Cisplatin

CISPLATIN

Terry Clayton

Biological Inorganic Chemistry

April 1, 2007

Outline

Discovery Define Chemotherapy as related to oncology Types of Cancer? Synthesis Mechanism

Discovery

Barnett Rosenberg, University of Michigan Cell Division/ Growth (NH4)2PtCl6

Nature 205, 698 - 699 (13 February 1965); doi:10.1038/205698a0 Inhibition of Cell Division in Escherichia coli by Electrolysis Products from a Platinum ElectrodeBARNETT ROSENBERG, LORETTA VAN CAMP & THOMAS KRIGASBiophysics Department, Michigan State University, East Lansing.

Pt NH4Cl (aq)I

hvPt(NH3)2Cl4+

Chemotherapeutic agents for Oncology

Kill tumor cells doing as little damage to healthy cells as possible

Young tumors Impair mitosis Trigger apoptosis

Results! Cured Swiss white mice of Sarcoma 180 Tumors, 1969. Clinical testing 1972 Antitumor chemotherapy for testicular, head and neck, cervical, melanoma,

bladder, lymphoma, and ovarian cancer

J. Med. Chem. 2004, 47, 761-763.

Nephrotoxicity Neurotoxicity Nausea and vomiting Ototoxicity Aquired or ab initio resistance

Side Effects

Nature, 1969, 222, 385-387.

Cisplatin Synthesis

PtCl

Cl Cl

ClK2

KI

PtI

I I

IK2

NH3Pt

I

I I

NH3

K2

PtI

I NH3

NH3

K2 2 KI+

2AgNO3

PtOH2

OH2 NH3

NH3

(NO3)2KCl

PtCl

Cl NH3

NH3

2 AgI

+

+

2KNO3

Dhara, S.C., A Rapid Method for the Synthesis of cis-[Pt(NH3)2Cl2], Indian Journal of Chemistry, vol. 8, No. 2, Feb. 1970, pp. 193-194.

F. Coste, J. M. Malinge, L. Serre, W. Shepard, M. Roth, M. Leng and C. Zelwer, "Crystal structure of a double-stranded DNA containing a cisplatin interstrand cross-link at 1.63 A resolution: hydration at the platinated site", Nucleic Acids Res, 1999, 27, 1837

Structural Requirement

One N-H group 2 labile groups cis

Reedijk (2003) Proc. Natl. Acad. Sci. USA, 100.(7), 3611-3616.

Sites for Pt binding

N

NN

N

NH2

O

HO

HHHH

PO

O-

O-

N

NH2

ON

O

HO

HHHH

PO

O

O-

NH

N

N

O

NH2N

O

H

HHHHO

PO

O

O-

NH

O

ON

O

HO

HHHH

PO

O

HO

O-

(T)

(G)

(C)

(A)

J. Chem. Ed. 83, 5, 2006

G-G, A-GIntrastrand

Mechanism? Chloride ion concentration Aquation/ Carbonate complexes [Syracuse] Kinetic preference to sulfur atoms of methionine

and cysteine over the N7 of guanine Within 24 hours 65-98% of cisplatin is bound to

blood plasma proteins Side effects or important for activity?

Transfer from protein to DNA Golgi organelles / urine

J. Am. Chem. Soc. 2001, 123, 3171-3172

J. Am. Chem. Soc. 2005, 127, 12768-12769

Why not trans? Trans effect Rapid deactivation Forms complexes 2X

faster than cis Activity of bulky amines

1: Eur J Cancer. 1997 Oct;33(11):1823-8

27% clearance in urine Not well understood

SH

NH

NH2

HO

O O

NH

HO

OO

glutathione

Analogues Increased doseage 2000mg/day

PtH3N

H3N

O

O

O

O

Carboplatin

H2N

NH2

Pt

O

O

O

O

Oxaliplatin

PtNH3

NH3

O

O

O

Nedaplatin

less nephrotoxic and neurotoxic compared to

both cisplatin and carboplatin

H3N

H2N

PtCl

Cl

O

O

O

O

Orally active JM-216

Future

More reactive with glutathione ???

Lacks cross-resistance 8 steps from cisplatin

H2NPt

OCOCH3

OCOCH3

Cl

H3N

Cl

SH

NH

NH2

HO

O O

NH

HO

OO

glutathioneBis(aceto)(1-adamantylamine)aminedichloroplatinum

J. Med. Chem., 2004, 47, 761-763

Cytotoxicity

H2NPt

OCOCH3

OCOCH3

Cl

H3N

Cl

Cisplatin-Resistant Tumor Lines IC50 (µM)

Cancer cell line cisplatin 1Chronic myelogenous leukemia K562 >80 3Chronic myelogenous leukemia KG-1 48 2Acute myelogenous leukemia ML-2 >80 1Mouse melanoma B16 >80 6Colon cancer HT-29N >80 12Colon cancer HT29 50 8Colon cancer HCT116 >80 9Lung carcinoma A427 63 6Breast carcinoma HBL100 63 6Breast carcinoma MCF-7 71 8Lung carcinoma CORL23/CTR >80 25Ovarian carcinoma A2780 4 4Ovarian carcinoma A2780/cis 40 3Ovarian carcinoma A2780/cis90 >80 7

Questions

Thank You