Synthesis and biological evaluation of novel amino-substituted derivatives of pyrido[2,3-d]pyrimidine as inhibitors of protein kinase CK2
Aim. A search for human protein kinase CK2 inhibitors in a series of new amino-substituted pyrido[2,3-d]pyrimidine derivatives. Methods. Organic synthesis, analytical and spectral methods, molecular docking, in vitro biochemical testing. Results. Synthesis of new pyrido[2,3-d]pyrimidine derivatives...
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Інститут молекулярної біології і генетики НАН України
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Zinchenko, A.N. Muzychka, L.V. Smolii, O.B. Bdzhola, V.G. Protopopov, M.V. Yarmoluk, S.M. 2019-06-13T12:06:14Z 2019-06-13T12:06:14Z 2017 Synthesis and biological evaluation of novel amino-substituted derivatives of pyrido[2,3-d]pyrimidine as inhibitors of protein kinase CK2 / A.N. Zinchenko, L.V. Muzychka, O.B. Smolii, V.G. Bdzhola, M.V. Protopopov, S.M. Yarmoluk // Вiopolymers and Cell. — 2017. — Т. 33, № 5. — С. 367-378. — Бібліогр.: 41 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.000960 https://nasplib.isofts.kiev.ua/handle/123456789/152990 547.828; 547.859; 577.151 Aim. A search for human protein kinase CK2 inhibitors in a series of new amino-substituted pyrido[2,3-d]pyrimidine derivatives. Methods. Organic synthesis, analytical and spectral methods, molecular docking, in vitro biochemical testing. Results. Synthesis of new pyrido[2,3-d]pyrimidine derivatives with various aminogroups in positions 4 and 6 of the heterocycle was developed. Two compounds inhibiting kinase CK2 in micromolar concentrations were found among these derivatives. Conclusion. New pyrido[2,3-d]pyrimidin-7-ones containing aminogroups in positions 4 and 6 of heterocyclic system and new 4-amino-substituted pyrido[2,3-d]pyrimidin-7-amine derivatives have been synthesized. The inhibition activity of new pyrido[2,3-d]pyrimidines has been examined and the optimization modes have been suggested. Methyl-2-[(7-aminopyrido[2,3-d]pyrimidine-6-yl)amino]benzoate and N-(4-anilino-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-3,4-dimethoxy- benzamide were found to inhibit protein kinase CK2 at IC50 of 6 and 19.5 μM, respectively. Мета. Пошук нових інгібіторів протеїнкінази СК2 людини в ряду нових амінозаміщених похідних піридо[2,3-d]піримідину. Методи. Органічний синтез, аналітичні та спектральні методи, молекулярний докінг, біохімічне тестування in vitro. Результати. Розроблено методи синтезу нових похідних піридо[2,3-d]піримідину з різноманітними аміногрупами в положеннях 4, 6, 7 гетероциклу. Серед синтезованих похідних піридо[2,3-d]піримідину виявлено дві сполуки, що інгібують кіназу СК2 в мікромолярних концентраціях. Висновки. Синтезовано нові піридо[2,3-d]піримідин-7-они, що містять аміногрупи в положеннях 4, 6 гетероциклічної системи, а також 4-амінозаміщені похідні піридо[2,3-d]піримідин-7-аміну. Досліджено інгібувальну активність похідних піридо[2,3-d]піримідину та запропоновано напрями хімічної оптимізації. Встановлено, що метил 2-[(7-амінопіридо[2,3-d]піримідин-4-іл)aмінo]бензоат та N-(4-aнілінo-7-oксo-7,8-дигідропіридо [2,3-d]піримідин-6-іл)-3,4-диметоксибензамід інгібують протеїнкіназу СК2 з ІС50 6 та 19,5 μМ відповідно. Цель. Поиск новых ингибиторов протеинкиназы СК2 человека в ряде новых аминозамещенных производных пиридо[2,3-d]пиримидина. Методы. Органический синтез, аналитические и спектральные методы, молекулярный докинг, биохимическое тестирование in vitro. Результаты. Разработаны методы синтеза новых производных пиридо[2,3-d]пиримидина с различными аминогруппами в положениях 4, 6, 7 гетероцикла. Среди синтезированных производных пиридо[2,3-d]пиримидина обнаружено два соединения, ингибирующие киназу СК2 в микромолярных концентрациях. Выводы. Синтезированы новые пиридо[2,3-d]пиримидин-7-оны, содержащие аминогруппы в положениях 4, 6 гетероциклической системы, а также 4-аминозамещенные производные