Using fast scanning calorimetry to study solid-state cyclization of dipeptide L-leucyl-L-leucine

Article abstract of DOI:10.1016/j.tca.2020.178748

The possibility of using fast scanning calorimetry (FSC) to study the kinetics of the solid-state cyclization of dipeptide was demonstrated in the present work for the first time. The activation energy and Arrhenius constant of the cyclization of _L

Full text of DOI:10.1016/j.tca.2020.178748

ThermochimicaActa692(2020)178748
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Using fast scanning calorimetry to study solid-state cyclization of dipeptide
L-leucyl-L-leucine
Aisylu S. Safiullinaa, Aleksey V. Buzyurova, Sufia A. Ziganshinab, Alexander V. Gerasimova,
Christoph Schicka, Valery V. Gorbatchuka, Marat A. Ziganshina,*
a A.M. Butlerov Institute of Chemistry, Kazan Federal University, Kremlevskaya ul. 18, Kazan, 420008, Russia
b Zavoisky Physical-Technical Institute of FRC Kazan Scientific Center of the Russian Academy of Sciences, Sibirsky Tract 10/7, Kazan, 420029, Russia
A R T I C L E I N F O
A B S T R A C T
Keywords:
The possibility of using fast scanning calorimetry (FSC) to study the kinetics of the solid-state cyclization of
dipeptide was demonstrated in the present work for the first time. The activation energy and Arrhenius constant
of the cyclization of L-leucyl-L-leucine (Leu-Leu) were estimated. FSC data obtained at heating rates from 18,000
to 54,000 K min−1 were evaluated by non-isothermal kinetics. The dependence of the specific heat capacity cp on
temperature was determined for linear and cyclic Leu-Leu dipeptides using differential scanning calorimetry
(DSC) and FSC. The application of FSC allows studies of solid-state reactions for expensive substances and
compounds synthesized in very small amounts.
Dipeptide
Solid-state synthesis
2,5-Diketopiperazines
Fast scanning calorimetry
Non-isothermal kinetics
1. Introduction
procedures. The current methods of CDPs synthesis, including con-
densation of individual amino acids at high temperature in the solid
2,5-Diketopiperazines (DKPs), also known as cyclic dipeptides
(CDPs), are of great interest [1,2] due to their potential advantages for
various applications [3,4]. These molecules, in comparison with their
linear counterparts, have a unique structural rigidity and less con-
formational freedom [5], which reduces restrictions for their practical
usage [6]. Small cyclic peptides are conveniently used as model com-
pounds, since they can mimic the major secondary structural motifs
(strands / sheets, turns, helices) found in proteins [7,8]. The formation
of such structures increases the resistance of short cyclic peptides to
cleavage by proteolytic enzymes [9]. Cyclic peptides have a better cell
permeability compared to linear peptides, which polar nature prevents
their penetration into the lipophilic cell membrane [10,11]. The orally
bioavailable 2,5-DKPs exhibit exceptional biological activity [12–14] as
anticancer [15,16], antiviral [17,18], antifungal [19,20], anticoagulant
and antimicrobial agents [21,22].
state (solid phase synthesis) or under reflux in solutions [1], and mi-
crowave cyclization of dipeptides in water [27] have several dis-
advantages associated with the use of solvents and the formation of by-
products [28]. The heat treatment of linear dipeptides in the solid state
allows obtaining DKPs in one step without any by‐products, except
water [29–32]. Unfortunately, the solid-state reactions of dipeptide
cyclization have not been studied sufficiently yet [33,34], because of
the possibility of their thermal decomposition upon heating [35,36], as
well as due to the relatively high cost of optically pure linear dipep-
tides.
The key to solving this problem may be the fast scanning calori-
metry (FSC) [37]. The main idea of the FSC method is to use a tiny
sample that allows to control the heating and cooling at scanning rates
up to 106 K s−1. The high heating and cooling rates help to avoid
thermal decomposition of low volatile and thermally unstable com-
pounds [38], to prepare the substances in the amorphous state [39] and
in various polymorphic modifications [40]. FSC is a convenient ex-
perimental method for studying the melting of bio-polymers [41,42],
amino acids [43], low molecular mass compounds [44–46] and nu-
cleobases [47,48]. The undoubted advantage of FSC is the fast mea-
surement (a few seconds) and low sample mass (less than 50 ng), which
is especially beneficial from an economic point of view, when expensive
substances of high purity should be studied.
Due to the ability to form various intermolecular bonds, including
four hydrogen bonds per molecule, CDPs are capable to self-assembly
with the formation of various highly ordered structures, which are used
in a wide range of applications, such as design of nanodevices and
sensors [23], hydro- and organogels [4,24] for ecology and biomedicine
[4,25,26].
To expand the scope of CDPs, the development of methods for their
synthesis is required, preferably using simple atom-economical
⁎ Corresponding author.
E-mail address: Marat.Ziganshin@kpfu.ru (M.A. Ziganshin).
https://doi.org/10.1016/j.tca.2020.178748
Received 14 July 2020; Received in revised form 7 August 2020; Accepted 7 August 2020
Availableonline14August2020
0040-6031/©2020ElsevierB.V.Allrightsreserved.

A.S. Safiullina, et al.
ThermochimicaActa692(2020)178748
In the present work, FSC was used to study the cyclization of
-
calibration was carried out using standard samples of indium, tin, bi-
phenyl and deionized water. The accuracy of the melting temperature
determination was better than 1 K. Optical images of the samples
were obtained using an Olympus BXFM microscope.
