Synthesis of new quinazoline-containing hydroxamic acids as potential HDAC/VEGFR inhibitors. Unusual rearrangements with pyrrolidone ring opening and dehydration of 3-N-hydroxyquinazoline fragment containing tetracycles

Article abstract of DOI:10.1016/j.tetlet.2019.151315

Synthesis pathways were developed and new hydroxamic acids were obtained as potential inhibitors of HDAC/VEGFR2, including tetracycles containing quinazolinone fragment as a “cap”. Further biological testing of the obtained compounds will give an opportunity to estimate the real prospects of the chosen research direction.

Full text of DOI:10.1016/j.tetlet.2019.151315

Journal Pre-proofs
Synthesis of new quinazoline-containing hydroxamic acids as potential HDAC/
VEGFR inhibitors. Unusual rearrangements with pyrrolidone ring opening and
dehydration of 3-N-hydroxyquinazoline fragment containing tetracycles
Anton V. Kolotaev, Karine R. Matevosyan, Vasiliy N. Osipov, Derenik S.
Khachatryan
PII:
S0040-4039(19)31099-8
DOI:
https://doi.org/10.1016/j.tetlet.2019.151315
TETL 151315
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
15 September 2019
21 October 2019
23 October 2019
Please cite this article as: Kolotaev, A.V., Matevosyan, K.R., Osipov, V.N., Khachatryan, D.S., Synthesis of new
quinazoline-containing hydroxamic acids as potential HDAC/VEGFR inhibitors. Unusual rearrangements with
pyrrolidone ring opening and dehydration of 3-N-hydroxyquinazoline fragment containing tetracycles, Tetrahedron
Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151315
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Synthesis of new quinazoline-containing hydroxamic acids as
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potential HDAC/VEGFR ihibitors . Unusual rearrangements
with pyrrolidone ring opening and dehydration of 3-N-
hydroxyquinazoline fragment containing tetracycles.
Anton V. Kolotaev , Karine R. Matevosyan , Vasiliy N., Osipov and Derenik S. Khachatryana
a
b
a,c
Zinc binding
group
O
Capping
group
O
N
N
O
O
N
H
Linker
H

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Synthesis of new quinazoline-containing hydroxamic acids as potential
HDAC/VEGFR inhibitors. Unusual rearrangements with pyrrolidone ring
opening and dehydration of 3-N-hydroxyquinazoline fragment containing
tetracycles.
a
b
a,c
a
Anton V. Kolotaev , Karine R. Matevosyan , Vasiliy N., Osipov and Derenik S. Khachatryan
a
The Federal State Unitary Enterprise «Institute of Chemical Reagents and High Purity Chemical Substances of National Research Centre «Kurchatov
Institute», Bogorodsky val,3, Moscow 107076, Russia
D.Mendeleev University of Chemical Technology of Russia, Miusskaya square, 9, Moscow, 125047, Russia
b
c
N.N. Blokhin NMRC of oncology of the Health Ministry of Russia, 115478, Moscow, Kashirskoye Highway,23, Russia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Synthesis pathways were developed and new hydroxamic acids were obtained as potential
inhibitors of HDAC/VEGFR2, including tetracycles containing quinazolinone fragment as a
"cap". Further biological testing of the obtained compounds will give an opportunity to estimate
the real prospects of the chosen research direction.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Targeted therapy
Hybrid inhibitors
HDAC/VEGFR2
Hydroxamic acids
Quinazoline
—
——

Corresponding author. Tel.: +7-903-613-3660; fax: +7-495-963-7247; e-mail: derenik-s@yandex.ru