пиридо[2,3-d]пиримидин-7-амина. Исследована ингибирующая активность производных пиридо[2,3-d]пиримидина и предложены направления химической оптимизации. Установлено, что метил-2-[(7-аминопиридо[2,3-d]пиримидин-4-ил)амин]бензоат и N-(4-анилин-7-оксо-7,8-дигидропиридо[2,3-d]пиримидин-6-ил)-3,4-диметоксибензамид ингибируют протеинкиназу СК2 с IC50 6 и 19,5 μМ соответственно. en Інститут молекулярної біології і генетики НАН України Вiopolymers and Cell Bioorganic Chemistry Synthesis and biological evaluation of novel amino-substituted derivatives of pyrido[2,3-d]pyrimidine as inhibitors of protein kinase CK2 Синтез та біологічна оцінка нових амінозаміщених похідних піридо[2,3-d]піримідину як інгібіторів протеїнкінази CK2 Синтез и биологическая оценка новых аминозамещенных производных пиридо[2,3-d]пиримидина в качестве ингибиторов протеинкиназы CK2 Article published earlier |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine |
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| title |
Synthesis and biological evaluation of novel amino-substituted derivatives of pyrido[2,3-d]pyrimidine as inhibitors of protein kinase CK2 |
| spellingShingle |
Synthesis and biological evaluation of novel amino-substituted derivatives of pyrido[2,3-d]pyrimidine as inhibitors of protein kinase CK2 Zinchenko, A.N. Muzychka, L.V. Smolii, O.B. Bdzhola, V.G. Protopopov, M.V. Yarmoluk, S.M. Bioorganic Chemistry |
| title_short |
Synthesis and biological evaluation of novel amino-substituted derivatives of pyrido[2,3-d]pyrimidine as inhibitors of protein kinase CK2 |
| title_full |
Synthesis and biological evaluation of novel amino-substituted derivatives of pyrido[2,3-d]pyrimidine as inhibitors of protein kinase CK2 |
| title_fullStr |
Synthesis and biological evaluation of novel amino-substituted derivatives of pyrido[2,3-d]pyrimidine as inhibitors of protein kinase CK2 |
| title_full_unstemmed |
Synthesis and biological evaluation of novel amino-substituted derivatives of pyrido[2,3-d]pyrimidine as inhibitors of protein kinase CK2 |
| title_sort |
synthesis and biological evaluation of novel amino-substituted derivatives of pyrido[2,3-d]pyrimidine as inhibitors of protein kinase ck2 |
| author |
Zinchenko, A.N. Muzychka, L.V. Smolii, O.B. Bdzhola, V.G. Protopopov, M.V. Yarmoluk, S.M. |
| author_facet |
Zinchenko, A.N. Muzychka, L.V. Smolii, O.B. Bdzhola, V.G. Protopopov, M.V. Yarmoluk, S.M. |
| topic |
Bioorganic Chemistry |
| topic_facet |
Bioorganic Chemistry |
| publishDate |
2017 |
| language |
English |
| container_title |
Вiopolymers and Cell |
| publisher |
Інститут молекулярної біології і генетики НАН України |
| format |
Article |
| title_alt |
Синтез та біологічна оцінка нових амінозаміщених похідних піридо[2,3-d]піримідину як інгібіторів протеїнкінази CK2 Синтез и биологическая оценка новых аминозамещенных производных пиридо[2,3-d]пиримидина в качестве ингибиторов протеинкиназы CK2 |
| description |
Aim. A search for human protein kinase CK2 inhibitors in a series of new amino-substituted pyrido[2,3-d]pyrimidine derivatives. Methods. Organic synthesis, analytical and spectral methods, molecular docking, in vitro biochemical testing. Results. Synthesis of new pyrido[2,3-d]pyrimidine derivatives with various aminogroups in positions 4 and 6 of the heterocycle was developed. Two compounds inhibiting kinase CK2 in micromolar concentrations were found among these derivatives. Conclusion. New pyrido[2,3-d]pyrimidin-7-ones containing aminogroups in positions 4 and 6 of heterocyclic system and new 4-amino-substituted pyrido[2,3-d]pyrimidin-7-amine derivatives have been synthesized. The inhibition activity of new pyrido[2,3-d]pyrimidines has been examined and the optimization modes have been suggested. Methyl-2-[(7-aminopyrido[2,3-d]pyrimidine-6-yl)amino]benzoate and N-(4-anilino-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-3,4-dimethoxy- benzamide were found to inhibit protein kinase CK2 at IC50 of 6 and 19.5 μM, respectively.