L
leucyl-L-leucine dipeptide in the solid state for the first time. Previously,
the cyclization of this dipeptide was studied by conventional methods
of thermal analysis [30]. In the present study, the kinetic parameters of
the reaction were estimated within the approaches of non-isothermal
kinetics using FSC data. The results obtained were compared with ki-
netic parameters of this reaction determined elsewhere [30]. The study
of kinetics of solid-state reactions of minute amounts allows to develop
effective and economical methods for preparation of biologically active
substances based on oligopeptides.
The Leu-Leu cyclization was studied at heating rates of 300, 700 and
900 K s−1. The higher heating rates led to a substantial broadening of
DSC peaks and an increase in errors.
Since the mass of the dipeptide FSC sample is not available due to
the nanogram sample mass, several approaches have been developed
for an indirect mass determination using the data on specific fusion
enthalpy, the specific heat of the solid or liquid sample, and the heat
capacity change at the glass transition [37]. In this study, we estimated
the sample mass (m) using the specific heat capacities of Leu-Leu and
cyclo(Leu-Leu) obtained from DSC and the heat capacities from FSC
measurements, by the following equation:
2. Experimental
2.1. Materials
Dipeptide L-leucyl-L-leucine (Leu-Leu) was purchased from Bachem
(Lot#: 1054344). Cyclic dipeptide cyclo(leucyl-leucyl) (cyclo(Leu-Leu))
was prepared by heating the Leu-Leu up to 473 K as described in Ref
[30]. For the experiments, Leu-Leu was recrystallized from methanol
and dried in vacuo (P = 7 kPa) to remove the solvent. Methanol (of
grade “for GC” with purity ≥99.9 %) was used without additional
purification.
m = Cp(T)/cp(T)
(1)
where Cp(T) is the heat capacity determined from the FSC experiment
as described below.
The heat capacities of dipeptides were calculated from the heat flow
rates on heating and cooling as described previously [46]. The heat
flow rates of empty sensors were determined before each sample
measurement. Then sample measurements were corrected by sub-
tracting the empty sensor measurement. Further corrections were made
for the heat loss from the sample and the reference to the surroundings.
The measurements were carried out in a temperature range, in which
there is no chemical reaction or phase transition: from 293 K to 423 K in
the case of Leu-Leu and from 293 K to 483 K for cyclo(Leu-Leu). So, the
corrected heat flow rates to the sample (Фh is the corrected heat flow
rate on heating and Фс is that on cooling) may be represented as the
sum of contributions from the heat capacity of the sample (Cp) and the
differential heat loss (Фloss) [37].
2.2. Differential scanning calorimetry
The DSC experiments were performed using the DSC204 F1 Phoenix
differential scanning calorimeter (Netzsch, Germany) in an argon at-
mosphere (flow rate 150 mL min−1) with the heating/cooling rate of
10 K min−1. DSC was calibrated according to the manufacturer's re-
commendations by measuring six standard compounds (Hg, In, Sn, Bi,
Zn, and CsCl) as described previously [31]. The 40 μL aluminum cru-
cibles sealed with a pierced lid having a hole of 0.5 mm hole were used.
Before the experiment, aluminum crucibles were annealed at 473 K for
30 min.
Heating:
(T) = C (T)
× dT/dth + loss,h (T)
h
p
(2)
Cooling:
(T) = C (T)
× dT/dtc + loss,c (T)
The specific heat capacities of Leu-Leu and cyclo(Leu-Leu) were
measured as described elsewhere [49]. The measurement procedure
included three steps. Firstly, the baseline for the empty crucibles was
determined. Then using the baseline obtained, a standard sample
(sapphire disc) with a weight of 21.05 mg and a powder of dipeptide
(8−9 mg) were sequentially measured in the same crucible. This pro-
cedure was repeated three times for each sample. The calculation of the
heat capacity was performed using the Netzsch Proteus Thermal Ana-
lysis 6.1.0 according equation:
c
p
(3)
The difference between the heat flow rates measured during heating
and cooling, taking into account, that dT/dth = - dT/dtc, can be written
h (T)
c (T) = 2 × Cp (T) × dT/dt
(4)
So, heat capacity may be calculated as
Cp (T) = [ h (T)
c (T)]2 × dT/dt
(5)
Before the experiments, the dipeptides were heated three times from
293 K to 423 K with the rate of 100 K s−1 to remove residual water and
methanol.
cp = msapphire/mdipeptide × (DSCdipeptide − DSCbaseline)/
(DSCsapphire − DSCbaseline) × cp,sapphire
where cp and cp,sapphire are specific heat capacities of dipeptide and
sapphire [J g−1 K−1], mdipeptide and msapphire are masses of dipeptide
and sapphire [mg], DSCdipeptide, DSCsapphire and DSCbaseline are DSC
signals obtained for sample, standard sample and baseline [μW].
Leu-Leu was previously heated up to 428 K to remove adsorbed
water [50]. The specific heat capacity (accuracy of 2%) was measured
in the range between 313 K and 413 K in case of Leu-Leu and between
313 K and 483 K for cyclo(Leu-Leu). Calculation of heat capacities was
made for a linear region on the DSC heating and cooling curves in the
temperature range from 343 to 411 K (Leu-Leu) and 363–453 K (cyclo
(Leu-Leu)).
