Dalton
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Cite this: Dalton Trans., 2011, 40, 8083
COMMUNICATION
Cytotoxic gold(I)-bearing dendrimers from alkyne precursors†
Thomas J. Robilotto,a Daniel S. Alt,b Horst A. von Recum*b and Thomas G. Gray*a
Received 4th April 2011, Accepted 22nd June 2011
DOI: 10.1039/c1dt10578g
A series of four dendrimers end-functionalized with gold(I)
has been prepared from alkyne-terminated precursors and
(tricyclohexylphosphine)gold(I) azide. Isolated yields range
from 84–89%, based on gold. The first-generation dendrimer
is cytotoxic toward 3T3 mouse fibroblast cells. Apoptosis
ensues within 6 h of treatment with gold(I).
We have reported that the [3 + 2] cycloaddition of (phos-
phine)gold(I) azides with terminal alkynes affords triazolato
complexes in good to excellent yields.11,12 In the product com-
plexes, triazolate ligands bind gold through carbon. The result-
ing organometallics are stable to air, moisture, and laboratory
lighting.13–15 We find this method of metalating alkyne precursors
simpler than classical deprotonation/metalation of alkynes.16
The reaction of Cy3PAuN3 (Cy = cyclohexyl) with the ethynyl-
terminated dendrimers of Hawker and co-workers17 yields den-
drimers bearing C-bound (phosphine)gold(I) triazolates. A rep-
resentative example appears in Scheme 1. Four generations
of dendrimer have been metalated this way, and the number
of bound gold atoms is 2n, where n is the cardinal number
corresponding to the dendrimer’s generation (e.g., the fourth-
generation dendrimer has 24 = 16 gold(I) centers). Isolated yields
based on Cy3PAuN3 are as follows: 84%, 1; 89%, 2; 89%, 3;
95%, 4. The dendrimers are soluble in THF, dimethyl sulfoxide
(DMSO), and DMSO/water mixtures. Solubility decreases with
each higher generation. The fourth-generation dendrimer, with
16 gold atoms, is insoluble in common solvents, and only the
first three generations are considered here. Fig. 1 depicts line-
drawings of the first three dendrimer generations. End-to-end
diameters, estimated from molecular mechanics minimization,
range from 2 nm for the first-generation dendrimer to 4 nm for the
fourth. These sizes fall below the £ 5.5-nm limit encountered for
kidney clearance of nanocrystals.18 Thus the new dendrimers are
potentially compatible with renal elimination.
Gold is prominent in restorative and prosthetic dentistry.1 Its
history in rheumatoid arthritis treatment reaches across decades.2
In recent years, the focus of medicinal gold(I) chemistry has shifted
toward cancer therapy in response to observations that gold(I)
anti-arthritics possess anti-inflammatory and immunosuppressive
activity.3,4 The orally bioavailable prodrug auranofin is toxic
to P388 leukemia and B16 melanoma cell lines.5 Results from
Berners-Price, Filipovska, and co-workers find bis(diphosphine)
gold(I) cations to be membrane-permeable, and indeed, to trigger
apoptosis in human breast-cancer cell lines.6–8 The mechanism of
this biological activity is drawing scrutiny. One hypothesis having
experimental support is that gold(I) inhibits the mitochondrial
form of the enzyme thioredoxin reductase. The single SeCys
residue of this enzyme, which lies near the protein’s C-terminus, is
thought to bind gold in a favorable soft-soft match.9 The inhibited
(gold-bound) reductase then fails to reduce thioredoxin, and
thereby triggers mitochondrial membrane permeability. Apoptosis
ensues. Malignant tissues up-regulate thioredoxin reductase, and
this enzyme is emerging as a chemotherapeutic target. The
anticancer propensities of gold(I) compounds continue to attract
clinical attention, and the medicinal prospects of gold chemistry
are far from exhausted.
Dendrimers are branched polymers having precisely control-
lable architectures and uniform composition. Their use as tar-
getable drug carriers now represents a mature field of study.10
Dendrimers exploit the enhanced permeability and retention of
tumors, where the blood vessels of cancerous tissue trap macro-
molecules. Polymeric drugs, or polymer-immobilized prodrugs,
linger inside tumors and acquire a longer residence time. Selectivity
results for malignant over healthy tissues.
Scheme 1 Synthesis of first-generation dendrimer 1.
Organometallic products were characterized by multinuclear
NMR and infrared spectroscopies. Mass spectra and elemental
analysis indicate that all terminal alkynyl groups in the or-
ganic precursors are transformed into (triazolato)gold(I) moi-
eties. Vibrational signatures corresponding to terminal alkynes
or azide complexes are absent in the products’ infrared
spectra. The organogold dendrimers are colorless, and the
aDepartment of Chemistry, Case Western Reserve University, 10900 Euclid
Avenue, Cleveland, Ohio, USA. E-mail: tgray@case.edu; Fax: (216)368-
3006; Tel: (216) 368-0991
bDepartment of Biomedical Engineering, Case Western Reserve University,
10900 Euclid Avenue, Cleveland, Ohio, USA. E-mail: hav1@case.edu;
Fax: (216)368-4969; Tel: (216) 368-5513
† Electronic supplementary information (ESI) available: Full experimental
details. See DOI: 10.1039/c1dt10578g
This journal is
The Royal Society of Chemistry 2011
Dalton Trans., 2011, 40, 8083–8085 | 8083
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