Мета. Пошук нових інгібіторів протеїнкінази СК2 людини в ряду нових амінозаміщених похідних піридо[2,3-d]піримідину. Методи. Органічний синтез, аналітичні та спектральні методи, молекулярний докінг, біохімічне тестування in vitro. Результати. Розроблено методи синтезу нових похідних піридо[2,3-d]піримідину з різноманітними аміногрупами в положеннях 4, 6, 7 гетероциклу. Серед синтезованих похідних піридо[2,3-d]піримідину виявлено дві сполуки, що інгібують кіназу СК2 в мікромолярних концентраціях. Висновки. Синтезовано нові піридо[2,3-d]піримідин-7-они, що містять аміногрупи в положеннях 4, 6 гетероциклічної системи, а також 4-амінозаміщені похідні піридо[2,3-d]піримідин-7-аміну. Досліджено інгібувальну активність похідних піридо[2,3-d]піримідину та запропоновано напрями хімічної оптимізації. Встановлено, що метил 2-[(7-амінопіридо[2,3-d]піримідин-4-іл)aмінo]бензоат та N-(4-aнілінo-7-oксo-7,8-дигідропіридо [2,3-d]піримідин-6-іл)-3,4-диметоксибензамід інгібують протеїнкіназу СК2 з ІС50 6 та 19,5 μМ відповідно.
Цель. Поиск новых ингибиторов протеинкиназы СК2 человека в ряде новых аминозамещенных производных пиридо[2,3-d]пиримидина. Методы. Органический синтез, аналитические и спектральные методы, молекулярный докинг, биохимическое тестирование in vitro. Результаты. Разработаны методы синтеза новых производных пиридо[2,3-d]пиримидина с различными аминогруппами в положениях 4, 6, 7 гетероцикла. Среди синтезированных производных пиридо[2,3-d]пиримидина обнаружено два соединения, ингибирующие киназу СК2 в микромолярных концентрациях. Выводы. Синтезированы новые пиридо[2,3-d]пиримидин-7-оны, содержащие аминогруппы в положениях 4, 6 гетероциклической системы, а также 4-аминозамещенные производные пиридо[2,3-d]пиримидин-7-амина. Исследована ингибирующая активность производных пиридо[2,3-d]пиримидина и предложены направления химической оптимизации. Установлено, что метил-2-[(7-аминопиридо[2,3-d]пиримидин-4-ил)амин]бензоат и N-(4-анилин-7-оксо-7,8-дигидропиридо[2,3-d]пиримидин-6-ил)-3,4-диметоксибензамид ингибируют протеинкиназу СК2 с IC50 6 и 19,5 μМ соответственно.