2.4. Kinetic analysis of cyclization of Leu-Leu in solid state
Kinetic analysis was performed following the ICTAC recommenda-
tions [52,53] using the NETZSCH Kinetics Neo 2.1.2.2 software
package. The “model-free” Ozawa-Flynn-Wall (OFW) [54–56] and
Kissinger-Akahira-Sunose (KAS) Eq. (6) methods [57,58] were used.
The same set of experimental data was used further for finding the
topochemical equation as described in Ref. [29–31,59]. A suitable ki-
netic model was estimated using the following model-based ap-
proaches: reaction of nth order with autocatalysis by product (CnB) Eq.
(7), reaction of nth order with m-Power autocatalysis by product (Cnm)
Eq. (8), expanded Prout-Tompkins equation (Bna) Eq. (9).
2.3. Fast scanning calorimetry
ln(β/T2) = Const – Ea/RT
d /dt = A exp(Ea/RT)(1
(6)
(7)
The FSC experiments were performed using the Flash DSC1 calori-
meter (Mettler-Toledo, Switzerland) with a UFS1 sensor and TC-100
cooler (Huber, Germany) [51] under an atmosphere of nitrogen with a
flow rate of 50 mL min−1. The sensor had been conditioned and cali-
brated before use as described previously [45]. The temperature
)n(1 + kcat
)n(1 + kcat
)
m
d /dt = A exp(Ea/RT)(1
d /dt = A exp(Ea/RT)(1
)
(8)
(9)
n
k
cat
)
2

A.S. Safiullina, et al.
ThermochimicaActa692(2020)178748
Fig. 1. DSC curves of (a) Leu-Leu, (b) cyclo(Leu-Leu) and sapphire.
where β is heating rate, dα / dt – reaction rate, A – Arrhenius constant
(pre-exponential factor), Ea – activation energy, R – gas constant, T –
temperature, n – reaction order, kcat – catalytic rate constant, α –
conversion degree (conversion rate), m – exponent.
3.2. Kinetic analysis of cyclization of Leu-Leu in solid state according to
FSC
The state of the Leu-Leu sample before and after the reaction is
shown in Fig. 5a, c, respectively. The FSC curves were measured at
heating rates of 300, 700 and 900 K s−1, Fig. 5b.
3. Results and discussion
Calculations of activation energies and logarithms of the Arrhenius
constant (pre-exponential factor) were made for temperature ranges
corresponding to the chemical reaction: from 452 to 471 K for the
heating rate of 300 K s−1, from 445 to 478 K for the heating rate of
700 K s−1, from 452 to 479 K for the heating rate of 900 K s−1. Results
of OFW and KAS analysis are given in Figs. 6 and 7.
The cyclization of dipeptide leucyl-leucine in the solid state was
studied using fast scanning calorimetry. Previously, for this dipeptide
the temperatures of water desorption (397 K) and chemical reaction
(450 K) were found using simultaneous thermogravimetry and differ-
ential scanning calorimetry with mass spectrometric analysis of the
evolved gases [30].
According
to
the
Ozawa-Flynn-Wall
(OFW)
and
Kissinger–Akahira–Sunose (KAS) methods the value of Ea decreases
from 584
36 kJ mol−1 (OFW) and 584
36 kJ mol−1 (KAS) to
371
44 kJ mol−1 (OFW) and 371
45 kJ mol−1 (KAS). The cal-
3.1. The heat capacity of dipeptides
culation was made for the interval of conversion 0.2−0.8.
The observed descending correlation indicates a complex nature of
the reaction and is in agreement with the previously established auto-
catalytic nature of this reaction [30]. One can assume that the accu-
mulation of the reaction product, which acts as a catalyst, leads to a
decrease in the activation energy with increasing conversion.
The dependencies of the activation energy Ea and the logarithm of
the Arrhenius constant (pre-exponential factor) logA on the conversion
α in Figs. 6 and 7 suggest the kinetic compensation effect. One can
assume that this effect may be due to decrease the sample mass used
simultaneously with increasing of the heating rate [60] as well as the
autocatalytic nature of this reaction [30].
First, the heat capacities of the dipeptides were determined by DSC.
For this, DSC curves were obtained for dipeptides and a standard
sample (sapphire), Fig. 1. To calculate the heat capacities, linear re-
gions of the curves were used.
The dependences of heat capacities of crystalline Leu-Leu and cyclo
(Leu-Leu) on the temperature calculated using the methods of ratios
and DIN 51007 are shown in Fig. 2. The linear dependences obtained
were extrapolated to 298 K. The standard values of specific cp
·
298 15 and
298 15
molar heat capacities cp,m
·
of crystalline Leu-Leu and cyclo(Leu-
Leu) at T =298.15 K are shown in Table 1. From the data obtained by
298 15
the used methods of ratios and DIN 51007, the average values of cp
·
Using linear regression methods, a search for the optimal kinetic
model was made. The best fit between theoretical and experimental
curves was achieved using the equations CnB, Cnm and BnA (extended
Prout–Tompkins equation), which are topochemical equations for the
nth-order reactions with autocatalysis [61]. The kinetic parameters
calculated using these models, as well as statistical quality parameters,
are given in Table 2.
were calculated.
Next, the heat capacity of the studies dipeptides was determined
using FSC. The dipeptides were recrystallized from methanol to obtain
individual crystals. Crystals were placed in the center of the measuring
region of the sensor on a drop of methanol, Fig. 3a, b.
