Tetrahedron Letters
Synthesis of tris-tertiary amine CycloTriVeratrilene (TACTV) derivatives
as water soluble pre-organized three aromatic ring containing molecular
scaffolds for the construction of protein mimics
a
a
a
a
a,b,
⇑
ˇ
Ondrej Longin , Helmus van de Langemheen , Susan Gannon , David Ward , Rob M.J. Liskamp
a School of Chemistry, Joseph Black Building, University of Glasgow, University Avenue, Glasgow G12 8QQ, UK
b Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, P.O. Box 80082, NL-3508 TB Utrecht, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2019
Revised 17 September 2019
Accepted 1 October 2019
Available online 22 October 2019
The synthesis of water soluble highly pre-organized Tris-tertiary Amine CycloTriVeratrilene (TACTV)
derivatives was developed. A semi-orthogonally protected derivative allowed one pot sequential intro-
duction of different peptide loops toward the molecular construction of synthetic antibody protein
mimics.
Ó 2019 Elsevier Ltd. All rights reserved.
Keywords:
Molecular scaffold
Cyclic peptide
Amine-CTV
CuAAC-click reaction
One of the great challenges faced in the development of protein
mimics is obtaining molecular constructs with sufficient water sol-
ubility. This is not different from trying to steer water solubility
and resulting absorption and permeation properties of lead com-
pounds in the small molecule drug discovery process. A poor
water-solubility of lead compounds is often responsible for the
large attrition rate in this process [1].
To a large extent the water solubility of protein mimics is deter-
mined by the cyclic peptides or peptide loops attached to the
molecular scaffold which are necessary for proper orientation
and positioning in space aiming at an adequate mimicry of the pro-
tein. Unfortunately, in many cases the amino acids present in these
peptide loops do not contain side chains, which contribute to a
good water-solubility. Evidently, the possibilities to change amino
acids in these peptide loops in order to increase water-solubility
are very limited, as their peptide sequences have to resemble the
mimicked peptide segments of the protein as closely as possible.
Recently, we have addressed the issue of poor solubility of
bicyclic peptides by development of polar hinges, which upon
incorporation led to a significant increase of polarity and therefore
water solubility of the resulting bicyclic peptides [2].
These polar hinges were also beneficial for increasing the
water-solubility of peptide loops for attachment to our molecular
scaffolds [3,4].
However, it was increasingly realized that the molecular scaf-
fold to which the peptide loops are attached plays a dominant role
in determining the water solubility of the final protein mimics.
Therefore, we have recently developed mono- and diethylene
glycol spacer containing CTV-analogues, which already led to a
considerable improvement of water solubility albeit still not suffi-
cient [4]. A major step forward towards a CTV derivative with the
structurally best possible aqueous solubility characteristics is pre-
sented herein by the development of
a Tris-tertiary Amine
CycloTriVeratrilene derivative (TACTV) of which the TFA-salt is
very soluble in water. In addition, the synthesis of a semi-orthog-
onally protected TACTV derivative is described, which enabled
the incorporation of different peptide loops onto this scaffold.
Probably, the cup or basket shape of the CTV structure in which
three aromatic rings are linked in a circle provides one of the most
pre-organized molecular scaffolds presently available. As a result
this scaffold is highly suitable for spatial mimicry of discontinuous
epitopes in proteins. Despite the fact that the molecular scaffold
forms only a small part of the entire protein mimic it often
contributes to
a poor solubility of the molecular construct.
With the presented TACTV scaffolds in this work outstanding
pre-organisation is combined with a good water-solubility.
In order to increase the water solubility of the CTV scaffold
⇑
Corresponding author at: School of Chemistry, Joseph Black Building, University
of Glasgow, University Avenue, Glasgow G12 8QQ, UK (R.M.J. Liskamp).
E-mail
addresses:
considerably we thought it was best to connect
a tertiary
(R.M.J. Liskamp).
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.