$NHVLPLQH\RODoWÕ÷ÕYHGLD]RQ\XP WX]ODUÕQÕQ ELU HOHNWURQ GRQ|U YDUOÕ÷ÕQGD '1$¶\Õ NHVWL÷L UDSRU HGLOPLúWLU86 $\QÕ

]DPDQGD ED]Õ ELWNL HNVWUDNODUÕQÕQ YH\D ELWNLOHUGHQ L]ROH HGLOHQ ELOHúLNOHULQ '1$ NHVLPLQL |QOHGL÷L \LQH ED]Õ ELWNL HNVWUDNWODUÕQÕQ YH\D ELWNLOHUGHQ L]ROH HGLOHQ ELOHúLNOHULQ &X+2 YDUOÕ÷ÕQGD '1$ NHVLPLQH \RO DoWÕ÷Õ GD \DSÕODQ OLWHUDWU oDOÕúPDVÕ

VRQXFX WHVSLW HGLOPLúWLU87 g]HOOLNOH \HQLOHELOHQ ELU NOWU PDQWDUÕ RODQ Agaricus

bisporus¶XQ SDUoDODQPD UQOHULQLQ IDUHOHUGH NDQVHURMHQ HWNL\H VDKLS ROPDVÕ YH EX

SDUoDODQPD UQOHULQGHQ ELULQLQ EHQ]HQGLD]RQ\XP L\RQX ROPDVÕ88 EL]L GH÷LúLN

diazonyumWX]ODUÕVHQWH]OH\LSEXQODUÕQ'1$NHVLPHWNLVLQLLQFHOHPH\H\|QHOWPLúWLU $\UÕFD DQWLRNVLGDQW |]HOOL÷L ELOLQHQ ELWNL HNVWUDNODUÕQÕQ ELU NÕVPÕQÕQ '1$ kesimini önlemesi antioksidant ve antimikrobiyal özellikleri belirlenen89 ED]Õ

Hypericum ve Achillea türü bitkilerin DNA kesimini önleme kapasitesine bakmaya

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Aril Radikali ve DNA Kesimi

*ULIILWKV YH $UN \DSPÕú ROGXNODUÕ oDOÕúPDGD ELU HOHNWURQ GRQ|U YDUOÕ÷ÕQGD EHQ]HQGLD]RQ\XP WHWUDIORURERUDWÕQ '1$¶\Õ NHVWL÷LQL J|VWHUPLúOHUGLU %X oDOÕúPDGD bHQ]HQGLD]RQ\XPVXGDL\Lo|]QPHVLYHSR]LWLI\NOROPDVÕQGDQGROD\Õ'1$NHVLPL LoLQJ]HOELUPRGHORODELOHFH÷LGúQOPú'LD]RQ\XPWX]ODUÕSR]LWLI\NOROGXNODUÕ LoLQ '1$ \DSÕVÕQGDNL QHJDWLI \NO IRVIDW JUXSODUÕ\OD HWNLOHúLUOHU (OHNWURQ GRQ|U YDUOÕ÷ÕQGDD]RWXQD\UÕOPDVÕ\ODDULOUDGLNDOLROXúXU$ULOUDGLNDOLGHGHRNVLULER]úHNHUGHQ KLGURMHQDWRPXNRSDUDUDN'1$NHVLPLQLJHUoHNOHúWLULU86 ùHNLO$ULOUDGLNDOLROXúXPPHNDQL]PDVÕ N N N N N N + +

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%DúND ELU oDOÕúPDGD \HQLOHELOHQ PDQWDUGD EXOXQDQ -(hidroksimetil)benzendiazonyum tuzunun (9  ROXúWXUGX÷X NDUERQ PHUNH]OL UDGLNDOLQ '1$ ED]ODUÕ YH GHRNVLULER] úHNHUL\OH PRGLILNDV\RQX oDOÕúÕOPÕúWÕU - KLGURNVLPHWLO EHQ]HQGLD]RQ\XP WX]XQXQ '1$ \DSÕVÕQGD EXOXQDQ ED]ODU LOH 1-8 SR]LV\RQXQGDQ ED÷ODQDUDN -HMP-dGuo (10) ve 8-HMP-dAdo (11  ROXúWXUGX÷XQX GHRNVLULER]úHNHULOHGHPDORQGLDOGHKLWROXúWXUGX÷XQXUDSRUHGLOPLúWLU88

(9) (10) (11)

5HV]ND YH DUN GLD]RQ\XP WX]ODUÕ 12a-d)’yi kullanarak, diazonyum ELOHúLNOHULQLQHOHNWURQGRQ|UYDUOÕ÷ÕQGDDULOUDGLNDOLQHG|QúW÷Q(35VSHNWUXPODUÕQÕ LQFHOH\HUHN EXOPXúODUGÕU %X oDOÕúPD VXOX o|]HOWLGH DULO UDGLNDOL HOGH HWPHN LoLQ DUHQGLD]RQ\XPL\RQODUÕQLQGLUJHQPHVLQLQX\JXQPHWRGROGX÷XQXJ|VWHUPLúWLU6RQXoWD EX DUDúWÕUPD ELRORMLN LQdirgeyici maddelerin ArN2+’nu parçalayarak aril radikaline

G|QúWUPH\HWHQH÷LQHVDKLSROGX÷XQXGR÷UXODU90 (12) a) X =MeO b) X = Cl c) X = Br d) X = NO2 e) X = N(Et)2 N N OH + O H N N N N H O N H2 CH2OH O HO N N N N NH2 CH2OH O X N+2 BF-4

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%DúNDELUoDOÕúPDGD'HY3$U\DYHDUNIDUNOÕLNLDULOKDONDVÕQGa diazonyum grubu içeren 1,4-ELVGLD]RQ\XP ELOHúLNOHULQLQ   EDNÕU NORUU YDUOÕ÷ÕQGD -GLUDGLNDOOHUL ROXúWXUDUDN HQHGL\HQ DQWLEL\RWLNOHUL JLEL '1$¶\Õ NHVWL÷LQL J|VWHUPLúOHUGLU91

(13)

Yine Dev P. Arya ve ark., 9-'LD]RIOXRUHQ  YH-naftal fenil diazometan (15) ELOHúLNOHULQLQ EDNÕU DVHWDW YDUOÕ÷ÕQGD RNVLMHQOL RUWDPGD S%5 SOD]PLG '1$¶\Õ NHVWL÷LQLJ|VWHUPLúOHUGLU5HDNVL\RQODUÕNDUDQOÕNWD\DSWÕNODUÕLoLQNHVLPPHNDQL]PDVÕQÕQ \D NDUERQ PHUNH]OL UDGLNDOLQ '1$ GHRNVLULER] úHNHULQGHQGHQ KLGURMHQ DWRPu NRSDUPDVÕ\OD \D GD EDNÕU  DVHWDWÕQ '1$ NHVLP HWNLVL RODQ &X , -Oksijen kompleksi YH\D KLGURNVLO UDGLNDOL JLEL DNWLI RNVLMHQ WUOHUL ROXúWXUDUDN JHUoHNOHúWL÷LQL UDSRU HWPLúOHUGLU92 (14) (15) %DúNDELUoDOÕúPDGDJHQHO\DSÕODUÕp-X-Ar+ RODQGLD]RQ\XPWX]ODUÕQGDQS-X-Ar . ROXúDELOHFHNNRúXOODUGDFW'1$\DGDKUHOHUOHHWNLOHúLPLVRQXFXJXDQLQ'1$UQOHUL ROXúWX÷XUDSRUHGLOPLúWLUp-X-Ar

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ROXúXPX(65LOHDoÕNODQPÕúWÕU93 ùHNLO$UHQGLD]RQ\XPL\RQODUÕYH'1$¶GDQHOGHHGLOHQ&-arilguanin ürünleri (X = CH3, CH2OCH3, CH2OH) H N H N O N H O O N N2 N2 H O N H N H + + + + N+2 _ N+2 X N+2 HSO4 HN N N N X H N H2

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:DUQHU YH DUN VEVWLWH WULDULODPLGOHU VHQWH]OH\HUHN EXQODUÕQ '1$ NHVLP HWNLVLQLQLQFHOHPLúOHU.HVLPHWNLVLQLQD!F!EROGX÷XQXJ|]OHPOHPLúOHU94 (16) a) Y = H b) Y = NO c) Y = OMe ùHNLO6EVWLWHWULDULODPLGOHULQ'1$¶\ÕNHVLPL