The heating and cooling curves were determined for the empty
sensor and samples prepared by FSC, Fig. 4a–c. The calculation of heat
capacities was made using the FSC heating and cooling curves in the
temperature range from 323 to 413 K (Leu-Leu) and 323–443 K (cyclo
(Leu-Leu). The examples of obtained dependencies are shown in
Fig. 4d, e.
The correlation of experimental points from FSC curves with the
calculated lines in accordance with equation CnB is shown in Fig. 8. We
believe that an improvement in correlation can be achieved by using
samples with equal masses. This will provide a close thermal contact
area between crystals of different samples and the sensor surface, and a
close topochemical reaction rate.
The values of absolute Cp and the values of specific cp were used to
estimate the mass of the dipeptide crystals. In the case of Leu-Leu,
The kinetic parameters obtained in the present work are in agree-
ment with the results of kinetic studies obtained by thermogravimetry
[30]. Thus, the FSC method allows to study the cyclization of dipeptide
in the solid state. The mass of samples can be calculated by using their
specific heat capacities. The information about samples mass allows to
take into account possible effects of different sample masses on the
samples were heated and cooled with rates of 300, 700, and 900 K s−1
.
Sample masses were determined from Eq.(1) as ca. 65, 53, and 13 ng.
The heating and cooling curves shown in Fig. 4a correspond to the Leu-
Leu sample with mass of 13 ng. The weight of cyclo(Leu-Leu) used to
measure the heat capacity was approximately 79 ng.
3

A.S. Safiullina, et al.
ThermochimicaActa692(2020)178748
Fig. 2. The dependence of the heat capacity on the temperature of the Leu-Leu, calculated in accordance with the methods of (a) ratios and (b) DIN 51007, and cyclo
(Leu-Leu), calculated in accordance with the methods of (c) ratios and (d) DIN 51007. Experimental data (red line) were extrapolated to temperature 298 K (For
interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).
experimental results [52].
Table 1
298.15
Standard specific heat capacity cp
and average molar heat capacity
It is interesting to note that for dipeptides consisting of glycine and
alanine residues, the cyclization was not observed under fast heating
with rates of 2000 K sec−1 and more [62]. Moreover, the cyclization of
Gly-Gly in the solid state is accompanied by its decomposition under
heating with rates of 5−20 K min-1 [33,63]. So, one can assume that
FSC can be used for study the cyclization of the dipeptides with rela-
tively large substituents.
cp,m298.15 of crystalline Leu-Leu (Mm =244.33 g mol−1) and cyclo(Leu-Leu) (Mm
=226.33 g mol−1).
298.15
J K−1 mol−1
Dipeptide
cp298.15, J K−1 g−1
cp,m
,
Method of ratios DIN 51007
Average value
Leu-Leu
Cyclo(Leu-
Leu)
1.56
1.47
0.03
0.03
1.56
1.48
0.03 1.56
0.03 1.48
0.03
0.03
381
335
8
7
Fig. 3. Images of crystals of (a) Leu-Leu and (b) cyclo(Leu-Leu).
4

A.S. Safiullina, et al.
ThermochimicaActa692(2020)178748
Fig. 4. Examples of heating and cooling curves obtained by FSC for (a) empty UFS1 sensor, (b) Leu-Leu sample without correction by subtracting the empty sensor
measurement, (c) cyclo(Leu-Leu) sample with correction by subtracting the empty sensor measurement and the dependences of the heat capacity of (d) Leu-Leu and
(e) cyclo(Leu-Leu) on temperature, calculated from the FSC data.
Fig. 5. Images of Leu-Leu sample before (a) and after (c) heating up to 220 °C with rate of 900 K s−1, (b) data of FSC analysis for Leu-Leu at different heating rates.
The curves were scaled for a better view.
Fig. 6. OFW analysis of Leu-Leu cyclization in solid state: correlations of (a) the activation energy Ea and (b) the logarithm of the Arrhenius constant logA (A =
[s−1]) versus degree of conversion α.
5

A.S. Safiullina, et al.
ThermochimicaActa692(2020)178748
Fig. 7. KAS analysis of Leu-Leu cyclization in solid state: correlations of (a) the activation energy Ea and (b) the logarithm of the Arrhenius constant logA (A = [s−1])
versus degree of conversion α.
Author contributions
Table 2
Kinetic parameters of the reaction of Leu-Leu cyclization in solid state and
statistical parameters of the calculation.
The manuscript was written through contributions of all authors. All
authors have given approval to the final version of the manuscript. All
authors contributed equally.
Equation A → B
Ea, kJ mol−1
log A, log(s−1
)
Reaction order
Corr. coeff.
CnB
Cnm
Bna
475
477
479
54.4
54.4
55.8
1.2
1.1
1.0
0.99311
0.99317
0.99229
Funding sources
The work was supported by Grant No. 14.Y26.31.0019 from
Ministry of Science and Higher Education of Russian Federation.
CRediT authorship contribution statement
Aisylu S. Safiullina: Investigation, Formal analysis. Aleksey V.
Buzyurov: Investigation. Sufia A. Ziganshina: Writing - original draft.
Alexander V. Gerasimov: Formal analysis. Christoph Schick: Writing
- review & editing. Valery V. Gorbatchuk: Writing - original draft.
Marat A. Ziganshin: Conceptualization.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgements
Fig. 8. Correlation of experimental points from FSC curves with the calculated
curves in accordance with the equation CnB. The curves were normalized to
sample mass.
S.A.Z. acknowledges financial support from the government as-
signment for FRC Kazan Scientific Center of RAS.