|
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0233-7657 |
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https://nasplib.isofts.kiev.ua/handle/123456789/152990 |
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Synthesis and biological evaluation of novel amino-substituted derivatives of pyrido[2,3-d]pyrimidine as inhibitors of protein kinase CK2 / A.N. Zinchenko, L.V. Muzychka, O.B. Smolii, V.G. Bdzhola, M.V. Protopopov, S.M. Yarmoluk // Вiopolymers and Cell. — 2017. — Т. 33, № 5. — С. 367-378. — Бібліогр.: 41 назв. — англ. |
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367
A. N. Zinchenko, L. V. Muzychka, O. B. Smolii
© 2017 A. N. Zinchenko et al.; Published by the Institute of Molecular Biology and Genetics, NAS of Ukraine on behalf of Bio-
polymers and Cell. This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium,
provided the original work is properly cited
UDC 547.828; 547.859; 577.151
Synthesis and biological evaluation of novel amino-substituted deriva-
tives of pyrido[2,3-d]pyrimidine as inhibitors of protein kinase CK2
A. N. Zinchenko1, L. V. Muzychka1, O. B. Smolii1, V. G. Bdzhola2,
M. V. Protopopov2, S. M. Yarmoluk2
1 Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine
1, Murmans'ka Str., Kyiv, Ukraine, 02094
2 Institute of Molecular Biology and Genetics, NAS of Ukraine
150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680
Smolii@bpci.kiev.ua
Aim. A search for human protein kinase CK2 inhibitors in a series of new amino-substituted
pyrido[2,3-d]pyrimidine derivatives. Methods. Organic synthesis, analytical and spectral
methods, molecular docking, in vitro biochemical testing. Results. Synthesis of new pyrido[2,3-
d]pyrimidine derivatives with various aminogroups in position[s] 4 and 6 of the heterocycle
was developed. Two compounds inhibiting kinase CK2 in micromolar concentrations were
found among these derivatives. Conclusion. New pyrido[2,3-d]pyrimidin-7-ones containing
aminogroups in position[s] 4 and 6 of heterocyclic system and new 4-amino-substituted
pyrido[2,3-d]pyrimidin-7-amine derivatives have been synthesized. The inhibition activity of
new pyrido[2,3-d]pyrimidines has been examined and the optimization modes have been sug-
gested. Methyl-2-[(7-aminopyrido[2,3-d]pyrimidine-6-yl)amino]benzoate and N-(4-anilino-7-
oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-3,4-dimethoxy- benzamide were found to in-
hibit protein kinase CK2 at IC50 of 6 and 19.5 μМ, respectively.
K e y w o r d s: pyrido[2,3-d]pyrimidine derivatives, synthesis, protein kinase CK2, the inhibi-
tion activity
Introduction
In recent years the development of protein
kinase inhibitors excites an increasing attention
in medical chemistry. Protein kinase СК2
(Casein kinase 2), one of significant molecular
targets, is the polysubstrate serine/threonine
kinase present in all eukaryotic cells. This
enzyme is an important link of numerous sig-
nal ways of a cell and is involved in various
pathological processes [4, 5]. This protein
kinase is known to have an increased activity
in inflammatory tissues and many tumors.
Therefore, protein kinase CK2 inhibitors are
of great therapeutical importance as anti-in-
flammatory and antitumor drugs [6–10]. This
Bioorganic Chemistry ISSN 1993-6842 (on-line); ISSN 0233-7657 (print)
Biopolymers and Cell. 2017. Vol. 33. N 5. P 367–378
doi: http://dx.doi.org/10.7124/bc.000960
368
A. N. Zinchenko, L. V. Muzychka, O. B. Smolii et al.
state is supported by the fact that “Silmitasertib”
(СХ-4945) is verified on the second stage of
clinical testing and might be a perspective
antitumor drug [4, 11]. Hence, the research for
new protein kinase inhibitors is fairly relevant.
CK2 inhibitors were found among deriva-
tives benzotriazole and benzimidazole [12, 13],
quinoline [14, 15], indolo[1,2-a]quinazoline
[16], thieno[2,3-d]pyrimidine [17, 18], pyr-
azine [19], pyrazolo[1,5-a]pyrimidine [20] and
other compounds.
The inhibition activity of pyrido[2,3-d]py-
rimidine derivatives toward CK2 kinase has
not been studied. Noteworthy, the substituted
pyrido[2,3-d]pyrimidines are the inhibitors of
EGFR [21-24], Cyclin-Dependent kinases [25,
26], Src-tyrosine kinase [27, 28] and c-Jun
N-Terminal kinase (JNK) [29,30]. It was found
that among 2-substituted pyrido[2,3-d]pyrim-
idin-7-one derivatives there are powerful selec-
tive inhibitors of CDK4/6 kinase (Palbociclib)
[25], Abl kinase (PD173955) [31, 32] and p38
MAP kinase (Pamapimod) [33] which are ef-
fective in the treatment of autoimmune and
cancer diseases.
In this work the search for CK2 inhibitors
amongst amino-substituted pyrido[2,3-d]py-
rimidine derivatives was carried out.
