Clicking Fe metallohelices tunes cancer-cell selectivity
Copper-click derivatisation of a stable Fe2L3 helix gives Δ-[Fe2L3a3]Cl4, which is more cancer-selective than the parent, hits cancer stem cells, and still has a fully characterised coordination core.
Source
Discovery of selective, antimetastatic and anti-cancer stem cell metallohelices <i>via</i> post-assembly modification
Inspect source passages
Clicking Fe metallohelices tunes cancer-cell selectivity
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Scratch wounds stayed 62% and 71% open with Δ-[Fe2L13]Cl4 and Δ-[Fe2L3a3]Cl4 versus 33% in the control.
While in a control sample a scratch in a monolayer of HCT116 p53 +/+ cells had healed in 24 h to 33%, the presence of non-toxic doses of Δ-[Fe 2 L 1 3 ]Cl 4 or Δ-[Fe 2 L 3a 3 ]Cl 4 suppressed healing, leaving 62% and 71% respectively of the wound open.
Invasion fell 35% and 58% with the parent and clicked Δ helices.
Using a Matrigel™ transwell assay,, (see ESI) it was shown that while Δ-[Fe 2 L 2 3 ]Cl 4 had no effect, Δ-[Fe 2 L 1 3 ]Cl 4 and Δ-[Fe 2 L 3a 3 ]Cl 4 reduced HCT116 p53 +/+ invasive ability by 35% and 58% [bottom panel in ].
What they did
Authors CuAAC-functionalised triplex alkynyl metallohelices, confirmed products by NMR/MS, then compared enantiomers in cancer versus non-cancer cells, wound-healing, invasion, Na+/K+ ATPase, and CD133+ colonosphere assays.
What they found
Click conversion raised ovarian/breast potency ~7–25-fold. Δ-[Fe2L3a3]Cl4 left 71% of a scratch open versus 33% control, cut invasion 58%, IC50 1.21 μM on CD133+ CSCs, and inhibited Rb+ uptake 35–47%. p53-null cells were not resistant.
The limits
What it doesn't show
These are cell-based pharmacology endpoints, not a clinical anticancer trial or a solved target co-crystal of the helix with Na+/K+ ATPase.
Key terms
- Metallohelix
- Self-assembled multimetallic helical coordination compound, here Fe2L3.
- Post-assembly modification (PAM)
- Covalent chemistry on an already-formed cage/helix, here CuAAC.
- Δ vs Λ
- Enantiomers of the helix; Δ is more cancer-selective for the clicked series.
- CuAAC
- Copper-catalysed azide–alkyne cycloaddition used to add benzyltriazoles.
- CSC
- Cancer stem cell–enriched CD133+ populations assayed as colonospheres.
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Quiz yourself
PAM on these helices used:
Common questions
What reaction did PAM use?
CuAAC of alkynyl helices with benzyl azides.
Which enantiomer is more cancer-selective after clicking?
The Δ isomer of [Fe2L3a3]Cl4.
CSC IC50 on HCT116.CD133+?
1.21 ± 0.25 μM.
Does p53 loss confer resistance?
Not for the Δ-metallohelices, unlike cisplatin.
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