%DúND ELU oDOÕúPDGD  %XUU YH DUN ELU %HUHQLO DQDOR÷X RODQ N-(3-Hydroxypropyl)-Berenil (18  ELOHúL÷L YH -amidinobenzendiazonyum tuzunun (17) '1$ NHVLPLQL LQFHOHPLúOHU YH EX ELOHúLNOHULQ '1$¶\Õ NHVWL÷LQL J|]OHPOHPLúOHU 18) ELOHúL÷LQLQ SDUoDODQDUDN 17  ELOHúL÷LQL ROXúWXUGX÷XQX YH E|\OHFH NHVLPLQ EDúODGÕ÷ÕQÕ UDSRUHWPLúOHUGLU95

ùHNLO N-(3-Hydroxypropyl)-Berenil sentezi (17) (18) CONH O2N NHCO CO2Et Y NH2 NH2 CN O H Br N CN H NH3 N NH H3N OH H OH N H H3N N2 NH N H N N N NH3 NH3 OH + + + + MeOH/HCl /MeOH %50 + %65 %50

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.Õ]ÕO YH DUN EHQ]HQGLD]RQ\XP WHWUDIORURERUDW 19a-c  WX]ODUÕQÕ Ventezleyip '1$NHVLPLQLLQFHOHPLúOHU6RQXoRODUDNIDUNOÕGLD]RQ\XPWX]ODUÕQÕQELUHOHNWURQGRQ|U YDUOÕ÷ÕQGD '1$¶\Õ NHVWL÷LQL J|]OHPOHPLúOHU .HVLP HWNLVL LQFHOHQHQ GLD]RQ\XP WX]ODUÕQÕQ UDGLNDO DNWLYLWHOHUL YH '1$ NHVLP HWNLOHUL DUDVÕQGD DQODPOÕ ELU IDUNOÕOÕN J|]OHQPHGL÷LQLUDSRUHWPLúOHUGLU96

19 a) R = H b) R = OH c) R = CO2H

DNA Kesiminin Önlenmesi

$WWDJXLOHYHDUNKDONDUDVÕQGDoHúLWOLGHULKDVWDOÕNODUÕQÕQWHGDYLVLQGHD\UÕFDD÷UÕ kesici olarak ve antidiaretik ilaç olarak kulODQÕODQ Cistus incanus L. ve Cistus

monspeliensis /¶QLQ ELWNL HNVWUDNODUÕQÕQ DQWLRNVLGDQW YH '1$ NHVLP HWNLOHULQL

DUDúWÕUPÕúODUGÕU %X WU ELWNLOHU IODYRQRLG LoHULUOHU YH '1$ ]LQFLULQL NÕUDELOHFH÷L GúQOHQDQWLRNVLGDQWPDGGHOHUGLU%XELWNLHNVWUDNWODUÕQÕQ'1$NHVLPLQL|QOHGL÷LYH GR]DED÷OÕRODUDNUDGLNDOV|QGUPHNDSDVLWHVLROGX÷XQXJ|]OHPOHPLúOHUGLU97

<LQH EDúND ELU oDOÕúPDGD ELRIODYRQRLGOHULQ DQWLUDGLNDO DQWLRNVLGDQW YH '1$ NHVLPLQL|QOHPHNDSDVLWHVLLQFHOHQPLúWLU'R÷DOSROLIHQROLNELOHúLNOHURODn flavonoidler LQVDQODU WDUDIÕQGDQ WNHWLOHQ PH\YHOHUGH YH VHE]HOHUGH EXOXQXUODU (Q E\N ND\QDN HOPDVR÷DQGXWJLEL\L\HFHNOHUYHoD\JLELLoHFHNOHUGLU6RQXoRODUDNELRIODYRQRLGOHULQ UXWLQFDWHFKLQYHQDULQJLQ GR]DED÷OÕRODUDNVHUEHVWUDGLNDOOHULsöndürdükleri ve DNA NHVLPLQL|QOHGLNOHULUDSRUHGLOPLúWLU98

<LQH5XVVRYHDUN+LQWúLIDOÕELWNLOHULQLQDQWLUDGLNDOYH'1$NHVLPLQL|QOHPH NDSDVLWHOHULQL DUDúWÕUPÕúODUGÕU Celastrus paniculatus L., Picrorhiza kurroa L. ve

Withania somnifera L., epilepsLX\NXVX]OXN UDúLWL]PJXWYHKDVÕPVÕ]OÕNWHGDYLVLQGH NXOODQÕODQ úLIDOÕ ELWNLOHUGLU %X oDOÕúPDGD ELWNLOHULQ PHWDQRO HNVWUDNODUÕQÕQ +2O2’tin

BF4N2

R

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UV-IRWROL]LVRQXFXROXúDQ'1$KDVDUՁ]HULQGHNLHWNLVLLQFHOHQPLúWLU%WQHNVWUDNODU GR]D ED÷OÕ RODUDN VHUEHVt radikal söndürme ve DNA kesimini önleme etkisi J|VWHUPLúOHUGLUPicrorhiza kurroa/¶QLQPHWDQROHNVWUDNWÕQÕQGL÷HUELWNLHNVWUDNWODUÕQD J|UHGDKDHWNLOLROGX÷XJ|]OHQPLúWLU99

%DúND ELU oDOÕúPDGD NÕUPÕ]Õ SRUWDNDO HNVWUDNWÕQÕQ '1$ NHVLPL ]HULQH HWNLVL LQFHOHQPLú.ÕUPÕ]ÕSRUWDNDOODUIODYRQODUKLGUR[\FLQQDPLFDVLWOHUYHDVNRUELNDVLWJLEL DQWLRNVLGDQW ELOHúLNOHULQ \DQÕQGD \NVHN RUDQGD DQWURF\DQLQOHU GH LoHULUOHU (NVWUDNW '1$ NHVLPL ]HULQGH NRUX\XFX HWNL YH GR]D ED÷OÕ RODUDN GD UDGLNDO V|QGUPH kapasLWHVLJ|VWHUPLúWLU100

$FTXDYLYDYHDUN5HVYHUDWURO¶Q'1$NHVLPL]HULQGHNLHWNLVLQLLQFHOHPLúOHU 5HVYHUDWURO úDUDSWD EXOXQDQ GR÷DO SK\WRDOH[LQ PDGGHVLGLU YH GDPDU KDVWDOÕNODUÕQGD NRUX\XFXHWNLVLROGX÷XELOLQLU%XoDOÕúPDGD5HVYHUDWURO¶QGR]DED÷OÕolarak serbest UDGLNDO V|QGUPH NDSDVLWHVL YH '1$ NHVLPLQL NRUX\XFX HWNL J|VWHUGL÷L WHVSLW HGLOPLúWLU101

:DQJYHDUNDGDúODUÕ/RWXV3OXPXOHYH%ORVVRP Nelumbo nucifera Gertn.)’um DQWLRNVLGDQWHWNLVLLQFHOHQPLú/RWXVSOXPXOHoHúLWOLDONDORLGOHULoHULUYHKDONDUDVÕQGD DQWLKLSHUWDQVLI LODo RODUDN NXOODQÕOÕU /RWXV EORVVRP LVH DONRORLGOHU RUJDQLN DVLWOHU DPLQR DVLWOHU YH -carotenoidler içerir. Hidroksil radikali söndürme etkisi LQFHOHQGL÷LQGH /RWXV 3OXPXOH YH %ORVVRP¶XQ GR]D ED÷OÕ RODUDN KLGURNVLO UDGLNDlini V|QGUG÷UDSRUHGLOPLúWLU102

Yine Acquaviva ve ark., cyanidin ve cyanidin 3---D-glikozid’in DNA NHVLPLQL |QOHPH NDSDVLWHVL YH DQWLRNVLGDQW |]HOOL÷LQL LQFHOHPLúOHUGLU dDOÕúPDGD cyanidin ve cyanidin 3---D-glikozid’in DNA kesimi üzerine koruyucXHWNLVLROGX÷X YHGR]DED÷OÕVHUEHVWUDGLNDOOHULV|QGUG÷J|]OHQPLúWLU103

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(20) R = H, Cyanidin

R = Glikoz, 3---D-glikozid

Russo ve ark., Bacopa monniera/¶QÕQVHUEHVWUDGLNDOV|QGUPHNDSDVLWHVLQLYH '1$KDVDUÕQÕ|QOHPHHWNLVLQLDUDúWÕUPÕúODUGÕUBacopa monniera/NOLQLNRODUDNKDIÕ]D ND\EÕQGD HSLOHSVLGH X\NXVX]OXN SUREOHPLQGH YH D÷UÕ NHVLFL RODUDN NXOODQÕOÕU dDOÕúPDGDBacopa monniera/¶QLQPHWDQROHNVWUDNWÕNXOODQÕOPÕúWÕU'R]DED÷OÕRODUDN KLGURNVLOUDGLNDOLQLV|QGUG÷YH'1$NHVLPLQL|QOHGL÷LUDSRUHGLOPLúWLU104