Materials and Methods
Chemistry
1Н and 13С NMR spectra were acquired on
Varian Mercury 400 (400 and 100 MHz for 1Н
and 13С nuclei, respectively) and Bruker
Avance DRX-500 (500 and 125 MHz for 1Н
and 13С nuclei, respectively) instruments, with
TMS as internal standard. 13С NMR signals
were assigned by using АРТ method. LCMS
spectra were performed on Agilent 1100 Series
HPLC equipped with diode array and Agilent
LC/MSD SL mass selective detector, ioniza-
tion method – chemical ionization at atmo-
spheric pressure, m/z scan range from 80 to
1000. Elemental analysis was performed at the
Analytical laboratory of the Institute of
Bioorganic Chemistry and Petrochemistry of
the NAS of Ukraine. Melting points were de-
termined on Boetius hot stage apparatus. The
reaction progress and purity of the obtained
compounds were controlled by TLC on Silufol
UV-254 plates using a 19:1 mixture of CHCl3–
MeOH as eluent.
Methyl (6-amino-4-chloro-7-oxopyrido
[2,3-d]pyrimidin-8(7H)-yl)acetate (2). Trie-
thy lamine (4.20 ml, 30 mmol) was added to a
suspension of aldehyde 1 (1.77 g, 10 mmol)
and glycine methyl ester hydrochloride (2.51 g,
20 mmol) in methanol (20 ml). Reaction mix-
ture was stirred for 5 h at 20–25 °С. The resul-
ting precipitate was filtered and recrystallized
from acetonitrile. Yield 0.96 g (36 %). M.p. =
192–194 ºС. 1H NMR (400 MHz, DMSO-d6),
δ: 3.65 s (3H, OCH3), 5.15 s (2H, CH2),
6.46 br.s (2H, NH2), 6.80 s (1H, H-5), 8.54 s
(1H, H-2); 13C NMR (100 MHz, DMSO-d6),
δ: 43.2 (CH2N), 52.7 (CH3O), 97.4 (CH), 114.7
(C), 140.6 (C), 148.7 (C), 150.7 (CH), 153.3
(C), 158.5 (C=O), 176.5 (C=O); MS: m/z 269
MH+. Calcd. for C10H9ClN4O3: C 44.71;
H 3.38; Cl 13.20; N 20.85. Found: C 44.78;
H 3.35; Cl 13.16; N 20.81.
6-Amino-4-chloropyrido[2,3-d]pyrimidin-
7(8H)-one (5). Triethylamine (3.37 ml,
22 mmol) was added to an aldehyde 4 (1.58 g,
10 mmol) and glycine methyl ester hydrochlo-
ride (1.38 g, 11 mmol) in methanol (20 ml)
and reaction mixture was refluxed within 7 h.
369
Novel amino-substituted deriva-tives of pyrido[2,3-d]pyrimidine as inhibitors of protein kinase CK2
The formed precipitate was filtered and recrys-
tallized from DMF. Yield 0.77 g (39%). M.p. =
318–320 ºС. 1H NMR (400 MHz, DMSO-d6),
δ: 6.27 br.s (2H, NH2), 6.73 s (1H, H-5), 8.46 s
(1H, H-2), 12.80 br.s (1H, NH); 13C NMR
(100 MHz, DMSO-d6), δ: 97.9 (С), 114.1
(СH), 141.6 (C), 149.5 (C), 151.6 (CH),
152.5(C), 159.6(C=O); MS: m/z 197 MH+.
Calcd. for C7H5ClN4O: C 42.77; H 2.56;
Cl 18.03; N 28.50. Found: C 42.81; H 2.54;
Cl 17.96; N 28.45.
General method of obtaining substituted
pyrido[2,3-d]pyrimidin-7(8H)-ones 3a-f,
6a-g. One of compounds 2, 5 (1 mmol), re-
spective amine (1 mmol) and triethylamine
(1 mmol) was refluxed for 6–8 h. Completion
of chemical reaction was controlled by TLC
method. Triethylamine (1 mmol) and corre-
sponding acid chloride (1 mmol) were added
to reaction mixture and obtained suspension
was refluxed within 2–3 h. The resulting pre-
cipitate was filtered and recrystallized from
propan-2-ol.
