Energetics of Complexation
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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. Chelating ligand (DOTA).

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

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Energetics of complexation of y with dota a model for cancer radiotherapy

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


Energetics of complexation of y with dota a model for cancer radiotherapy

Chelating ligand (DOTA)

90

Antibody

targeting

b-emitting

(2.25 MeV, t1/2=64h)

Tumor cell

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)


Energetics of complexation of y with dota a model for cancer radiotherapy

Criteria of Good Chelating Agent

DOTA

(log K=24.8)

DTPA

(log K=22.1)

Thermodynamic

stability

Kinetic inertness

at pH 2~8w.r.t. acid-

promoted dissociation

<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)


Energetics of complexation of y with dota a model for cancer radiotherapy

fast

slow

Kinetics of metal binding of DOTA

E.T. Clark and A.E. Martell,

Inorg.Chim.Acta 190, 27 (1991)

X.Y. Wang, et al.

Inorg.Chem. 31, 1095 (1992)

Y3+

+

Y3+

or

Y3+

Y3+

Type II: stable/inert

Y3+ + H2(DOTA)2-

Type I: labile


Energetics of complexation of y with dota a model for cancer radiotherapy

Objectives

  • 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

Calculation method

  • 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.)


Energetics of complexation of y with dota a model for cancer radiotherapy

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 Å.

  • Deprotonation is the rate-determining step.


Energetics of complexation of y with dota a model for cancer radiotherapy

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


Energetics of complexation of y with dota a model for cancer radiotherapy

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 Å for r(Y)

** 1.673 Å for r(Y)

in solvation calculation

YH(DOTA)

21.6* (24.6)** kcal/mol


Energetics of complexation of y with dota a model for cancer radiotherapy

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)

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

  • Proton transfer is easier than conformation change.

  • Calculated activation free energy is in agreement with experimental value.


Energetics of complexation of y with dota a model for cancer radiotherapy

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)


Energetics of complexation of y with dota a model for cancer radiotherapy

DO3A1Pr: Protonation site

Hpr(DO3A1Pr): 0.0 kcal/mol

Hac(DO3A1Pr): 7.8 kcal/mol

Protonation at propionate site is more stable.  6-membered ringTS


Energetics of complexation of y with dota a model for cancer radiotherapy

Summary

  • 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.

Future work

  • Explicitly-coordinated water molecules

  • How many water molecules?

  • Effect on structure/energetics

  • Introduction of amide linkage


Energetics of complexation of y with dota a model for cancer radiotherapy

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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