Tian ve ark., aloin (21) ve aloe-emodin’in (22  NRQVDQWUDV\RQD ED÷OÕ RODUDN SURRNVLGDQW YH DQWLRNVLGDQW HWNLOHULQL LQFHOHPLúOHUGLU <NVHN NRQVDQWUDV\RQODUGD DORLQ¶LQKLGURNVLOUDGLNDOLQHED÷OÕRODQ'1$NHVimini %5-RUDQÕQGD|QOHGL÷LWDP WHUVLQH GúN NRQVDQWUDV\RQODUGD LVH NHVLPL DUWWÕUGÕ÷Õ J|]OHQPLúWLU $ORH-emodin’in GúN NRQVDQWUDV\RQODUGD oRN D] DQWLRNVLGDQW HWNL J|VWHUGL÷L \NVHN konsantrasyonlarda ise prooksidant etki göstererek DNA kesimini %29- RUDQÕQGD D]DOWWÕ÷ÕWHVSLWHGLOPLúWLU105 (21) (22) O OH OH OR OH O H + OH O OH O CH2OH O OH O OH CH2OH OH OH O H CH2OH

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%DúND ELU oDOÕúPDGD 5RRLERV oD\ÕQÕQ Aspalathus linearis) antioksidant DNWLYLWHVL YH '1$ NHVLPLQL |QOHPH NDSDVLWHVL DUDúWÕUÕOPÕúWÕU dDOÕúPDGD HWDQRO YH VX HNVWUDNWODUÕ NXOODQÕOPÕúWÕU +HP HWDQRO HNVWUDNWÕQÕQ KHP GH VX HNVWUDNWÕQÕQ SR]LWLI NRQWURORODQ7UROR[LOHKHPHQKHPHQD\QÕRUDQGDKLGURNVLOUDGLNDOLQGHQND\QDNODQDQ '1$NHVLPLQL|QOHGL÷LJ|]OHQPLúWLU106

<HQYHDUNORWXVVHHGHNVWUDNWÕQÕQDQWLRNVLGDQW|]HOOLNOHULQLYHLQVDQOHQIRVLWOHUL üzerLQGHNL '1$ NHVLP HWNLVLQL DUDúWÕUPÕúODUGÕU /RWXV VHHG¶LQ ND\QDWÕOPÕú VX HNVWUDNWÕQÕQ JoO DQWLRNVLGDQW HWNL J|VWHUGL÷L EXOXQPXúWXU 6X HNVWUDNWÕQÕQ OLSLW SHURNVLGDV\RQX YH '1$ KDVDUÕ ]HULQGH KHP KLGURMHQ SHURNVLWOL RUWDPGD KHP GH hidrojen peroksitsiz orWDPGDKLoELUHWNLVLROPDGÕ÷ÕJ|]OHQPLúWLU107

<DPDJXFKL YH DUN %UH]LO\D oDPÕ Araucaria angustifolia¶QÕQ LoHUGL÷L ELRIODYRQRLGOHULQ '1$ KDVDUÕ ]HULQGHNL NRUXPD HWNLVLQLQ LQFHOHPLúOHU Araucaria

angustifolia’da bulunan 6 tane biflavonoidi HPLC/MS ile aQDOL]HWPLúOHU'R]DED÷OÕ olarak Araucaria angustifolia¶QÕQ'1$NHVLPLQL|QOHGL÷LQLEXOPXúODUGÕU108

R1 = R2 = R3 = R4 = OH amentoflavone Mono-O-methylamentoflavone Di-O-methylamentoflavone R1 = R2 = R3 = R4 = OMe ginkgetin Tri-O-methylamentoflavone R1 = R2 = R3 = R4 = OMe tetra-O-methylamentoflavone ùHNLO%UH]LO\DoDPÕAraucaria angustifolia¶QÕQLoHUGL÷LELIODYRQRLGOHU O R OH O O R4 OH O R 1 3 2 R

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$KPDG YH DUN ELWNL ND\QDNOÕ ELU SROLIHQROLN ELOHúLN RODQ UHVYHUDWUROQ SURRNVLGDQWDNWLYLWHVLQLEDNÕUL\RQXYDUOÕ÷ÕQGDLQFHOHPLúOHU5HVYDUDWUROQDQWLNDQVHUYH NDUGL\RYDVNOHU|]HOOLNOHULQLQROPDVÕELUoRNDUDúWÕUPDFÕODUÕQEXPROHNOHRODQLOJLVLQL DUWWÕUPÕúWÕU %X oDOÕúPDGD UHVYDUDWUROQ EDNÕU L\RQX YDUOÕ÷ÕQGD SURRNVLGDQW |]HOOL÷L ROGX÷XJ|VWHULOPLúWLU5HVYHUDWUROQEDNÕUL\RQXYDUOÕ÷ÕQGDSOD]PLG'1$¶GDPXWDV\RQD VHEHSROGX÷XWHNEDúÕQDLVHELUoRN*XDQLQED]ÕQÕVLOGL÷LEHOLUOHQPLúWLU87

%LWNLOHUøOH'1$.HVLPL

%LUGR÷DOUQRODQ5HVYHUDWURO¶Q -trihidroksi-trans-stilben, 23 EDNÕU ,,  NORUU YH RNVLMHQ YDUOÕ÷ÕQGD S%5 SOD]PLG '1$¶\Õ NHVWL÷L J|VWHULOPLúWLU 'L÷HU PHWDOOHU YDUOÕ÷ÕQGD 5HVYHUDWURO¶Q '1$ NHVLPLQL EDúODWPDGÕ÷Õ için Cu+2‘nin DNA

NHVLPLQGH5HVYHUDWUROVSHVLILNPHWDOL\RQXROGX÷XUDSRUHGLOPLúWLU86

(23)

Hadi ve ark., serotoninin (24) Cu+2 varlÕ÷ÕQGD'1$NHVLPHWNLVLQLLQFHOHPLúOHU Serotonin (5-hydroxytryptamine) beyinde ve omurilikte önemli bir nörotransmitterdir; X\NX ELOLQo KX\VX]OXN YH VDOGÕUÕ NRQWUROQGH J|UHY DOÕU %X oDOÕúPDGD 6HURWLQLQ¶LQ Cu+2 YDUOÕ÷ÕQGD RNVLGDWLI PHNDQL]PD LOH '1$ NHVLPLQH VHEHS ROGX÷X EHOLUOHQPLúWLU 6HURWRQLQ&X ,, ¶\L&X , ¶LQGLUJHUYHEDNÕUL\RQXYDUOÕ÷ÕQGDKLGURNVLOUDGLNDOLROXúXU110 (24) OH OH O H Cu , O2+ 2 pH ,7 2 DNA Kesimi N H O H NH2

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8GGLQYHDUNELIODYRQRLGRODQDPHQWRIODYRQHQXQEDNÕUL\RQXYDUOÕ÷ÕQGD'1$ NHVLPLQHVHEHSROGX÷XQXUDSRUHWPLúOHUGLU. Ametoflavone Cu(II)’yi Cu(I)’ indirger ve EDNÕU L\RQX YDUOÕ÷ÕQGD KLGURNVLO UDGLNDOL ROXúXU $\UÕFD VSHNWURVNRSLN YHULOHU &X ,,  YDUOÕ÷ÕQGD DPHWRIODYRQHQXQ 25  EDNÕU L\RQXQD ED÷ODQPD NDSDVLWHVL ROGX÷XQX J|VWHUPLúWLU111

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Ma ve ark. Alangium javanicum’dan izole ettikleri Javaniside’in (26) Cu2+ YDUOÕ÷ÕQGD'1$NHVLPLQLEDúODWWÕ÷ÕQÕWHVSLWHWPLúOHUGLU112

(26)

Ma ve ark., Piper caninum¶XQKDPHNVWUDNWÕQÕQS%5SOD]PLG'1$¶\Õ&X+2

YDUOÕ÷ÕQGD NHVWL÷L EHOLUOUQPLúWLU 'DKD VRQUD HNVWUDNW IUDQNVL\RQODQGÕUÕODUDN LQ YLWUR

RODUDN'1$NHVLPHWNLOHULLQFHOHQPLúYHoWDQHDNWLIELOHúLNL]ROHHGLOPLú%XQODUN-cis-feruloyl tyramine (27), N-trans-feruloyl tyramine (28) ve 1-cinnamoylpyrrolidine’dir (29). 27-29ELOHúLNOHUL'1$NHVLPLJHUoHNOHúWLUHQPDGGHOHr LoHULVLQGH\DSÕVDORODUDN\HQLELUVÕQÕIÕWHPVLOHGHUOHU113 O O H OH O M O 2+ N H O N O O H H O O OH OH CH2OH O H

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(27) (28)

(29)

0DYHDUNEDúNDELUoDOÕúPDODUÕQGD\LQHPiper caninum’un DNA kesim etkisi gösteren bir fraksiyonundan 4,5-dioxoaporphine alkoloid cepharadione A (30 ELOHúL÷LQL izROHHWPLúOHUGLU114

