Bioorganic & Medicinal Chemistry Letters 18 (2008) 2440–2444
Design, synthesis and antiproliferative properties of oligomers
with chromophore units linked by amide backbones
a
b,c,e
d
d,f
´
´
Isabel Navarro, Juan Aymamı,
Josep Farrera-Sinfreu, Anna Avino,
˜
a
a
g
g
`
`
´
´
´
Natalia G. Beteta, Sonia Varon, Ricardo Perez-Tomas, Wilmar Castillo-Avila,
Ramon Eritja,b,c,e, Fernando Albericio
and Miriam Royo
b,c,h,
a,c,
*
*
*
aCombinatorial Chemistry Unit, Barcelona Scientific Park (PCB), Josep Samitier 1-5, E-08028 Barcelona, Spain
bInstitute for Research in Biomedicine (IRB Barcelona), Josep Samitier 1-5, E-08028 Barcelona, Spain
cNetworking Centre on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Josep Samitier 1-5, E-08028 Barcelona, Spain
dCrystax Pharmaceuticals S.L., Josep Samitier 1-5, E-08028 Barcelona, Spain
eInstitute for Advanced Chemistry of Catalonia (IQAC), Spanish Research Council (CSIC), Jordi Girona 18-26,
E-08034 Barcelona, Spain
f
`
Department d’Enginyeria Quı´mica, Universitat Politecnica de Catalunya (UPC), Diagonal 647, E-08028 Barcelona, Spain
gDepartment of Pathology and Experimental Therapeutics, Cancer Cell Biology Research Group, University of Barcelona (UB),
Feixa llarga, E-08907 L’Hospitalet de Llobregat, Barcelona, Spain
hDepartment of Organic Chemistry, University of Barcelona (UB), Martı´ i Franque´s 1, E-08028 Barcelona, Spain
Received 30 January 2008; revised 14 February 2008; accepted 17 February 2008
Available online 5 March 2008
Abstract—The preparation of oligomers made up of several chromophore units as compounds with potential fluorescent and anti-
proliferative properties is described. Specifically, chromophore units with protected-amino groups and one carboxylic group are
described, together with methods to assemble these units using peptide chemistry. Some of these compounds have antiproliferative
activity.
Ó 2008 Elsevier Ltd. All rights reserved.
Interest in new DNA-intercalating drugs has led to the
development of protocols for the rapid synthesis of com-
pounds carrying several chromophore units. In the pre-
vious paper we described the preparation of oligomers
with phosphodiester bonds using the phosphoramidite
method and solid-phase synthesis protocols. Here we de-
scribe the synthesis of oligomers carrying amide bonds.
viously for the synthesis of conformational constrained
peptide nucleic acids.1,2 Polyproline oligomers form a
rigid backbone that is suitable for drug delivery.3,4 The
2-aminoethylglycine backbone is more flexible and has
been used for the design of peptide nucleic acids
(PNA) DNA backbone mimetics.5,6 The synthesis of
several functionalized PNA oligomers containing
7
anthracene, flavin,8 pyrene,9 and naphthalimide10 has
For the synthesis of these polymers, three trifunctional
scaffolds were chosen: 4-aminoproline, 2-aminoethylgly-
cine, and ornithine. All three have two amino groups
and one carboxylic acid function. This distribution al-
lows both the growth of a polyamide skeleton and the
incorporation of the DNA-intercalating unit on the
other amino group if suitable amino-protecting groups
are used. c-Aminoproline backbones had been used pre-
led to compounds with improved DNA binding proper-
ties. Using similar procedures, ornithine has also been
used as a DNA mimetic; deoxyribose has been replaced
with a poly-ornithine chain.11
For the synthesis of 4-aminoproline polymers the back-
bone was grown on solid-phase, and then the intercalat-
ing agent was assembled on solid support. This strategy
is more convenient for the rapid synthesis of large li-
braries, as it is unnecessary to construct each monomer
with its intercalating agent. The synthesis protocols were
based on a previous study.12 Thus, the assembly of
4-aminoproline oligomers was carried out using the
Keywords: Chromophore; Fluorescence; Peptides; Peptide nucleic acids;
Ornithine; 4-Aminoproline; Solid-phase synthesis; Antiproliferative.
*
Corresponding authors. Tel.: +34 934039942; fax: +34 932045904
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.02.045