2
Tetrahedron
In one of our previous works30 we described the total synthesis of
1
. Introduction
derivatives of quinazolinone by interaction of amides of anthranilic
acid with appropriate aldehydes. Applying this methodology in
present work, 6aH-isoindolo[2,3-a]quinazoline-5,11-diones and their
One of the most promising strategies for the treatment of cancer,
autoimmune and some neurodegenerative diseases is the use of
targeted drugs. The basis of targeted therapy is the presence of a
target in the cellular signaling pathway, which can be affected by
applying a substance with a high degree of affinity to this target. To
expand the arsenal of already known targeted drugs, many new
compounds are synthesized and studied in the world. Among them
the derivatives of quinazoline as well. They are known to have a
number of important pharmacological effects and can be found as
6
-hydroxy-analogues
were synthesized by the interaction of
anthranilamides and 2-amino-N-hydroxybenzamides with 2-formyl
benzoic acids. By further alkylation and treatment of the obtained
esters with hydroxylamine we wanted to obtain target derivatives of
hydroxamic acids connected to dihydroquinazolinone containing
condensed tetracycles as a "caps" (figure 2).
R
O
1
2
3
part of more than 100 drugs: antibiotics , pacemakers , vasodilators
R
O
O
O
H
O
4
X
O
and analgesics . In addition, these derivatives actively inhibit the
O
N
N
Br
O
X
4
O
5
3a,b
N
proliferation of tumor cells .
N
O
N
H
X
NH2
O
X=H
clorobenzene, refluxe
a) R=H, b) R=OMe
O
R
R
In the last decade, there are methods that develops rapidly to
overcome multiple drug resistance (MDR) of malignant tumors, by
R
R
1(X=H), 2(X=OH)
4
5
a,b (X=H),
a,b (X=OH)
NH2OH
6a,b
6
-9
O
N
creating a hybrid multi-functional inhibitors , combining two or
more multidirectional ligands in one molecule, which are able to
suppress tumor growth by different mechanisms. For example,
hybrid inhibitors of histone deacetylase (HDAC) in combination
O
H
N
N
O
H
O
R
7a,b
R
1
0,11
with inhibitors of receptors of vascular endothelial growth factor
VEGFR2, multi-functional inhibitors of EGFR/HER2/HDAC12-14,
Figure 2. Scheme of synthesis of tetracyclic derivatives of
hydroxamic acids.
1
5
5,16-18
HDAC/TUBULINE and others
. Most HDACi have a three-
component structure consisting of a zinc-binding site (zinc binding
group, ZBG), a linker, capable of occupying the enzyme channel,
and a functional group interacting with amino acid residues at the
entrance to the active HDAC center ("cap", capping group) (figure
It was found that the synthesis of quinazoline-containing
tetracycles proceeds smoothly with high yields when anthranilamides
1
3
and 2 boils in chlorobenzene with 2-carboxybenzaldehyde 3a and
b. The methods of synthesis, yield and physico-chemical data of the
obtained tetracyclic amides 4a,b and its hydroxy analogs 5a,b are
1
).
given in supplementary information.
Zinc binding
group
Subsequently, it was unexpectedly discovered that amides 4a,b in
classical alkylation conditions (RT, K CO or Cs CO /DMSO or
2 3 2 3
DMF) do not lead to esters 6a,b (products of normal N-alkylation).
When these processes carrying out with heating (80-100°C)
uninterpretable mixture of products are obtained.
Capping
group
3
1
O
Linker
H
N
O
N
H
O
H
The cyclic hydroxamic acids 5a, b under the same conditions are
alkylated with ethyl 6-bromohexanoic acid giving low yield of esters
8
a,b. In the latter case, in a detailed analysis of the reaction mixtures,
Figure 1. Pharmacophore structure of HDACi on the example of the
drug Vorinostat.
it was found that, along with the corresponding esters 8a,b, they
contain compounds with acidic functions, which were easily
separated in crystalline form upon neutralization of the mother liquor
with hydrochloric acid. A physicochemical study of the obtained
acids showed that they have the structure of compounds 9a,b. It is
A lot of research has been done to find different "caps" for
HDACi. In particular, it is shown that the quinazoline cycle can act
as an effective domain of surface interaction ("cap") with active sites
1
9-23
24,25
1
of HDAC
,
matrix metalloproteinases
(MMPs) peptide
of VEGFR–2.
indicated by proton signals in the H NMR spectrum and masses in
2
6
10,11,27-29
mass spectra, as well as by comparison with known literature data31,
deformylase (PDF), and as novel inhibitors
3
2
.
2
. Main
O
O
O
O
O
N
OH
O
N
N
OEt
In this study, a number of new hydroxamic acids, which are
Br
Base /
4 OEt
5
2
NH CO H
+
N
N
R
connected through a linker with polycondensated heterocycles
containing a quinazolinone fragment, are synthesized. Such bulk
Solvent
O
O
R
R
R
R
R
"caps" may become suitable structures for interaction with active
5
a (R = H)
5b (R = OMe)
9a,b
8
a,b
HDAC sites and inhibit VEGFR2 receptors as well.
Figure 3. Scheme of the transformations of the tetracyclic
hydroxamic acids 5a,b in the compounds 8a,b and 9a,b.
By changing the conditions of alkylation reactions (the ratio of
reagents, reaction temperature, solvents, etc.), we tried to direct the
reaction towards the selective formation of target products 8a,b (see
table 1). Determined that when reaction is carried out without
alkylhalogenide (figure 4) cyclic hydroxamic acid 5a turns into the
compound 9a with almost quantitative yield (TLC of reaction
mixture after the completion of the process indicates the absence of a
spot of compound 5a and the presence of a single product 9a). By
replacing potassium carbonate with cesium carbonate and carrying
out the reaction in DMF at standard conditions we managed to direct
the reaction towards the formation of the desired compounds 8a,b
with a sufficiently high selectivity (63% and 74%, respectively; see
table 1).