References
4. Conclusions
[1] A.D. Borthwick, 2,5-Diketopiperazines: synthesis, reactions, medicinal chemistry,
and bioactive natural products, Chem. Rev. 112 (2012) 3641–3716, https://doi.
org/10.1021/cr200398y.
The principal possibility of using the fast scanning calorimetry to
study the cyclization of dipeptides in the solid state has been demon-
strated for the first time. The kinetic parameters of the leucyl-leucine
cyclization were determined, which are in good convergence with the
results obtained by classical thermal analysis, regardless of the huge
difference in the used scanning rates of ∼103 times of these two
methods. The heat capacities of leucyl-leucine and cyclo(leucyl-leucyl)
determined by the methods of classical differential calorimetry and fast
scanning calorimetry were used for calculation of the samples weight.
The relatively small amount of dipeptide required for FSC experiments
allows the studies of expensive and hardly available highly pure sub-
stances. One can assume that the high heating and cooling rates in FSC
will allow to study cyclization of dipeptides even if it decomposes upon
heating with relatively slow rates of several degrees per minute. This
approach may be also applied for non-homogeneous samples, from
which crystals with different habits may be selected and studied.
[2] A.D. Borthwick, N.C. Da Costa, 2,5-Diketopiperazines in food and beverages: taste
and bioactivity, Crit. Rev. Food Sci. Nutr. 57 (2017) 718–742, https://doi.org/10.
1080/10408398.2014.911142.
[3] S. Manchineella, T. Govindaraju, Molecular self-assembly of cyclic dipeptide deri-
vatives and their applications, ChemPlusChem 82 (2017) 88–106, https://doi.org/
10.1002/cplu.201600450.
[4] A.S. Safiullina, S.A. Ziganshina, N.M. Lyadov, A.E. Klimovitskii, M.A. Ziganshin,
V.V. Gorbatchuk, Role of water in the formation of unusual organogels with cyclo
(leucyl-leucyl), Soft Matter 15 (2019) 3595–3606, https://doi.org/10.1039/
c9sm00465c.
[5] T.A. Hill, N.E. Shepherd, F. Diness, D.P. Fairlie, Constraining cyclic peptides to
mimic protein structure motifs, Angew. Chem. Int. Ed. 53 (2014) 13020–13041,
https://doi.org/10.1002/anie.201401058.
[6] A.K. Malde, T.A. Hill, A. Iyer, D.P. Fairlie, Crystal structures of protein-bound cyclic
peptides, Chem. Rev. 119 (2019) 9861–9914, https://doi.org/10.1021/acs.
chemrev.8b00807.
[7] W.A. Loughlin, J.D. Tyndall, M.P. Glenn, D.P. Fairlie, Update 1 of: beta-strand
mimetics, Chem. Rev. 104 (2004) 6085–6117, https://doi.org/10.1021/cr040648k.
[8] A.D. De Araujo, H.N. Hoang, W.M. Kok, F. Diness, P. Gupta, T.A. Hill, R.W. Driver,
D.A. Price, S. Liras, D.P. Fairlie, Comparative α-helicity of cyclic pentapeptides in
water, Angew. Chem. Int. Ed. 53 (2014) 6965–6969, https://doi.org/10.1002/anie.
201310245.
6

A.S. Safiullina, et al.
ThermochimicaActa692(2020)178748
[9] A.K. Mishra, J. Choi, S.-J. Choi, K.-H. Baek, Cyclodipeptides: an overview of their
biosynthesis and biological activity, Molecules 22 (2017) 1796–1809, https://doi.
org/10.3390/molecules22101796.
diphenylalanine: a chiral phase built from achiral subunits, Chirality 32 (2020)
693–703, https://doi.org/10.1002/chir.23195.
[33] A.J. Smith, F.I. Ali, D.V. Soldatov, Glycine homopeptides: the effect of the chain
length on the crystal structure and solid state reactivity, CrystEngComm 16 (2014)
7196–7208, https://doi.org/10.1039/c4ce00630e.
[10] Z. Qian, T. Liu, Y.Y. Liu, R. Briesewitz, A.M. Barrios, S.M. Jhiang, D. Pei, Efficient
delivery of cyclic peptides into mammalian cells with short sequence motifs, ACS
Chem. Biol. 8 (2013) 423–431, https://doi.org/10.1021/cb3005275.
[11] Z. Kang, G. Ding, Z. Meng, Q. Meng, The rational design of cell-penetrating peptides
for application in delivery systems, Peptides 121 (2019) 170149–170158, https://
doi.org/10.1016/j.peptides.2019.170149.
[34] M. Jaworska, A. Jeziorna, E. Drabik, M.J. Potrzebowski, Solid state NMR study of
thermal processes in nanoassemblies formed by dipeptides, J. Phys. Chem. C 116
(2012) 12330–12338, https://doi.org/10.1021/jp302616n.
[35] F. Rodante, G. Marrosu, G. Catalani, Thermal analysis of different series of dipep-
tides, Thermochim. Acta 197 (1992) 147–160, https://doi.org/10.1016/0040-
6031(92)87046-D.
[12] D.S. Nielsen, N.E. Shepherd, W. Xu, A.J. Lucke, M.J. Stoermer, D.P. Fairlie, Orally
absorbed cyclic peptides, Chem. Rev. 117 (2017) 8094–8128, https://doi.org/10.
1021/acs.chemrev.6b00838.
[36] F. Rodante, F. Fantauzzi, G. Catalani, Thermal analysis of a series of dipeptides
having α‐alanine as the first term. Mutual influence of structures, Thermochim.