(30)

Yine Ma ve ark., Malotus resinosus¶XQN|NOHULQGHQKD]ÕUODGÕNODUÕKDPHNVWUDNWÕQ Cu+2YDUOÕ÷ÕQGD'1$NHVLPHWNLVLROGX÷XQXEHOLUOHPLúOHU'DKDVRQUD'1$NHVLPLQLQ basit bir coumarin olan scopoletin (31a  ELOHúL÷LQGHQ ND\QDNODQGÕ÷ÕQÕ UDSRU HWPLúOHU S%5SOD]PLG'1$NXOODQDUDNNHVLPHWNLVLQLLQYLWURRODUDNJ|]OHPOHPLúOHU 31a) ELOHúL÷LQLQ GDKD DNWLI RODFD÷ÕQÕ GúQGNOHUL o DQDOR÷XQXQ GD '1$ NHVLP HWNLVLQL LQFHOHPLúOHU'1$NHVLPHWNLOHULQLQ31c>31a=31b>31dROGX÷XQXUDSRUHWPLúOHUGLU115 N H O OH O H MeO O H MeO N H O OH N O O O N O O

(43)

(31) a) R1 = CH3 R2 = H b) R1 = H R2 = CH3 c) R1 = H R2 = H d) R1 = CH3 R2 = CH3 O O R1O R2O

(44)

3. MATERYAL VE METOT 3. 1. Materyal

%X oDOÕúPDQÕQ PDWHU\DOLQL ROXúWXUDQ ELWNL |UQHNOeri Dicle Üniversitesi, Fen (GHEL\DW )DNOWHVL %L\RORML %|OP¶QGHQ 3URI 'U $ 6HOoXN (57(.ø1 WDUDIÕQGDQ WRSODQGÕYHWHúKLVHGLOGL7HúKLVHGLOHQELWNL|UQHNOHUL'LFOHhQLYHUVLWHVL)HQ(GHEL\DW )DNOWHVL+HUEDU\XPXQGD '8) VDNODQPDNWDGÕU

3. 1. 1. KXOODQÕODQ%LWNL7UOHUL7DQÕPODUÕ<D\ÕOÕúODUÕYH.XOODQÕP$ODQODUÕ

Hypericum retusum, 'L\DUEDNÕU dQJú dHUPLN-dQJú  NP WDUOD

NHQDUÕQGDQWDULKLQGHWRSODQGÕ1R'8)

Hypericum scabrum, 'L\DUEDNÕU (UJDQL (UJDQL 0DGHQ  NP \DPDoODUdan

WDULKLQGHWRSODQGÕ1R'8)

Hypericum lysimachioides, 'L\DUEDNÕU (UJDQL (UJDQL-Çermik 11 km,

\DPDoODUGDQWDULKLQGHWRSODQGÕ1R'8)

Achillea aleppica subsp. aleppica,'L\DUEDNÕU'L\DUEDNÕU-Silvan 38 km, yol NHQDUÕQGDQWDULKLQGHWRSODQGÕ1R'8)

Achillea aleppica subsp. zederbaueri,

0DUGLQ0D]ÕGD÷Õ<XNDUÕ.RQDNN|\-NP\DPDoODUGDQWDULKLQGHWRSODQGÕ1R'8)

Achillea biebersteinii 'L\DUEDNÕU 'L\DUEDNÕU-6LYHUHN  NP \RO NHQDUÕndan

WDULKLQGHWRSODQGÕ1R'8)

Hypericum WUOHUL oRN \ÕOOÕN RWVX ELWNLOHUGLU hONHPL]GH  WU EXOXQDQ Hypericum¶XQ  WU *QH\GR÷X $QDGROX %|OJHVLQGH \D\ÕOÕú J|VWHUPHNWHGLUOHU

.DQWDURQ NDQWDUXP NR\XQNÕUDQ YH ELQELUGHOLN RWX RODUDN bilinirler. Geleneksel WHGDYLGH \DSUDNOÕ oLoHNOL YH PH\YHOL GDOODUÕ LOH N|NOHUL NXOODQÕOÕU 0LGH UDKDWVÕ]OÕNODUÕQGDLQIODPDV\RQGDYHGHSUHV\RQWHGDYLVLQGHNXOODQÕOÕUODU116 Hypericum

WUOHULIODYRQRLGOHUYHWHPHO\D÷DVLWOHULLoHULUOHU

Achillea türleri oRN\ÕOOÕNW\VYHRWVXELWNLOHUGLUhONHPL]GHWUEXOXQXUYH

EXQODUGDQ  WU *QH\GR÷X $QDGROX %|OJHVLQGH \D\ÕOÕú J|VWHUPHNWHGLUOHU &LYDQSHUoHPLDNEDúOÕEDUVDPRWXELQELU\DSUDNRWXPDUVDPRWXNDQGLOoLoH÷LRODUDN bilinirler. Geleneksel tedaviGH UDKLP KDVWDOÕNODUÕQGD LGUDU V|NWUF YH LúWDK DoÕFÕ

(45)

RODUDNNXOODQÕOÕUODU116 Achillea türleri eucalyptol, camphor ve .-terpineoller içerirler.

.XOODQÕODQ.LP\DVDO0DGGHOHU

2,3-dimetil anilin, 2,6-dimetil anilin, 2,6-dietil anilin, 2-etil anilin, 3-etil anilin, 4-etil anilin, 2-kloro, 4-nitro anilin, 4-kloro, 2-nitro anilin, 2-anilin etanol, 4-hidroksi metil anilin, izoamil nitrit Fluka’dan, aseton Riedell’den, etanol Merck’ten, dietil eter, floro borik asit Aldrich’den, agaroz, etilendiamin tetraasetik asit (EDTA  EDNÕU ,  NORUU EDNÕU ,,  NORUU VRG\XP L\RGU DVNRUELN DVLW 6LJPD¶GDQ WLFDUL RODUDN WHPLQ edildi.

.XOODQÕODQ$OHWOHU

Jel görüntüleme sistemi (Bio Rad Gel Doc XR), elektroforez (Bio Rad), güç ND\QD÷Õ :HDOWHF  105 %UXNHU  0+]  )7–IR (Mattson 1000 FTIR UNICAM Spectrometer), UV Spektrofotometre (Shimadzu, UV/Visible Recording spektrofotometre), santrifüj (Centruin 8000 Series), vorteks (Heidolph), sterilizatör +HUDHXV RWRNODYoDONDOD\ÕFÕ 0HPPHUW WHUD]LS+PHWUH 0HWWOHU7ROHGo), vakumlu evaporatör (RE 100B, Bibby Strilin Ltd.), membran filtresi (Schleicher&Schuell), EOHQGHUGHULQGRQGXUXFX 6DQ\R PLNURGDOJDIÕUÕQYHEX]GRODEÕ $UoHOLN NXOODQÕOGÕ

3. 2. Metot

3. 2. 1. Agaroz Jel Elektroforezi

Moleküllerin sahip olduklaUÕQHWHOHNWULN\NOHULEXPROHNOOHULQELUHOHNWULNVHO DODQLoLQGHNLKDUHNHWOHULQLHWNLOHU(OHNWURIRUH]WHNQL÷LGHEXSUHQVLEHGD\DQÕU1NOHLN DVLWIUDJPHQWOHULQLQWDQÕPODQPDVÕVDIODúWÕUÕOPDVÕYHD\UÕOPDVÕLoLQNXOODQÕODQHQ\D\JÕQ yöntem agaroz jel eOHNWURIRUH]LGLU%XQHGHQOHoHúLWOLDPDoODULoLQL]ROHHGLOHQ'1$YH 51$¶ODUÕQWDQÕPODQDELOPHVLKDQJLIRUPGDROGX÷XQXQEHOLUOHQHELOPHVLE\NO÷QQ VDSWDQDELOPHVL YH |]HOOLNOH JHQHWLN PKHQGLVOL÷L WHNQLNOHUL LOH '1$ \DSÕVÕQGD ROXúWXUXODQ GH÷LúLNOLNOHUGHQ VRQUD HOGH HGLOHQ \HQL IRUPODUÕQ LQFHOHQPHVL \|QQGHQ

(46)

DJDUR]MHOHOHNWURIRUH]LWHNQL÷LPROHNOHUJHQHWLNDODQÕQGD|QHPOLELUGHQH\VHOVLVWHP ROXúWXUPDNWDGÕU

Agaroz jelde örnekler yatay pozisyonda, sabit güç ve yöndeki elektriksel alanda yürütülmektedir '1$ úHNHU IRVIDW RPXUJDVÕQGDQ GROD\Õ QHJDWLI \NOGU YH ELU HOHNWULNVHO DODQD NRQXOGX÷X ]DPDQ EX QHJDWLI \NQGHQ GROD\Õ DQRWWDQ NDWRGD GR÷UX hareket eder.

