- 學位論文
DIHB-TTDA及TTDA-BOM配位子及其金屬錯合物之合成、物性及化性研究
Synthesis and Physicochemical Characterization of Ligands DIHB-TTDA and TTDA-BOM and Their Complexes with Lanthanide(III), Ca(II), Zn(II), and Cu(II) Ions
摘要
本研究主要為合成含3,5-雙碘-4-羥苯甲基及及中間氮上的羧酸上含苯氧甲基的TTDA(3,6,10-tri(carboxymethyl)-3,6,10- triazadodecanedioic acid)衍生物，DIHB-TTDA(3,5- diiodo-4-hydroxybenzyl-3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid)與TTDA-BOM(6-carboxylmethyl-benzyloxymethyl- 3,10-di(carboxymethyl)-3,6,10-triazadodecanedioic acid)。利用電位滴定法求得配位子的質子化常數以及與不同金屬形成錯合物的穩定常數。其釓金屬錯合物弛緩率與pH值及溫度間關係乃利用20 MHz NMR進行研究。另外，由鏑金屬錯合物在pH 6.30中17O-NMR化學位移之變化可求出內層水分子數（q）。釓金屬錯合物的弛緩率受到內層水分子的存在時間 (τm)及分子轉動相關時間(τr)的影響。實驗結果顯示[Gd(DIHB-TTDA)(H2O)]2-的內層水分子存在時間（τm＝3.4±1.3 ns）遠低於[Gd(DTPA)(H2O)]2-（τm＝143±26 ns）。另外，[Gd(DIHB-TTDA)(H2O)]2-（tr＝86 ± 6 ps）略高於[Gd(DTPA)(H2O)]2-（tr＝58）。由於[Gd(DIHB-TTDA)(H2O)]2-及[Gd(TTDA- BOM)(H2O)]2-皆具有脂溶性之特性，因此預測能與血清蛋白產生非共價鍵結（non-covalent bonding）。實驗結果顯示[Gd(DIHB-TTDA)(H2O)]2-及[Gd(TTDA-BOM)(H2O)]2-之結合常數（KA）分別為4.7×103 M-1及3.1×102 M-1，表示[Gd(DIHB-TTDA)]2-與HSA之間的結合能力很強，但發現其脂溶性太大，因此影響其與HSA之鍵結百分比。而[Gd(TTDA-BOM)(H2O)]2-與HSA之結合能力與其他肝膽造影對比劑之結合常數類似。因此未來可利用[Gd(TTDA)(H2O)]2-的優點（適當的tm），加入不同的親脂性取代基所形成之衍生物，將能成為目標化之磁振造影對比劑。
並列摘要
Two derivatives of TTDA (3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid), (DIHB-TTDA)(3,5-diiodo-4-hydroxybenzyl-3,6,10-tri(carboxymethyl)-3,6,10- triazadodecanedioic acid) and TTDA-BOM(6-carboxylmethyl-benzyloxy-methyl- 3,10-di(carboxymethyl)-3,6,10-triazadodecanedioic acid), were synthesized and characterized. The stability constants of the complexes formed with Ca2+, Zn2+, Cu2+, and Gd3+ were determined by potentiometric methods at 25.0 ± 0.1 °C and 0.1M ionic strength in Me4NNO3. The observed water proton relaxivity values of [Gd(DIHB-TTDA)]2- and [Gd(TTDA-BOM)]2- remain constant with respect to pH changes over the range of 4.5-12.0 and 5.0-12.0. 17O-NMR chemical shift of H2O induced by [Dy(DIHB-TTDA)]2- at pH 7.4 has 0.8 inner-sphere water molecule. Water proton spin-lattice relaxation rates for [Gd(DIHB-TTDA)]2- and [Gd(TTDA-BOM)]2- at 37.0 ± 0.1 °C and 20 MHz are 4.78 ± 0.05 mM -1 s-1 and 4.44 ± 0.05 mM -1 s-1, respectively. The EPR and 17O-NMR transverse relaxation rate data were analyzed together in a simultaneous multiple parameter least-squares fitting procedure to determine the water residence lifetime (tm). The 2H-NMR was used to determine the rotational correlation time (tr). The results were compared with those previously reported for the other lanthanide (III) complexes. The exchange lifetime (tm) for [Gd(DIHB-TTDA)]2- (3.4 ± 1.3 ns) is significantly shorter than that of [Gd(DTPA)(H2O)]2- (143 ns) complex. The rotational correlation time (tr) for [Gd(DIHB-TTDA)]2- (85 ± 6 ps) is slightly longer than that of [Gd(DTPA)(H2O)]2- (58 ps) complex. The marked increase of relaxivity of [Gd(DIHB-TTDA)]2- mainly results from its longer rotational time instead of its fast water-exchange rate. The non-covalent interaction between human serum albumin (HSA) with [Gd(DIHB-TTDA)]2- and [Gd(TTDA-BOM)]2- complexes containing hydrophobic substituent was investigated by measuring the solvent proton relaxation rate of the aqueous solutions. The binding association constant (KA) values of [Gd(DIHB-TTDA)]2- and [Gd(TTDA-BOM)]2- with HSA are 4.7×103 M-1 and 3.1×102 M-1, respectively, which indicate the stronger interaction of [Gd(DIHB-TTDA)]2- and [Gd(TTDA-BOM)]2- with HSA.