Acta 284 (1996) 351–365, https://doi.org/10.1016/0040-6031(96)02827-4.
[37] C. Schick, V. Mathot, Fast Scanning Calorimetry, Springer, Cham, 2016.
[38] A. Abdelaziz, D.H. Zaitsau, A. Buzyurov, A.A. Minakov, S.P. Verevkin, C. Schick,
Fast scanning calorimetry: sublimation thermodynamics of low volatile and ther-
mally unstable compounds, Thermochim. Acta 676 (2019) 249–262, https://doi.
org/10.1016/j.tca.2019.05.008.
[13] A.F.B. Rader, F. Reichart, M. Weinmuller, H. Kessler, Improving oral bioavailability
of cyclic peptides by n-methylation, Bioorg. Med. Chem. 26 (2018) 2766–2773,
https://doi.org/10.1016/j.bmc.2017.08.031.
[14] M.B. Martins, I. Carvalho, Diketopiperazines: biological activity and synthesis,
Tetrahedron 63 (2007) 9923–9932, https://doi.org/10.1016/j.tet.2007.04.105.
[15] S.N. Kumar, C. Dileep, C. Mohandas, B. Nambisana, J. Ca, Cyclo(D-Tyr-D-Phe): a
new antibacterial, anticancer, and antioxidant cyclic dipeptide from Bacillus sp. N
strain associated with a rhabditid entomopathogenic nematode, J. Pept. Sci. 20
(2014) 173–185, https://doi.org/10.1002/psc.2594.
[39] S.E. Lapuk, L.S. Zubaidullina, M.A. Ziganshin, T.A. Mukhametzyanov, C. Schick,
A.V. Gerasimov, Kinetic stability of amorphous solid dispersions with high content
of the drug: a fast scanning calorimetry investigation, Int. J. Pharm. 562 (2019)
113–123, https://doi.org/10.1016/j.ijpharm.2019.03.039.
[16] M. Yang, C. Yuan, G. Shen, R. Chang, R. Xing, X. Yan, Cyclic dipeptide nanoribbons
formed by dye-mediated hydrophobic self-assembly for cancer chemotherapy, J.
Colloid Interface Sci. 557 (2019) 458–464, https://doi.org/10.1002/psc.2594.
[17] H. Habashita, M. Kokubo, S.-I. Hamano, N. Hamanaka, M. Toda, S. Shibayama,
H. Tada, K. Sagawa, D. Fukushima, K. Maeda, H. Mitsuya, Design, synthesis, and
biological evaluation of the combinatorial library with a new spirodiketopiperazine
scaffold. Discovery of novel potent and selective low-molecular-weight CCR5 an-
tagonists, J. Med. Chem. 49 (2006) 4140–4152, https://doi.org/10.1021/
jm060051s.
[40] K.V. Gataullina, A.V. Buzyurov, M.A. Ziganshin, P.L. Padnya, I.I. Stoikov, C. Schick,
V.V. Gorbatchuk, Using fast scanning calorimetry to detect guest-induced poly-
morphism by irreversible phase transitions in the nanogram scale, CrystEngComm
21 (2019) 1034–1041, https://doi.org/10.1039/c8ce01865k.
[41] P. Cebe, X. Hu, D.L. Kaplan, E. Zhuravlev, A. Wurm, D. Arbeiter, C. Schick, Beating
the heat-fast scanning melts silk beta sheet crystals, Sci. Rep. 3 (2013) 1130–1137,
https://doi.org/10.1038/srep01130.
[18] W. Lee, S.-H. Lee, M. Kim, J.-S. Moon, G.-W. Kim, H.-G. Jung, I.H. Kim, J.E. Oh,
H.E. Jung, H.K. Lee, K.B. Ku, D.-G. Ahn, S.-J. Kim, K.-S. Kim, J.-W. Oh, Vibrio
vulnificus quorum-sensing molecule cyclo(Phe-Pro) inhibits rig-i-mediated antiviral
innate immunity, Nat. Commun. 9 (2018) 1606–1619, https://doi.org/10.1038/
s41467-018-04075-1.
[42] P. Cebe, D. Thomas, J. Merfeld, B.P. Partlow, D.L. Kaplan, R.G. Alamo, A. Wurm,
E. Zhuravlev, C. Schick, Heat of fusion of polymer crystals by fast scanning ca-
lorimetry, Polymer 126 (2017) 240–247, https://doi.org/10.1016/j.polymer.2017.
08.042.
[43] Y.Z. Chua, H.T. Do, C. Schick, D. Zaitsau, C. Held, New experimental melting
properties as access for predicting amino-acid solubility, RSC Adv. 8 (2018)
6365–6372, https://doi.org/10.1039/c8ra00334c.
[19] K. Strom, J. Sjogren, A. Broberg, J. Schnurer, Lactobacillus plantarum MiLAB 393
produces the antifungal cyclic dipeptides cyclo(L-Phe-L-Pro) and cyclo(L-Phe-trans-
4-OH-L-Pro) and 3-phenyllactic acidб, Appl. Environ. Microbiol. 68 (2002)
4322–4327, https://doi.org/10.1128/AEM.68.9.4322-4327.2002.
[44] Y. Corvis, A. Wurm, C. Schick, P. Espeau, Vitreous state characterization of phar-
maceutical compounds degrading upon melting by using fast scanning calorimetry,
J. Phys. Chem. B 119 (2015) 6848–6851, https://doi.org/10.1021/acs.jpcb.
5b03041.