$JDUR]-HO¶LQ+D]ÕUODQPDVÕ

Agaroz (1 g) 100 mL Tris asetat tamponuna (40 mM tris asetat, 1mM EDTA, S+   LODYH HGLOGL YH PLNURGDOJD IÕUÕQGD ND\QDWÕOGÕ o& µ\H VR÷XWXOGX  —O

HWLG\XPEURPU PJP/ LODYHHGLOGLYHNDUÕúWÕUÕOGÕd|]HOWLNHQDUODUÕRWRNODYEDQGÕ LOH VDUÕOPÕú YH WDUDN \HUOHúWLULOPLú FDP WDEDND\D G|NOG -HO GRQPDVÕ LoLQ RGD VÕFDNOÕ÷ÕQGD-45 dakika bekletildi.

$JDUR]-HO(OHNWURIRUH]L<DSÕOPDVÕ -HONXOODQÕPDKD]ÕUKDOHJHOGLNWHQVRQUDRWRNODYEDQGÕDoÕOGÕYHWDUDNoÕNDUÕOGÕ +D]ÕUODQDQ'1$NDUÕúÕPODUÕX\JXQELUSLSHWLOHNX\XFXNODUDDNWDUÕOGÕ-HO00 mL Tris DVHWDWWRPSRQX P0WULVDVHWDWP0('7$S+ LoHUHQHOHNWURIRUH]WDQNÕQD \HUOHúWLULOGL7DQNÕQNDSD÷ÕNDSDWÕOGÕYHHOHNWULNED÷ODQWÕODUÕ\DSÕOGÕ(OHNWURIRUH] 9¶WDP$DNÕPX\JXODQDUDNGDNLNDVUH\OH\UWOG(OHNWULNDNÕPÕNesildi, tel ED÷ODQWÕODUÕYHNDSDNoÕNDUÕOGÕ'DKDVRQUDMHOLQIRWR÷UDIÕoHNLOGL 3OD]PLG6DIODúWÕUPD

DNA kesiminin incelemenin bir yolu VXSHUFRLOHG '1$¶QÕQ  VSHU NÕYUÕPOÕ oHPEHUVHO'1$NÕUÕN\RN)RUP, RSHQFLUFXODU WHN]LQFLUNÕUÕ÷ÕLoeren çembersel '1$'1$]LQFLUOHULQGHQELULQGHNÕUÕNYDU)RUP,, YH\DOLQHDU GR÷UXVDO'1$LNL ]LQFLUGH GH ELU YH\D ELUGHQ ID]OD NÕUÕN )RUP ,,,  IRUPD G|QúPQ LQFHOHPHNWLU $JDUR] -HO (OHNWURIRUH]LQGH EX IRUPODU IDUNOÕ KÕ]ODUOD KDUHNHW HGHUOHU )RUP I, yük \R÷XQOX÷XID]OD KDFPL GH GúNROGX÷XLoLQ MHOGH HQ KÕ]OÕ KDUHNHW HGHU)RUP,,¶QLQ

(47)

\R÷XQOX÷XGDKDD]ROGX÷XLoLQGDKD\DYDúKDUHNHWHGHU)RUP,,,LVH)RUP,YH)RUP ,,¶QLQDUDVÕQGDELUKÕ]DVDKLSWLU ùHNLO

dDOÕúPDGD NXOODQÕODQ S%OXHVFULSW 0 SOD]PLG '1$¶VÕ  NE  7(16 \|QWHPLYH4LDJHQHSOD]PLGNLWLNXOODQÕODUDNVDIODúWÕUÕOGÕ

Form I Form II Form III

ùHNLO Plazmid DNA

3. 2. 2. 1. TENS Yöntemi

37 0C’ de Ampisilinli Louria Bertani (2.5g Tripton,1.25 g yeast extract, 2.5 g VRG\XP NORUU  J DPSLVLOLQ  P/ VDI VX  VÕYÕ EHVL\HULQGH UHWLOHQ EDNWHUL NOWUQGHQ  WDQH (SSHQGRUI WSH ¶HU  P/ DOÕQGÕ  USP¶GH  GDNLND VDQWULIMOHQGLVWVÕYÕODUX]DNODúWÕUÕOGÕ+HUELUWSH/7(16çözeltisi (100 mL‘de: P/07ULV&OS+0/('7$S+J1D&OJ1D2+  eklendi ve ters düz edildi. 150 / VRG\XP DVHWDW çözeltisi (3 M pH 5.2) eklendi ve NDUÕúWÕUÕOGÕ2GDVÕFDNOÕ÷ÕQGDGDNLNDLQNEDV\RQDEÕUDNÕOGÕGDNLNDUSP¶GH santrifM\DSÕOGÕ6SHUQDWDQWWHPL]ELUWSHDNWDUÕOGՁ]HULQHP/VR÷XNPXWODNHWLO alkol ilave edildi. -200&¶GHGDNLNDLQNEDV\RQDEÕUDNÕOGÕ'DKDVRQUDUSP¶GH GDNLNDVDQWULIM\DSÕOGÕ(WLODONROX]DNODúWÕUÕOGÕSHOOHW¶OLNHWLODONROLOH\ÕNDQGÕ USP¶GHGDNLNDVDQWULIM\DSÕOGÕNWDQVRQUDDONROX]DNODúWÕUÕOGÕ(WYGH0C’ GHDONROXQNDODQNÕVPÕX]DNODúWÕUÕOGÕYH/7(WDPSRQXLODYHHGLOGL+HUELUWüpe NRQVDQWUDV\RQJP/RODFDNúHNLOGHULERQNOHD]o|]HOWLVLLODYHHGLOGL Form II Form III Form I

(48)

3. 2. 2. 2. Mini Prep

S%OXHVFULSW 0 SOD]PLG '1$¶ VÕ 4LDJHQH SOD]PLG NLWL NXOODQÕODUDN VDIODúWÕUÕOGÕ96

S%OXHVFULSW0SOD]PLG'1$¶QÕQVDIOÕ÷ÕQDKHPHOHNWURIRUH]KHPGH 89 VSHNWURVNRSLVLQGH  QP DEVRUEDQVODUÕQÕQ RUDQÕ |OoOHUHN EDNÕOGÕ '1A NRQVDQWUDV\RQXQPDEVRUEDQV|OoPLOHKHVDSODQGÕ JP/Lçin A260=1.0)

'LD]RQ\XP7X]ODUÕQÕQ6HQWH]OHQPHVL

<HQLOHELOLQLUELUNOWUPDQWDUÕRODQAgaricus bisporusKLGUD]LQ\DSÕVÕQDVDKLS DJDULWLQH −Ν−[γ−L(+)-glutamil)]-4-hidroksimetilfenilhidrazin ve bunun parçalanma ürünlerini içermektedir. Agaricus bisporus’un parçalanma ürünlerinin farelerde NDQVHURMHQHWNL\HVDKLSROPDVÕYHEXSDUoDODQPDUQOHULQGHQELULQLQEHQ]HQGLD]RQ\XP L\RQXROPDVÕ87 D\UÕFD\HQLOHPH\HQELUPDQWDURODQAgaricus xanthodermus\DSÕVÕQGD p-KLGURNVLEHQ]HQGLD]RQ\XPL\RQXEXOXQPDVÕ117EL]LIDUNOÕVEVWLWHGLD]RQ\XPWX]ODUÕ VHQWH]OH\LSEXQODUÕQ'1$NHVLPHWNLVLQLLQFHOHPH\H\|QHOWWL *HQHOGHGLD]RQ\XPWX]ODUÕNORUWX]ODUÕRODUDNKD]ÕUODQÕUODUIDNDWWHWUDIORURERUDW WX]ODUÕNORUWX]ODUÕQDRUDQODGDKDNDUDUOÕROGX÷XLoLQEXoDOÕúPDGDGLD]RQ\XPWX]ODUÕ tetrafloroborat tuzu olarak sentezlendi.