3
The obtained results indicate that the side reaction of formation of
compounds 9a,b occurs is due to the opening of the pyrrolidinone
tetracycle fragment under the action of a strongly basic solution
(
almost super-basic solution) with sequential dehydration and
hydration or vice versa according to the scheme:
O
O
O
OH
O M
N
M2CO3
MHCO3
N
N
N
N
N
-
-MOH
O
O
O
R
R
R
R
R
R
11a,b
+MHCO3
5
a,b
10a,b
-CO2
+MOH
O
O
O
O M
N
N
CO2M
NH
CO2M
R
R
-MOH
R
R
N
R
R
H
N
H
N
MO2C
14a,b
12a,b
13a,b
H
O
NH
CO2H
R
R
N
9
a,b
Figure 4. Probable directions for deriving by-products 9a,b.
As noted above, the direct alkylation of amides 4a,b didn’t lead to
positive results and for the synthesis of compounds 7a,b we had to
design another way, consisting in the initial preparation of
anthranilamide, corresponding to the amino acid ester, followed by
the construction of tetracycles 6a,b with the already replaced amide
group in the "one-pot" reaction:
R
O
R
O
H
O
O
O
O
O
N
O
3a,b
O
O
O
H2N
O
N
H
N
4
3 O
N
O
NH2
clorobenzene, refluxe
O
R
R
15
14
NH2OH
6a,b
O
N
a) R=H, b) R=OMe
O
H
N
N
O
H
O
R
R
7a,b
Figure 5. Scheme of the synthesis of the tetracyclic hydroxamic
acids 7a,b.
It should be noted that the implementation of this pathway was
very successful and the target products 7a,b (hydroxamic acids
bound through a linker with a tetracycle containing a quinazolinone
fragment) were obtained with satisfactory total yields (70-80%) and
with high purity (more than 96% by LSMS).
Conclusion
Thus, in the course of research, synthesis pathways were
developed and new hydroxamic acids were obtained as potential
inhibitors of HDAC/VEGFR2, including tetracycles containing
quinazolinone fragment as a "cap". Further biological testing of the
obtained compounds will give an opportunity to estimate the real
prospects of the chosen research direction.
Acknowledgements
We appreciate the Ministry of Education and Science of
Russia (grant agreement N 075-11-2018-172 from 03.12.18.
RFMEFI62418X0051) for financial support.
Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/

4
Tetrahedron
Table 1. Dependences of yields of normal alkylation products 8a,b and side products 9a,b from the conditions of the synthesis
№
exp.
Initial
tetracycle
Molar ratio of
*1: 2: Base
Base
Temp., °C (Time, h)
Solvent
Yield, %
8
9
(
a or b)
35(a)
16(b)
48(b)
74(b)
63(a)
(a or b)
57(a)
63(b)
24(b)
-**
1
2
3
4
5
6
7
5a
5b
5b
5b
5a
5b
5a
1.05: 1: 2
1.10: 1: 2
1: 1.15: 1
1: 1.5:1.25
1: 1.5:1.25
1: 1.5:1.25
1: 0: 2
K
K
2
CO
CO
3
RT (16), 75 (2)
RT (23)
RT (50)
RT (9)
DMSO
DMSO
DMF
DMF
DMF
2
3
NaH60% (in oil)
Cs
Cs
2
CO
CO
3
2
3
RT (20)
RT (6)
70 (1)
-**
K
K
2
CO
CO
3
DMF
DMSO
55(b)***
13(b)
83(a)
2
3
-
*
*
*
1 – compound 5a or 5b; 2 – ethyl 6-bromohexanoate
* Compound 9 by TLC was observed in the mother liquor (didn’t isolate)
** + 1:1 mixture of compounds 8b and 9b (not separated from each other)
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