[20] H. Kim, J.-Y. Hwang, J. Shin, K.-B. Oh, Inhibitory effects of diketopiperazines from
marine-derived streptomyces puniceus on the isocitrate lyase of Candida albicans,
Molecules 24 (2019) 2111–2120, https://doi.org/10.3390/molecules24112111.
[21] H.H. Zhang, W.Y. Yu, L. Li, F. Wu, Q. Chen, Y. Yang, C.-H. Yu, Protective effects of
diketopiperazines from Moslae Herba against influenza a virus‐induced pulmonary
inflammation via inhibition of viral replication and platelets aggregation, J.
Ethnopharmacol. 215 (2018) 156–166, https://doi.org/10.1016/j.jep.2018.01.005.
[22] M.P. De Carvalho, W.-R. Abraham, Antimicrobial and biofilm inhibiting diketopi-
perazines, Curr. Med. Chem. 19 (2012) 3564–3577, https://doi.org/10.2174/
092986712801323243.
[45] M.I. Yagofarov, S.E. Lapuk, T.A. Mukhametzyanov, M.A. Ziganshin, C. Schick,
B.N. Solomonov, Application of fast scanning calorimetry to the fusion thermo-
chemistry of low-molecular-weight organic compounds: fast-crystallizing m-ter-
phenyl heat capacities in a deeply supercooled liquid state, Thermochim. Acta 668
(2018) 96–102, https://doi.org/10.1016/j.tca.2018.08.015.
[46] M.I. Yagofarov, S.E. Lapuk, T.A. Mukhametzyanov, M.A. Ziganshin, C. Schick,
B.N. Solomonov, Thermochemical properties of 1,2,3,4-tetraphenylnaphthalene
and 1,3,5-triphenylbenzene in crystalline and liquid states studied by solution and
fast scanning calorimetry, J. Mol. Liq. 278 (2019) 394–400, https://doi.org/10.
1016/j.molliq.2019.01.046.
[23] A. Jeziorna, K. Stopczyk, E. Skorupska, K. Luberda-Durnas, M. Oszajca, W. Lasocha,
M. Górecki, J. Frelek, M.J. Potrzebowski, Cyclic dipeptides as building units of
nano- and microdevices: synthesis, properties, and structural studies, Cryst. Growth
Des. 15 (2015) 5138–5148, https://doi.org/10.1021/acs.cgd.5b01121.
[24] S. Manchineella, N.A. Murugan, T. Govindaraju, Cyclic dipeptide-based ambidex-
trous supergelators: minimalistic rational design, structure-gelation studies, and in
situ hydrogelation, Biomacromolecules 18 (2017) 3581–3590, https://doi.org/10.
1021/acs.biomac.7b00924.
[47] A. Abdelaziz, D.H. Zaitsau, T.A. Mukhametzyanov, B.N. Solomonov, P. Cebe,
S.P. Verevkin, C. Schick, Melting temperature and heat of fusion of cytosine re-
vealed from fast scanning calorimetry, Thermochim. Acta 657 (2017) 47–55,
https://doi.org/10.1016/j.tca.2017.09.013.
[48] A. Abdelaziz, D.H. Zaitsau, N.V. Kuratieva, S.P. Verevkin, C. Schick, Melting of
nucleobases. Getting the cutting edge of “Walden’s Rule”, Phys. Chem. Chem. Phys.
21 (2019) 12787–12797, https://doi.org/10.1039/c9cp00716d.
[25] M. Yang, R. Xing, G. Shen, C. Yuan, X. Yan, A versatile cyclic dipeptide hydro-
gelator: self-assembly and rheology in various physiological conditions, Colloids
Surf. A Physicochem. Eng. Asp. 572 (2019) 259–265, https://doi.org/10.1016/j.
colsurfa.2019.04.020.
[49] R.N. Nagrimanov, A.A. Samatov, A.V. Buzyurov, A.G. Kurshev, M.A. Ziganshin,
D.H. Zaitsau, B.N. Solomonov, Thermochemical properties of mono- and di-cyano-
aromatic compounds at 298.15 K, Thermochim. Acta 668 (2018) 152–158, https://
doi.org/10.1016/j.tca.2018.07.026.
[26] C.L. Esposito, P. Kirilov, V.G. Roullin, Organogels, promising drug delivery systems:
an update of state-of-the-art and recent applications, J. Control. Release 271 (2018)
1–20, https://doi.org/10.1016/j.jconrel.2017.12.019.
[50] M.A. Ziganshin, A.S. Safiullina, S.A. Ziganshina, A.V. Gerasimov, V.V. Gorbatchuk,
Non-zeolitic properties of the dipeptide L-leucyl-L-leucine as a result of the specific
nanostructure formation, Phys. Chem. Chem. Phys. 19 (2017) 13788–13797,
https://doi.org/10.1039/c7cp01393k.
[27] M. Kurbasic, S. Semeraro, A.M. Garcia, S. Kralj, E. Parisi, C. Deganutti, R. De Zorzi,
S. Marchesan, Microwave‐assisted cyclization of unprotected dipeptides in water to
2,5‐piperazinediones and self‐assembly study of products and reagents, Synthesis
51 (2019) 2839–2844, https://doi.org/10.1055/s-0037-1612376.