2,3-Dimetil benzendiazonyum tetrafloroborat (32), 2,6-Dimetil benzendiazonyum tetrafloroborat (33), 2,6-Dietil benzendiazonyum tetrafloroborat (34), 2-Etil benzendiazonyum tetrafloroborat (35), 3-Etil benzendiazonyum tetrafloroborat (36),4-Etil benzendiazonyum tetrafloroborat (37), 2-Kloro, 4-nitrobenzen diazonyum tetrafloroborat (38), 4-Kloro, nitrobenzen diazonyum tetrafloroborat (39), 2-Hidroksietil benzendiazonyum tetrafloro borat (40), 4-Hidroksimetil benzen diazonyum tetrafloroborat tuzu (41) bilinen yöntemlerle sentezlendi.89,96

(49)

.XOODQÕODQNLP\DVDOODUYHNRúXOODU øVRDP\OQLWULW+%)4 (aq.), EtOH, 0o C, 30 dakika

ùHNLO'LD]RQ\XPWX]ODUÕQÕQVHQWH]L

2,3-Dimetil benzendiazonyum tetrafloroborat (32)

2,3-Dimetil anilin (0.25 mL, 0.25 g, 2.06 mmol, 1.0 eq) etanol (1 mL) içinde çözüldü. Üzerine sulu floro borik asit (%48’lik çözelti; 0.46 mL, 0.54g, 6.19 mmol, 3.0 HT LODYHHGLOGLYHNDUÕúÕP-5 o

&µ\HVR÷XWXOGX.DUÕúÕPDLVRDPLOQLWULW P/J PPROHT GDPODGDPODLODYHHGLOGLYHGDNLNDNDUÕúWÕUÕOGÕ'LHWLO eter (30 mL) ilavesiyle 2,3-GLPHWLO EHQ]HQGLD]RQ\XP WHWUDIORURERUDW NDWÕ RODUDN o|NWUOG d|NWUOHQNDWÕV]OHUHND]PLNWDUGDVR÷XNDVHWRQGD aP/ o|]OSVR÷XNHWHU  P/ LODYHHGLOHUHNEH\D]NULVWDOOHUKDOLQGHVDIODúWÕUÕOGÕ JPPRO% 74). e.n. 69-71 oC νmax (KBr)/cm-1 3043, 2932, 2264, 1609, 1562, 1094, 812; 1H NMR (400Mz, CD3COCD3) δ 7.12 (1H, dd, J 8.2, 1.1 Hz, ArH), 7.05 (1H, ddd, J 8.0, ,8.0, 1.1 Hz, ArH), 6.9 (1H, dd, J 8.2, 1.1 Hz, ArH), 2.28 (3H, s, CH3), 2.16 (3H, s, CH3); 13C NMR (100Mz, CD3COCD3) δ 9.7 (q), 18.6 (q), 112.2 (d), 122.9 (d), 125.2 (d), 139.1 (s), 159.9 (s), 162.3 (s) N+ -2 BF4 NH2 N2 BF4 R R -+

(50)

2,6-Dimetil benzendiazonyum tetrafloroborat (33)

2,6-Dimetil anilin (0.26 mL, 0.25 g, 2.06 mmol, 1.0 eq) etanol (1 mL) içinde çözüldü. Üzerine sulu floro borik asit (%48’lik çözelti; 0.46 mL, 0.54 g, 6.19 mmol, 3.0 HT LODYHHGLOGLYHNDUÕúÕP-5 o&µ\HVR÷XWXOGX.DUÕúÕPDLVRDPLOQLWULW P/J

PPROHT GDPODGDPODLODYHHGLOGLYHGDNLNDNDUÕúWÕUÕOGÕ'LHWLOHWHU  mL) ilavesiyle 2,6-GLPHWLO EHQ]HQGLD]RQ\XP WHWUDIORURERUDW NDWÕ RODUDN o|NWUOG d|NWUOHQNDWÕV]OHUHND]PLNWDUGDVR÷XNDVHWRQGD aP/ o|]OSVR÷XNHWHU  P/ LODYHHGLOHUHNEH\D]NULVWDOOHUKDOLQGHVDIODúWÕUÕOGÕ JPPRO HQ 86-87 oC νmax (KBr)/cm-1 3063, 2932, 2257, 1610, 1584, 1080, 822; 1H NMR (400Mz, CD3COCD3) δ 7.06 (1H, ddd, J = 8.0, 8.0, 1.2 Hz, ArH), 6.6 (2H, dd, J = 8.3, 1.5, ArH), 2.9 (6H, s, CH3); 13C NMR (100Mz, CD3COCD3) δ 15.6 (q), 119.4 (d), 123.6 (d), 128.2 (s), 129.5 (s).

2,6-Dietil benzendiazonyum tetrafloroborat (34)

2,6-Dietil anilin (0.26 mL, 0.25 g, 2.06 mmol, 1.0 eq) etanol (1 mL) içinde çözüldü. Üzerine sulu floro borik asit (%48’lik çözelti; 0.37 mL, 0.441g, 5.03 mmol, 3.0 HT LODYHHGLOGLYHNDUÕúÕP-5 o&µ\HVR÷XWXOGX.DUÕúÕPDLVRDPLOQLWULW P/

N2 BF4 +

-N2 BF4 +

(51)

-JPPROHT GDPODGDPODLODYHHGLOGLYHGDNLNDNDUÕúWÕUÕOGÕ'LHWLOHWHU  mL) ilavesiyle 2,6-GLHWLO EHQ]HQGLD]RQ\XP WHWUDIORURERUDW NDWÕ RODUDN o|NWUOG d|NWUOHQNDWÕV]OHUHND]PLNWDUGDVR÷XNDVHWRQGD aP/ o|]OSVR÷XNHWHU  P/ LODYHHGLOHUHNEH\D]NULVWDOOHUKDOLQGHVDIODúWÕUÕOGÕ JPPRO HQ 99-101 oC νmax (KBr)/cm-1 3063, 2932, 2251, 1630, 1576, 1086, 816; ; 1H NMR (400Mz, CD3COCD3) δ 7.06 (1H, ddd, J = 8.0, 8.0, 1.2 Hz, ArH), 6.9 (2H, dd, J = 8.3, 1.5, ArH), 2.9 (4H, m, CH2), 2.6 (4H, m, CH3); 13C NMR (100Mz, CD3COCD3) δ 13.5 (q), 15.6 (q), 119.4 (d), 123.6 (d), 128.2 (s) 128.9 (s).

2-Etil benzendiazonyum tetrafloroborat (35)

2-Etil anilin (0.26 mL, 0.25 g, 2.06 mmol, 1.0 eq) etanol (1 mL) içinde çözüldü. Üzerine sulu floro borik asit (%48’lik çözelti; 0.46 mL, 0.54 g, 6.19 mmol, 3.0 eq) ilave HGLOGLYHNDUÕúÕP-5 o&µ\HVR÷XWXOGX.DUÕúÕPDLVRDPLOQLWULW P/J

mmol, 1.2 eT GDPODGDPODLODYHHGLOGLYHGDNLNDNDUÕúWÕUÕOGÕ'LHWLOHWHU P/  ilavesiyle 2-HWLO EHQ]HQGLD]RQ\XP WHWUDIORURERUDW NDWÕ RODUDN o|NWUOG d|NWUOHQ NDWÕV]OHUHND]PLNWDUGDVR÷XNDVHWRQGD aP/ o|]OSVR÷XNHWHU P/ LODYH HGLOHUHNDoÕNPDYLNULVWDOOHUKDOLQGHVDIODúWÕUÕOGÕ JPPRO HQ-74 oC

νmax (KBr)/cm-1 2978, 2937, 2264, 1641, 1562, 1094, 776; 1H NMR (400Mz,

CD3COCD3) δ 9.5 (1H, dd, J 8.3, 1.5 Hz, ArH), 9.3 (1H, ddd, J 8.1, 8.1, 1.6 Hz, ArH),

9.2 (1H, dd, J 8.2, 1.1 Hz, ArH), 9.0 (1H, ddd, J 8.0, 8.0, 1.2 Hz, ArH), 3.4 (2H, m,

N2 BF4 +

(52)

-CH2CH3) 1.6 (3H, t, J 4.8 CH2CH3); 13C NMR (100Mz, CD3COCD3) δ 13.7 (q), 22.9

(t), 114.7 (d), 119.5 (d), 126.6 (d), 129.1 (d), 130.2 (s), 209.0 (s).

