1. Peptidomimetics in the Treatment of Cancer
Yogesh Morjaria
Peter Scott
Y.Morjaria@warwick.ac.uk
Current cancer treatments damage cellular DNA, where only a small portion of the drug molecules attack the desired target cells. Resulting side
effects from widely regarded drugs e.g., Cis-Platin, include renal damage and severe nausea. This has provided the driving force behind research
into peptide mimicking systems -peptidomimetics- that exhibit higher selectivity to cancer cells and reduced cytotoxicity to the host1. By fine-tuning
the coordination chemistry of such complexes, a variety of cancers can be specifically targeted, creating a new generation of cancer drugs.
Whilst conventional cancer treatments function by cleaving DNA, anti-cancer
peptidomimetics are thought to induce apoptosis in cells. The active molecule
crosslinks at a specific sequence in a DNA strands major groove, altering the
structure of the DNA peptide. In doing so the populations present within the
G1 stage of mitosis are increased from as much as 3% up to 30%2 These
cells are considered apoptotic resulting in induced cell death and reduction in
tumorous growths.
The binding sequence is aided through non covalent interactions such
as pi-stacking or polar functional groups on the ligand creating secondary
Interactions. The cross-linkages instigate aggregation of DNA as seen in fig.2 Fig 1: Effect of Λ-[Fe2L3]CI4
metallohelices on colon cancer meiosis
stage populations2
Fig 2: AFM showing impact of increasing
peptidomimetic concentration from top to
bottom for 2 anti cancer compounds2
Proteasomes are biological catalysts responsible for protein
degradation which helps trigger the cell division. One drug
aiming to exploit this key step to reduce cell division within
breast cancer is AuD8 [Au(III)Br2(dtc-Sar-AA-O(t-Bu))].
The peptide chain ligand allows the complex to bind into the β5
active site of proteasome. The Au(lll) complex directly bonds to
the substrate pocket via an associative mechanism. The
inhibition leads to an accumulation of ubiquitin proteins and the
eventual induction of apoptosis within the cell.
Research showed an inhibition of tumour growth in vitro of
IC50= 17±1µM whilst in vivo trials on live mice showing a
significant reduction in tumour volume of ~1000mm3 shown in
the graph below3.
Triplex metallohelices present a α-helix mimetic structure
through self assembled strands (scheme.1). The antiparallel
α-helix strand formed are amphipathic and highly selective
molecules allowing them to show structure dependant
cytotocitiy to cancer cell lines. This is shown by the half
inhibition concentration of such mimics against various
cancers in table 1 below, adapted from Howson et.al4.
IC50 (µM)
Complex MCF7 A2780 A2780cis HCT116
Cisplatin 1.33 0.93 10.46 3.51
Fac-[Fe2L3]Cl4 3.67 4.8 2.18 1.66
Mer-[Fe 2 L3]Cl4 2.95 3.75 2.39 0.61
Pi- stacking and secondary interactions work in combination
to produce thermodynamically stable molecules. Ligands on
the triple structures can be functionalised to suit the desired
target cells.5
Graph 1: Showing reduction in tumour volume with 1mg/Kg doses of
AuD8 and AuD6 against control tissue, taken from Nardon. Et .al
Whilst peptidomimetics show vast potential very few are yet to go to clinical trials. In depth
mechanistic studies must be built up in order to translate such molecules into practical and affordable
medicines6.
Currently the yield of such organometallics is low due to the difficulty in extraction of non racemic
products desired. Furthermore it is costly to produce such highly specific biochemical molecules as
shown in table 1 where effectiveness is unique to the cancer type present.
Scheme 1: Showing synthesis of triplex metallohelice and its dinuclear linkage.
References
1. Fu D, Calvo JA, Samson LD. Balancing repair and tolerance of
DNA damage caused by alkylating agents. Nat. Rev.Cancer
12(2), 104–120 (2012).
2. Brabec V, Howson SE, Kaner RA et al. Metallohelices with activity
against cisplatin-resistant cancer cells; does the mechanism
involve DNA binding? Chem. Sci. 4(12), 4407–4416 (2013).
3. Nardon C, Schmitt SM, Yang H, Zuo J, Fregona D, et al. (2014)
Gold(III)-Dithiocarbamato Peptidomimetics in the Forefront of the
Targeted Anticancer Therapy: Preclinical Studies against Human
Breast Neoplasia. PLoS ONE 9(1): e84248.
doi:10.1371/journal.pone.0084248
4. Howson SE, Bolhuis A, Brabec V et al. Optically pure, water stable
metallo-helical ‘flexicate’ assemblies with antibiotic activity. Nat.
Chem. 4(1), 31–36 (2012).
5. Faulkner AD, Kaner RA, Abdallah QMA et al. Asymmetric triplex
metallohelices with high and selective activity against cancer
cells. Nat. Chem. 6(9), 797–803 (2014).
6. Davis JM, Tsou LK, Hamilton AD. Synthetic non-peptide mimetics of
alpha-helices. Chem. Soc. Rev. 36(2), 326–334(2007).