[51] V. Mathot, M. Pyda, T. Pijpers, G.V. Poel, E. Van de Kerkhof, S. Van Herwaarden,
F. Van Herwaarden, A. Leenaers, The Flash DSC 1, a power compensation twin-type,
chip-based fast scanning calorimeter (FSC): first findings on polymers,
Thermochim. Acta 522 (2011) 36–45, https://doi.org/10.1016/j.tca.2011.02.031.
[52] S. Vyazovkin, A.K. Burnham, J.M. Criado, A. Luis, L.A. Perez-Maqueda, C. Popescu,
N. Sbirrazzuoli, ICTAC kinetics committee recommendations for performing kinetic
computations on thermal analysis data, Thermochim. Acta 520 (2011) 1–19,
https://doi.org/10.1016/j.tca.2011.03.034.
[28] M. Weiss, C. Muth, R. Drumm, H.O.K. Kirchner, Thermal decomposition of the
amino acids glycine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine,
arginine and histidine, BMC Biophys. 11 (2018) 1–15, https://doi.org/10.1186/
s13628-018-0042-4.
[29] M.A. Ziganshin, A.V. Gerasimov, S.A. Ziganshina, N.S. Gubina, G.R. Abdullina,
A.E. Klimovitskii, V.V. Gorbatchuk, A.A. Bukharaev, Thermally induced dipheny-
lalanine cyclization in solid phase, J. Therm. Anal. Calorim. 125 (2016) 905–912,
https://doi.org/10.1007/s10973-016-5458-y.
[53] S. Vyazovkin, K.Di Chrissafis, M.-R. Lorenzo, N. Koga, M. Pijolat, B. Roduit,
N. Sbirrazzuoli, J.-J. Suñol, ICTAC kinetics committee recommendations for col-
lecting experimental thermal analysis data for kinetic computations, Thermochim.
Acta 590 (2014) 1–23, https://doi.org/10.1016/j.tca.2014.05.036.
[54] T. Ozawa, A new method of analyzing thermogravimetric data, Bull. Chem. Soc.
Jpn. 38 (1965) 1881–1886, https://doi.org/10.1246/bcsj.38.1881.
[55] T. Ozawa, Estimation of activation energy by isoconversion methods, Thermochim.
Acta 203 (1992) 159–165, https://doi.org/10.1016/0040-6031(92)85192-X.
[56] J.H. Flynn, L.A. Wall, General treatment of the thermogravimetry of polymers, J.
Res. Bur. Stand. 70 (1966) 478–523, https://doi.org/10.6028/jres.070a.043.
[57] H.E. Kissinger, Variation of peak temperature with heating rate in differential
thermal analysis, J. Res. Bur. Stand. 57 (1956) 217–221, https://doi.org/10.6028/
[30] M.A. Ziganshin, A.S. Safiullina, A.V. Gerasimov, S.A. Ziganshina, A.E. Klimovitskii,
K.R. Khayarov, V.V. Gorbatchuk, Thermally induced self-assembly and cyclization
of L-leucyl-L-leucine in solid state, J. Phys. Chem. B 121 (2017) 8603–8610, https://
doi.org/10.1021/acs.jpcb.7b06759.
[31] M.A. Ziganshin, R.A. Larionov, A.V. Gerasimov, S.A. Ziganshina, A.E. Klimovitskii,
K.R. Khayarov, T.A. Mukhametzyanov, V.V. Gorbatchuk, Thermally induced cy-
clization of L-isoleucyl-L-alanine in solid state: effect of dipeptide structure on re-
action temperature and self-assembly, J. Pept. Sci. 25 (2019) e3177, https://doi.
org/10.1002/psc.3177.
[32] A. Pérez-Mellor, K. Le Barbu-Debus, A. Zehnacker, Solid-state synthesis of cyclo LD-
7

A.S. Safiullina, et al.
ThermochimicaActa692(2020)178748
jres.057.026.
[61] J. Opfermann, Kinetic analysis using multivariate non-linear regression. I. Basic
concepts, J. Therm. Anal. Calorim. 60 (2000) 641–658, https://doi.org/10.1023/
A:1010167626551.
[58] T. Akahira, T. Sunose, Method of determining activation deterioration constant of
electrical insulating materials, Res. Rep. Chiba Inst. Technol. 16 (1971) 22–31.
[59] V.A. Logvinenko, D.N. Dybtsev, V.A. Bolotov, V.P. Fedin, Thermal decomposition of
inclusion compounds on the base of the metal-organic framework
[Zn2(bdc)2(dabco)], J. Therm. Anal. Calorim. 121 (2015) 491–497, https://doi.org/
10.1007/s10973-015-4430-6.
[62] H.T. Do, Y.Z. Chua, J. Habicht, M. Klinksiek, M. Hallermann, D. Zaitsau, C. Schick,
C. Held, Melting properties of peptides and their solubility in water. Part 1: di-
peptides based on glycine or alanine, RSC Adv. 9 (2019) 32722–32734, https://doi.
org/10.1039/c9ra05730g.
[60] N. Koga, A review of the mutual dependence of Arrhenius parameters evaluated by
the thermoanalytical study of solid-state reactions: the kinetic compensation effect,
Thermochim. Acta 244 (1994) 1–20, https://doi.org/10.1016/0040-6031(94)
80202-5.
[63] M.A. Ziganshin, S.A. Ziganshina, N.S. Gubina, A.V. Gerasimov, V.V. Gorbatchuk,
A.A. Bukharaev, Thermal stability, sorption properties and morphology of films of
dipeptide and tripeptide based on glycine, Orient J Chem. 31 (2015) 1977–1984,
https://doi.org/10.13005/ojc/310415.
8