3-Etilbenzen diazonyum tetrafloroborat (36)

3-Etil anilin (0.26 mL, 0.25 g, 2.06 mmol, 1.0 eq) etanol (1 mL) içinde çözüldü. Üzerine sulu floro borik asit (%48’lik çözelti; 0.46 mL, 0.54 g, 6.19 mmol, 3.0 eq) ilave HGLOGLYHNDUÕúÕP-5 o&µ\HVR÷XWXOGX.DUÕúÕPDLVRDPLOQLWULW P/ g, 2.47

PPROHT GDPODGDPODLODYHHGLOGLYHGDNLNDNDUÕúWÕUÕOGÕ'LHWLOHWHU P/  ilavesiyle 3-HWLO EHQ]HQGLD]RQ\XP WHWUDIORURERUDW NDWÕ RODUDN o|NWUOG d|NWUOHQ NDWÕV]OHUHND]PLNWDUGDVR÷XNDVHWRQGD aP/ o|]OSVR÷XNHWHU P/) ilave HGLOHUHNSHPEHNULVWDOOHUKDOLQGHVDIODúWÕUÕOGÕ JPPRO HQ-70 oC

νmax (KBr)/cm-1 2970, 2932, 2270, 1642, 1470, 1080, 803; 1H NMR (400Mz,

CD3COCD3) δ 8.8 (1H, dd, J 8.3, 1.5 Hz, ArH), 8.7 (1H, ddd, J 8.1, 8.1, 1.6 Hz, ArH),

7.2 (1H, dd, J 8.2, 1.1 Hz, ArH), 6.9 (1H, ddd, J 8.0, 8.0, 1.2 Hz, ArH), 2.9 (1H, s, J 7.5, ArH) 2.6 (2H, m, CH2CH3) 1.2 (3H, t, J 4.8 CH2CH3); 13C NMR (100Mz, CD3COCD3) δ 14.0 (q) 15.1 (t), 112.4 (d), 114.6 (d), 186.9 (d), 129.2 (d), 145.7 (s), 157.3 (s). N2 BF4 +

(53)

-4-Etil benzendiazonyum tetrafloroborat (37)

4-Etil anilin (0.26 mL, 0.25 g, 2.06 mmol, 1.0 eq) etanol (1 mL) içinde çözüldü. Üzerine sulu floro borik asit (%48’lik çözelti; 0.46 mL, 0.54 g, 6.19 mmol, 3.0 eq) ilave HGLOGLYHNDUÕúÕP-5 o

&µ\HVR÷XWXOGX.DUÕúÕPDLVRDPLOQLWULW P/J PPROHT GDPODGDPODLODYHHGLOGLYHGDNLNDNDUÕúWÕUÕOGÕ'LHWLOHWHU P/  ilavesiyle 4-HWLO EHQ]HQGLD]RQ\XP WHWUDIORURERUDW NDWÕ RODUDN o|NWUOG d|NWUOHQ NDWÕV]OHUHND]PLNWDUGDVR÷XNDVHWRQGD aP/ o|]OSVR÷XNHWHU P/ LODYH HGLOHUHNVDUÕNULVWDOOHUKDOLQGHVDIODúWÕUÕOGÕ JPPRO HQ-88 o C νmax (KBr)/cm-1 2978, 2932, 2264, 1641, 1584, 1086, 849; 1H NMR (400Mz, CD3COCD3) δ 7.8 (2H, dd, J 8.3, 1.5 Hz, ArH), 7.5 (2H, dd, J 8.1, 1.5 Hz, ArH), 3.0 (2H, m, CH2CH3) 1.3 (3H, t, J 4.8, CH2CH3 ); 13C NMR (100Mz, CD3COCD3) δ 13.9 (q),105.0 (t), 111.7 (s) 131. (d), 133.0 (d), 160.7 (s).

2-Kloro, 4-nitrobenzen diazonyum tetrafloroborat (38)

2-Kloro, 4-nitro anilin (0.25 g, 1.45 mmol, 1.0 eq) etanol (1 mL) içinde çözüldü. Üzerine sulu floro borik asit (%48’lik çözelti; 0.32 mL, 0.382 g, 4.35 mmol, 3.0 eq) LODYHHGLOGLYHNDUÕúÕP-5 o&µ\HVR÷XWXOGX.DUÕúÕPDLVRDPLOQLWULW P/J N2 BF4 Cl NO2 + -N2 BF4 +

(54)

-1.74 mmol, 1.2 eq) damlDGDPODLODYHHGLOGLYHGDNLNDNDUÕúWÕUÕOGÕ'LHWLOHWHU  mL) ilavesiyle 2-kloro, 4-QLWUREHQ]HQGLD]RQ\XPWHWUDIORURERUDWNDWÕRODUDNo|NWUOG d|NWUOHQNDWÕV]OHUHND]PLNWDUGDVR÷XNDVHWRQGD aP/ o|]OSVR÷XNHWHU  mL) ilave edilerek EH\D]NULVWDOOHUKDOLQGHVDIODúWÕUÕOGÕ JPPRO HQ 162-163 oC νmax (KBr)/cm-1 3063, 2991, 2276, 1641, 1562, 1080, 843; 1H NMR

(400Mz, CD3COCD3) δ 9.27 (1H, dd, J 8.3, 1.5 Hz, ArH), 9.01 (1H, dd, J 8.3, 1.5 Hz,

ArH), 8.82 (1H, s, ArH); 13C NMR (100Mz, CD3COCD3) δ 121.78 (s), 124.88 (s),

127.33 (d), 136.88 (d), 138.52 (d), 154.48 (s).

4-Kloro, 2-nitro benzendiazonyum tetrafloroborat (39)

4-Kloro, 2-nitro anilin (0.25 g, 1.45 mmol, 1.0 eq) etanol (1 mL) içinde çözüldü. Üzerine sulu floro borik asit (%48’lik çözelti; 0.32 mL, 0.382 g, 4.35 mmol, 3.0 eq) LODYHHGLOGLYHNDUÕúÕP-5 o&µ\HVR÷XWXOGX.DUÕúÕPDLVRDPLOQLWUDW P/J

PPROHT GDPODGDPODLODYHHGLOGLYHGDNLNDNDUÕúWÕUÕOGÕ'LHWLOHWHU  mL) ilavesiyle 4-kloro, 2-QLWUREHQ]HQGLD]RQ\XPWHWUDIORURERUDWNDWÕRODUDNo|NWUOG d|NWUOHQNDWÕV]OHUHND]PLNWDUGDVR÷XNDVHWRQGD aP/ o|]OSVR÷XNHWHU  P/ LODYHHGLOHUHNEH\D]NULVWDOOHUKDOLQGHVDIODúWÕUÕOGÕ JPPRO HQ 125-127 oC νmax (KBr)/cm-1 3063, 2967, 2284, 1649, 1562, 1344, 1173, 849; 1H NMR

(400Mz, CD3COCD3) δ 9.2 (1H, dd, J 8.3, 1.5 Hz, ArH), 8.7 (1H, dd, J 8.3, 1.5 Hz,

ArH), 7.4 (1H, s, ArH); 13C NMR (100Mz, CD3COCD3) δ 118.6 (s), 124.9 (s), 129.01

(d), 136.88 (d), 137.96 (d), 149.64 (s).

N2 BF4

Cl

NO2 +

(55)

-2-Hidroksietil benzendiazonyum tetrafloro borat (40)

4-Anilin etanol (0.25 g, 1.82 mmol, 1.0 eq) etanol (1 mL) içinde çözüldü. Üzerine sulu floro borik asit (%48’lik çözelti; 0.41 mL, 0.480 g, 5.47 mmol, 3.0 eq) ilave edilGLYHNDUÕúÕP-5 o&µ\HVR÷XWXOGX.DUÕúÕPDLVRDPLOQLWULW P/J

PPROHT GDPODGDPODLODYHHGLOGLYHGDNLNDNDUÕúWÕUÕOGÕ'LHWLOHWHU  mL) ilavesiyle 2-KLGURNVLHWLO EHQ]HQGLD]RQ\XP WHWUDIORURERUDW NDWÕ RODUDNo|NWUOG ÇöktüUOHQNDWÕV]OHUHND]PLNWDUGDVR÷XNDVHWRQGD aP/ o|]OSVR÷XNHWHU  P/ LODYHHGLOHUHN\HúLONULVWDOOHUKDOLQGHVDIODúWÕUÕOGÕ JPPRO HQ 118-120 oC νmax (KBr)/cm-1 2924, 2507, 2264, 1603, 1497, 1067, 756; 1H NMR

(400Mz, CD3COCD3) δ 7.9 (1H, dd, J 8.3, 1.5 Hz, ArH), 7.7 (1H, ddd, J 8.1, 8.1, 1.6

Hz, ArH), 7.6 (1H, dd, J 8.2, 1.1 Hz, ArH), 7.5 (1H, ddd, J 8.0, 8.0, 1.2 Hz, ArH), 3.9 (2H, t, J 4.8 CH2CH2OH) 3.48 (2H, m, J 4.8 CH2CH2OH), 1.13 (1H, t, CH2OH ); 13C NMR (100Mz, CD3COCD3) δ 54.86 (t), 55.9 (t), 57.1 (s), 60.9 (d), 123.25 (d), 130.5 (d), 134.95 (d), 141.02 (s). N2 BF4 OH +

Şekil

Tablo 1. 1.  *HQHWRNVLN ;HQRELRWLNOHUGHQ ROXúDQ NDUERQ PHUNH]OL VHUEHVW UDGLNDO metabolitleri.

Tablo 1.

