Cisplatin and Haemoglobin

Learning Objectives (OCR Spec 5.3.1)

By the end of this lesson you should be able to:

• Describe the structure of cisplatin and explain why only the cis isomer is effective
• Explain the mechanism by which cisplatin kills cancer cells
• Discuss the ethical and clinical issues of using cisplatin (side effects, resistance)
• Describe the structure of haem in haemoglobin and identify the role of Fe2+
• Explain how oxygen is transported by haemoglobin
• Explain why carbon monoxide is toxic in terms of ligand binding

Cisplatin: A Square Planar Anti-Cancer Drug

Cisplatin is the common name for cis-diamminedichloroplatinum(II), formula [Pt(NH3)2Cl2]. It is one of the most widely used chemotherapy drugs in medicine and has dramatically improved survival rates for testicular, ovarian, bladder, lung, and head-and-neck cancers since it was approved in 1978.

Structure of Cisplatin

Platinum(II) is a d8 ion, and like all d8 metals it preferentially forms square planar complexes. Four ligands sit in a plane around Pt2+ at 90 degrees to each other. With two NH3 and two Cl-, there are two possible arrangements:

• cis isomer: the two Cl- ligands are adjacent (at 90 degrees) - this is the active drug
• trans isomer: the two Cl- ligands are opposite (at 180 degrees) - this is inactive as a drug

  cis:                  trans:
       Cl   NH3             Cl   NH3
        \ /                 \ /
         Pt                   Pt
        / \                 / \
       Cl   NH3            H3N   Cl

Only the cis isomer can bind DNA in the way that produces its anti-cancer action, which is why the drug must be made and used in the cis form.

How Cisplatin Works

Cisplatin is administered as an intravenous infusion. Once inside cells, the chloride concentration drops (intracellular [Cl-] is about 4 mM compared with ~100 mM outside), and one or both chloride ligands are replaced by water:

[Pt(NH3)2Cl2] + H2O -> [Pt(NH3)2Cl(H2O)]+ + Cl-

[Pt(NH3)2Cl(H2O)]+ + H2O -> [Pt(NH3)2(H2O)2]2+ + Cl-

The water ligand is a good leaving group, which allows the Pt2+ to bind to DNA. Specifically, the N7 atoms of two adjacent guanine bases (or a guanine and an adenine) on the same DNA strand coordinate to the Pt2+, displacing the two waters:

Pt2+ + 2 G (guanine) -> Pt(NH3)2(G)(G)

This cross-links the DNA. The DNA cannot be unwound properly for transcription or replication, and the cell's repair machinery recognises the lesion as irreparable. The cell enters apoptosis (programmed cell death). Rapidly dividing cells - including cancer cells, but also hair follicles, gut lining, and bone marrow - are most affected.

Only the cis form can make the required two-point cross-link to adjacent purines on the same DNA strand, because the two bonding sites on Pt must be close together (90 degrees apart). In the trans form the two binding sites are on opposite sides of the Pt, which geometrically cannot reach two adjacent bases.

Ethical and Clinical Issues

Cisplatin is an effective drug but has serious side effects:

• Nephrotoxicity (kidney damage)
• Ototoxicity (hearing loss, especially in children)
• Peripheral neuropathy (nerve damage)
• Severe nausea and vomiting
• Bone marrow suppression and hair loss
• Risk of secondary cancers from DNA damage to healthy cells

Because cisplatin kills all rapidly dividing cells (not just cancer cells), it is a "blunt instrument" of cancer treatment. Newer platinum drugs like carboplatin and oxaliplatin are derivatives designed to be better tolerated - they use chelating ligands that are less readily displaced, giving slower release and milder side effects.

Drug resistance is another issue: some cancers develop mechanisms (glutathione quenching, increased DNA repair) that reduce the effectiveness of cisplatin.

Ethical considerations include informed consent (patients must understand the trade-off between cure and suffering), cost and access in poor healthcare systems, and the use of animal testing in drug development.

Haemoglobin: An Octahedral Iron(II) Complex

Haemoglobin is the oxygen-transport protein in red blood cells. Each haemoglobin molecule contains four subunits, each of which carries a haem prosthetic group.

Structure of Haem

The haem group is a flat, planar organic molecule called a porphyrin ring. The ring has four nitrogen atoms pointing inward, and at its centre sits a single Fe2+ ion coordinated by all four nitrogens. The porphyrin is therefore a tetradentate ligand - it provides four dative bonds to the Fe2+ in a roughly square planar arrangement.

However, the iron is octahedrally coordinated - it has two additional coordination sites perpendicular to the porphyrin plane: