Question: Both cisplatin and transplatin are [Pt($NH_{3}$)_{2}$Cl_{2}$] — same formula, different geometry. Why does only the cis form work as an anticancer drug?

Step 1 — Establish the geometry: $Pt^{2+}$ has $d^{8}$ configuration. Strong field ligands ($NH_{3}$, $Cl^{-}$ though weaker) → square planar geometry (d$sp^{2}$ hybridisation). In square planar, two identical ligands can be cis (90° apart, same side) or trans (180° apart, opposite sides).

Step 2 — Mechanism of entry into the cell: Both isomers enter the cell through aquaporin channels. Once inside, the $Cl^{-}$ ligands are hydrolysed (replaced by $H_{2}O$) because intracellular $Cl^{-}$ concentration is low (~4 mM, vs ~100 mM extracellularly). $[\text{Pt(NH}_3)_2\text{Cl}_2] + \text{H}_2\text{O} \longrightarrow [\text{Pt(NH}_3)_2\text{Cl(H}_2\text{O})]^+ + \text{Cl}^-$

Step 3 — DNA cross-linking: The activated cisplatin (with one Cl replaced by $H_{2}O$, then another) binds to the N7 positions of guanine bases on DNA. Cisplatin (cis geometry) allows both Pt–N7(guanine) bonds to form on the same strand of DNA (intrastrand crosslinks) because the two binding sites are 90° apart — exactly the right geometry for adjacent guanines.

Step 4 — Why trans fails: In transplatin, the two reactive sites are 180° apart. Adjacent guanines on the same strand are spaced ~60–90° apart in the helix — incompatible with transplatin's 180° geometry. Transplatin cannot form intrastrand crosslinks. It forms interstrand crosslinks (between two DNA strands) which cells can repair more efficiently using specific DNA repair enzymes.

Step 5 — Consequence: Cisplatin-induced intrastrand crosslinks cause DNA to bend (~45°), block replication and transcription, and trigger apoptosis in rapidly dividing cancer cells. Transplatin-induced damage is repairable and does not trigger sufficient apoptosis.

Conclusion: The geometric isomerism at the platinum centre determines the spatial reach of the two reactive sites, and only the cis geometry is compatible with forming persistent, apoptosis-inducing intrastrand DNA crosslinks.