1. *HQHWRNVLN ;HQRELRWLNOHUGHQ ROXúDQ NDUERQ PHUNH]OL VHUEHVW UDGLNDO metabolitleri. p.31
Tablo 4. 1.  S%OXHVFULSW 0 SOD]PLG '1$¶QÕQ  NE EDNÕU , NORUU DVNRUELNDVLWYHVRG\XPL\RGUYDUOÕ÷ÕQGDGLD]RQ\XPWX]X32) ile supercoiled formdan  )RUP,RSHQFLUFXODUIRUPD)RUP,,G|QúP

Tablo 4.

1. S%OXHVFULSW 0 SOD]PLG '1$¶QÕQ  NE  EDNÕU ,  NORUU DVNRUELNDVLWYHVRG\XPL\RGUYDUOÕ÷ÕQGDGLD]RQ\XPWX]X 32) ile supercoiled formdan )RUP, RSHQFLUFXODUIRUPD )RUP,, G|QúP p.61
Tablo 4. 2.  S%OXHVFULSW 0 SOD]PLG '1$¶QÕQ  NE EDNÕU , NORUU YDUOÕ÷ÕQGDGLD]RQ\XPWX]X 32), (33) ve (34) ile supercoiled formdan (Form I), open  FLUFXODUIRUPD)RUP,,G|QúP

Tablo 4.

2. S%OXHVFULSW 0 SOD]PLG '1$¶QÕQ  NE  EDNÕU ,  NORUU YDUOÕ÷ÕQGDGLD]RQ\XPWX]X 32), (33) ve (34) ile supercoiled formdan (Form I), open FLUFXODUIRUPD )RUP,, G|QúP p.63
Tablo 4. 3.  S%OXHVFULSW 0 SOD]PLG '1$¶QÕQ  NE EDNÕU , NORUU YDUOÕ÷Õnda diazonyum tuzu (35), (36) ve (37) ile supercoiled formdan (Form I), open  FLUFXODUIRUPD)RUP,,YH\DOLQHDUIRUPDIRUP,,,G|QúP

Tablo 4.

3. S%OXHVFULSW 0 SOD]PLG '1$¶QÕQ  NE  EDNÕU ,  NORUU YDUOÕ÷Õnda diazonyum tuzu (35), (36) ve (37) ile supercoiled formdan (Form I), open FLUFXODUIRUPD )RUP,, YH\DOLQHDUIRUPD IRUP,,, G|QúP p.65
Tablo 4. 4.  S%OXHVFULSW 0 SOD]PLG '1$¶QÕQ  NE EDNÕU , NORUU YDUOÕ÷ÕQGDGLD]RQ\XPWX]X38) ve (39) ile supercoiled formdan (Form I), open circular  IRUPD)RUP,,YH\DOLQHDUIRUPD)RUP,,,G|QúP

Tablo 4.

4. S%OXHVFULSW 0 SOD]PLG '1$¶QÕQ  NE  EDNÕU ,  NORUU YDUOÕ÷ÕQGDGLD]RQ\XPWX]X 38) ve (39) ile supercoiled formdan (Form I), open circular IRUPD )RUP,, YH\DOLQHDUIRUPD )RUP,,, G|QúP p.67
Tablo 4. 5.  S%OXHVFULSW 0 SOD]PLG '1$¶QÕQ  NE EDNÕU , NORUU YDUOÕ÷ÕQGDGLD]RQ\XPWX]X40) ve (41) ile supercoiled formdan (Form I), open circular  IRUPD)RUP,,G|QúP

Tablo 4.

5. S%OXHVFULSW 0 SOD]PLG '1$¶QÕQ  NE  EDNÕU ,  NORUU YDUOÕ÷ÕQGDGLD]RQ\XPWX]X 40) ve (41) ile supercoiled formdan (Form I), open circular IRUPD )RUP,, G|QúP p.69
Tablo 4. 6.  S%OXHVFULSW 0 SOD]PLG '1$¶QÕQ  NE EDNÕU ,, NORUU YDUOÕ÷ÕQGDGLD]RQ\XPWX]X41) ile supercoiled formdan (Form I), open circular forma  )RUP,,G|QúP

Tablo 4.

6. S%OXHVFULSW 0 SOD]PLG '1$¶QÕQ  NE  EDNÕU ,,  NORUU YDUOÕ÷ÕQGDGLD]RQ\XPWX]X 41) ile supercoiled formdan (Form I), open circular forma )RUP,, G|QúP p.71
Tablo 4. 7.  S%OXHVFULSW 0 SOD]PLG '1$¶QÕQ  NE EDNÕU , NORUU YDUOÕ÷ÕQGD GLD]RQ\XP WX]X 32) ile aril UDGLNDOL V|QGUPH NDSDVLWHVL ROGX÷X ELOLQHQ sistein, etanol ve ß- PHUNDSWR HWDQRO YDUOÕ÷ÕQGD supercoiled formdan (Form I),

Tablo 4.

7. S%OXHVFULSW 0 SOD]PLG '1$¶QÕQ  NE  EDNÕU ,  NORUU YDUOÕ÷ÕQGD GLD]RQ\XP WX]X 32) ile aril UDGLNDOL V|QGUPH NDSDVLWHVL ROGX÷X ELOLQHQ sistein, etanol ve ß- PHUNDSWR HWDQRO YDUOÕ÷ÕQGD supercoiled formdan (Form I), p.73
Tablo 4. 8. pBluescript  0 SOD]PLG '1$¶QÕQ  NE EDNÕU , NORUU YDUOÕ÷ÕQGDGLD]RQ\XPWX]ODUÕ37) ve (41) ile DULOUDGLNDOLV|QGUPHNDSDVLWHVLROGX÷X

Tablo 4.

8. pBluescript 0 SOD]PLG '1$¶QÕQ  NE  EDNÕU ,  NORUU YDUOÕ÷ÕQGDGLD]RQ\XPWX]ODUÕ 37) ve (41) ile DULOUDGLNDOLV|QGUPHNDSDVLWHVLROGX÷X p.75
Tablo 4. 9.  S%OXHVFULSW 0 SOD]PLG '1$¶QÕQ  NE EDNÕU , NORUU YDUOÕ÷ÕQGDGLD]RQ\XPWX]X32) ile ++YH+YDUOÕ÷ÕQGDsupercoiled formdan (Form  ,RSHQFLUFXODUIRUPD)RUP,,G|QúPnün önlenmesi

Tablo 4.

9.  S%OXHVFULSW 0 SOD]PLG '1$¶QÕQ  NE  EDNÕU ,  NORUU YDUOÕ÷ÕQGDGLD]RQ\XPWX]X 32) ile ++YH+YDUOÕ÷ÕQGDsupercoiled formdan (Form , RSHQFLUFXODUIRUPD )RUP,, G|QúPnün önlenmesi p.78
Tablo 4. 10.  S%OXHVFULSW 0 SOD]PLG '1$¶QÕQ  NE EDNÕU , NORUU YDUOÕ÷ÕQGDGLD]RQ\XPWX]X32) ile $$YH$YDUOÕ÷ÕQGDsupercoiled formdan (Form  ,RSHQFLUFXODUIRUPD)RUP,,G|QúPQQ|QOHQPHVL

Tablo 4.

10.  S%OXHVFULSW 0 SOD]PLG '1$¶QÕQ  NE  EDNÕU ,  NORUU YDUOÕ÷ÕQGDGLD]RQ\XPWX]X 32) ile $$YH$YDUOÕ÷ÕQGDsupercoiled formdan (Form , RSHQFLUFXODUIRUPD )RUP,, G|QúPQQ|QOHQPHVL p.80
Tablo 4. 11.  S%OXHVFULSW 0 SOD]PLG '1$¶QÕQ  NE EDNÕU ,, NORUU YDUOÕ÷ÕQGD++YH+LOHVXSHUFRLOHGIRUPGDQ)RUP,RSHQFLUFXODUIRUPD)RUP ,,G|QúP

Tablo 4.

11. S%OXHVFULSW 0 SOD]PLG '1$¶QÕQ  NE  EDNÕU ,,  NORUU YDUOÕ÷ÕQGD++YH+LOHVXSHUFRLOHGIRUPGDQ )RUP, RSHQFLUFXODUIRUPD )RUP ,, G|QúP p.83
Tablo 4. 12.  S%OXHVFULSW 0 SOD]PLG '1$¶QÕQ  NE EDNÕU , NORUU YDUOÕ÷ÕQGD$$YH$LOHVXSHUFRLOHGIRUPGDQ)RUP,RSHQFLUFXODU forma (Form  ,,YH\DOLQHDUIRUPD)RUP,,,G|QúP

Tablo 4.

12. S%OXHVFULSW 0 SOD]PLG '1$¶QÕQ  NE  EDNÕU ,  NORUU YDUOÕ÷ÕQGD$$YH$LOHVXSHUFRLOHGIRUPGDQ )RUP, RSHQFLUFXODU forma (Form ,, YH\DOLQHDUIRUPD )RUP,,, G|QúP p.85

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