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Energetics of Complexation of Y with DOTA, a Model for Cancer
Energetics of Complexation of Y with DOTA, a Model for Cancer
Cancer Radioimmunotherapy: Bifunctional Chelating Agent
Cancer Radioimmunotherapy: Bifunctional Chelating Agent
Criteria of Good Chelating Agent
Criteria of Good Chelating Agent
Kinetics of metal binding of DOTA
Kinetics of metal binding of DOTA
Objectives
Objectives
Optimized structure after sequential deprotonation
Optimized structure after sequential deprotonation
How can the proton be removed
How can the proton be removed
How can the proton be removed
How can the proton be removed
How can the proton be removed
How can the proton be removed
Suggestion: DO3A1Pr
Suggestion: DO3A1Pr
DO3A1Pr: Protonation site
DO3A1Pr: Protonation site
Summary
Summary
Acknowledgement
Acknowledgement

Презентация на тему: «Energetics of Complexation of Y with DOTA, a Model for Cancer Radiotherapy». Автор: Sungu Hwang. Файл: «Energetics of Complexation of Y with DOTA, a Model for Cancer Radiotherapy.ppt». Размер zip-архива: 1180 КБ.

Energetics of Complexation of Y with DOTA, a Model for Cancer Radiotherapy

содержание презентации «Energetics of Complexation of Y with DOTA, a Model for Cancer Radiotherapy.ppt»
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1 Energetics of Complexation of Y with DOTA, a Model for Cancer

Energetics of Complexation of Y with DOTA, a Model for Cancer

Radiotherapy

Yun Hee Jang, Mario Blanco, Siddharth Dasgupta, William A. Goddard, III MSC, Beckman Institute, Caltech David A. Keire, John E. Shively The Beckman Research Institute of the City of Hope

2 Cancer Radioimmunotherapy: Bifunctional Chelating Agent

Cancer Radioimmunotherapy: Bifunctional Chelating Agent

Therapy: 90Y3+(64h) Diagnosis: 111In3+(2.8d) 64Cu2+(12.8h) MRI contrast agent: Gd3+

D. Parker, Chem. Soc. Rev. 19, 271 (1990)

3 Criteria of Good Chelating Agent

Criteria of Good Chelating Agent

Kinetic inertness at pH 2~8 w.r.t. acid- promoted dissociation

DOTA (log K=24.8)

DTPA (log K=22.1)

Thermodynamic stability

<0.5% dissociated over 18 days in serum (pH 7.4, 37oC): inert

Not inert leading to bone-marrow toxicity

Rapid complexation

x1600 slower than Y-DTPA formation

Lewis, Raubitschek and Shively, Bioconjugate Chem. 5, 565 (1994)

4 Kinetics of metal binding of DOTA

Kinetics of metal binding of DOTA

+

Y3+

Y3+

Y3+

Y3+

Type II: stable/inert

Y3+ + H2(DOTA)2-

Type I: labile

E.T. Clark and A.E. Martell, Inorg.Chim.Acta 190, 27 (1991) X.Y. Wang, et al. Inorg.Chem. 31, 1095 (1992)

or

5 Objectives

Objectives

Calculation method

Calculate structure/energy change occurring during complex-formation

Identify the rate-determining step: Deprotonation or conformation change?

Design new chelating agent and predict its energetics/kinetics

B3LYP/LACVP* // HF/LACVP* (6-31g* for C/H/O/N; Hay-Wadt ECP for Y)

Vibration analysis ? ZPE / thermodynamic quantity ? Gibb’s free energy

Continuum solvation calculation by solving Poisson-Boltzmann equation

Jaguar 3.5 (Schrodinger Inc.)

6 Optimized structure after sequential deprotonation

Optimized structure after sequential deprotonation

-H+

-H+

YH2(DOTA)+

YH(DOTA)

Y(DOTA)-

Y3+ outside the cage

the same as x-ray structure of final complex

Y3+ moves into the cage spontaneously with deprotonation. RMS deviation between ring conformations < 0.5 ?. Deprotonation is the rate-determining step.

7 How can the proton be removed

How can the proton be removed

Direct attack of outside base on the ring proton? No room for it.

top view

side view

bottom view

8 How can the proton be removed

How can the proton be removed

Conformation change to the one favorable to attack? Too high cost, especially, for YH(DOTA)

4-coordinate

3-coordinate

2-coordinate

YH2(DOTA)+

16.6* (12.1)** kcal/mol

42.7* (34.5)** kcal/mol

* 1.807 ? for r(Y) ** 1.673 ? for r(Y) in solvation calculation

YH(DOTA)

21.6* (24.6)** kcal/mol

9 How can the proton be removed

How can the proton be removed

Proton transfer from ring NH to COO (more accessible to outside base)?

reactant (NH...COO)

TS (N..H..COO)

product (N...COOH)

Proton transfer is easier than conformation change. Calculated activation free energy is in agreement with experimental value.

***experimental DG for Eu,Gd,Ce,Ca-complexes (Inorg.Chem. 32, 4193 (1993))

10 Suggestion: DO3A1Pr

Suggestion: DO3A1Pr

Structural change leading to more stable TS: 6-membered ring of DO3A1Pr rather than 5-membered ring of DOTA

TS (DO3A1Pr)

DO3A1Pr (Pr=propionate)

TS (DOTA)

11 DO3A1Pr: Protonation site

DO3A1Pr: Protonation site

Protonation at propionate site is more stable. ? 6-membered ring TS

Hpr(DO3A1Pr): 0.0 kcal/mol

Hac(DO3A1Pr): 7.8 kcal/mol

12 Summary

Summary

Future work

Deprotonation from ring nitrogen is the rate-determining step.

Deprotonation occurs by proton transfer from ring nitrogen to carboxylate.

Adding CH2 to one carboxylate arm can improve the incorporation rate.

Explicitly-coordinated water molecules How many water molecules? Effect on structure/energetics

Introduction of amide linkage

13 Acknowledgement

Acknowledgement

Caltech William A. Goddard, III Siddharth Dasgupta Mario Blanco Daniel Mainz Sungu Hwang

City of Hope John E. Shively David Keire

Supported by NSF

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