Tetrahedron Letters
Synthesis of hexaphenylbenzene-based template assembled synthetic
proteins
Suresh Madhu a,b, Krishnaprasad Madica a,b, Rajesh Gonnade b,c, Gangadhar J. Sanjayan a,b,
⇑
a
Division of Organic Chemistry, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
b
c
Center for Material Characterization, National Chemical Laboratory, Pune, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Template-assembled synthetic proteins (TASPs) synthesized from rigid templates have attracted atten-
tion due to their interesting structural architectures and potential biomedical applications. Herein, we
report the design, synthesis and characterizations of TASPs based on hexaphenylbenzene template
Received 8 May 2019
Revised 5 July 2019
Accepted 6 July 2019
Available online 16 July 2019
(HPB) having twelve peptide attachable axial-arms in its structure. The peptides were attached to all
the axial-arms of the template in a single step using simple solution phase peptide coupling strategy.
The reaction conditions were standardized systematically using simple amines from smaller size to larger
ones.
Keywords:
TASP
Hexaphenylbenzene
Peptides
Ó 2019 Elsevier Ltd. All rights reserved.
Proteins
Introduction
species by assembling small proteins on a cyclic decapeptide-tem-
plate [13]. Fairlie et al. showed synthetic four-helix bundles using a
Proteins, macromolecules that constitute the major building
units of cells, are very essential for the life of any living species
series of aromatic scaffolds and a cyclic octapeptide and they found
that the size, shape and directionality of the rigid templates are
extremely important for designing TASP [10c]. Further,
carbohydrates [14], several aromatic ring-based templates [15]
and porphyrin rings [16] were also used for the construction of
TASPs. Vase-shaped rigid molecules called as cavitands were also
used as scaffolds in TASPs chemistry in which four functional arms
were employed for protein tethering [17]. Recently, we have
shown tethering of long peptides on diimidone-based template
in an anti-parallel fashion [18]. Another interesting scaffold used
for the synthesis of TASPs was polyhedral oligomeric silsesquiox-
anes (POSS) in which total eight peptide attachable arms were pre-
sent in its structure [19]. However, more than eight peptide
attachable multivalent templates are still rare in the literature.
Considering the above mentioned importance of TASPs and the
need of novel multivalent scaffolds for the peptide attachments,
we envisaged that axially substituted double basket-shaped
hexaphenylbenzene (HPB) could serve as a good platform for con-
structing TASPs (Fig. 1, vide supra). Therefore, we attempted to
tether peptide units on the axial arms of HPB(COOH)12 using solu-
tion-phase simple peptide coupling strategy.
[
1]. Proteins consist of one or more long chains of amino acid resi-
dues or poly peptides [2]. Proteins are involved in a vast array of
biological functions such as DNA replication [3], catalyzing meta-
bolic reactions [4], transporting molecules from one location of
the organism to the other location [5] and so on. The structures
and functions of the proteins are dictated by the nucleotide
sequence of specific genes [6]. Scientific communities have long
been involved in the study of protein folding and the factors that
affecting it [7]. Since Emil Fischer attempted the synthesis of
polypeptide chain, the design and synthesis of proteins have pro-
gressed significantly till to date [8]. The idea of template assembled
synthetic proteins (TASPs) was initiated by Mutter and Vulleumies
[
9]. In TASPs, peptides are tethered into rigid scaffolds which could
alter their folding as well as their secondary and tertiary structure
10]. Several rigid scaffolds or templates have been used to con-
[
struct the TASPs in the literature. Mutter et al. assembled TASPs
by tethering four un-ordered peptide strands on cyclic or acyclic
peptide-based rigid templates [9,11]. The resultant structure of
the TASP had shown four-helix bundles on the peptide-based tem-
plate [9,12]. Haehnel et al. reported a library of combinatorial
Results and discussion
⇑
Corresponding author at: Division of Organic Chemistry, National Chemical
The reaction of HPB(COOH)12 (1) [20] with free amines were
performed under conventional solution-phase coupling condition
0
040-4039/Ó 2019 Elsevier Ltd. All rights reserved.