Methyl [6-(benzoylamino)-4-(methyla-
mino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl]
acetate (3a). Yield 0.21 g (57 %). M.p. = 247–
249 ºС. 1H NMR (400 MHz, DMSO-d6),
δ: 2.97 s (3H, CH3), 3.67 s (3H, OCH3), 5.16 s
(2H, CH2), 7.54–7.63 m (3H, CHarom), 7.96–
7.98 m (2H, J 7.2 Hz, CHarom), 8.30 br.s (1H,
NH), 8.37s (1H, H-5), 8.84 s (1H, H-2),
9.56 br.s (1H, NH); 13C NMR (125 MHz,
DMSO-d6), δ: 28.1 (CH3), 43.0 (CH2), 52.7
(OCH3), 97.9 (C), 112.8 (C), 127.0 (2CH),
128.6 (CH), 128.8 (2CH), 132.2 (CH), 132.3
(C), 149.2 (C), 156.5 (CH), 158.7 (C), 159.3
(C), 166.0 (C), 168.4 (C); MS: m/z 368 MH+.
Calcd. for C18H17N5O4: C 50.85; H 4.66;
N 19.06. Found: C 50.87; H 4.71; N 19.02.
Methyl [4-(ethylamino)-6-[(2-fluorobenzo-
yl)amino]-7-oxopyrido[2,3-d]pyrimidin-8(7H)-
yl]acetate (3b). Yield 0.21 g (53 %). M.p. =
219–221 ºС. 1H NMR (400 MHz, DMSO-d6),
δ: 1.19 t (3H, J 7.2 Hz, CH3), 3.50–3.54 m (2H,
CH2), 3.67 s (3H, OCH3), 5.16 s (2H, CH2),
7.41 q (2H, J 6.8 Hz, CHarom), 7.67 d (1H, J
6.8 Hz, CHarom), 7.97 d (1H, J 7.2 Hz, CHarom),
8.34 s (1H, H-5), 8.37 br.s. (1H, NH), 8.97 s
(1H, H-2), 9.80 br.s (1H, NH); 13C NMR (125
MHz, DMSO-d6), δ: 14.9 (CH3), 36.2 (CH2),
43.2 (CH2), 52.8 (OCH3), 97.3 (C), 116.5 (CH),
117.2 (C), 121.7 (C), 125.7 (CH), 126.3 (CH),
131.5 (CH), 134.9 (CH), 149.9 (C), 157.0 (CH),
158.3 (C), 159.0 (C), 161.2 (C), 161.8 (C),
168.8 (C); MS: m/z 400 MH+. Calcd. for
C19H18FN5O4: C 57.14; H 4.54; F 4.76; N 17.54.
Found: C 57.18; H 4.57; F 4.72; N 17.50.
Methyl [6-[(2-ethylbutanoyl)amino]-4-[(2-
methoxyethyl)amino]-7-oxopyrido[2,3-d]py-
rimidin-8(7H)-yl]acetate (3c). Yield 0.22 g
(54 %). M.p. = 138–140 ºС. 1H NMR
(400 MHz, DMSO-d6), δ: 0.84–0.90 m (6H,
2CH3), 1.43–1.50 m (2H, CH2), 1.53–1.60 m
(2H, CH2), 2.58–2.65 m (1H, CH), 3.53 t (2H,
J 7.6 Hz, CH2), 3.68 s (6H, 2OCH3), 5.14 s
(2H, CH2), 8.30-8.35 m (2H, H-5, NH), 8.85 s
(1H, H-2), 9.44 br.s (1H, NH), the protons of
the CH2 group are overlapped with water; 13C
NMR (125 MHz, DMSO-d6), δ: 12.0 (2CH3),
25.7 (2CH2), 43.1 (CH2), 49.0 (CH), 49.2
(CH2), 52.4 (OCH3), 58.2 (OCH3), 70.6 (CH2),
97.4 (C), 116.3 (C), 126.7 (CH), 149.8 (C),
156.3 (CH), 158.4 (C), 159.1 (C), 168.9 (C),
175.5 (C); MS: m/z 406 MH+. Calcd. for
C19H27N5O5: C 56.29; H 6.71; N 17.27. Found:
C 56.32; H 6.74; N 17.23.
Methyl [6-(acetylamino)-4-[(4-methoxy-
phenyl)amino]-7-oxopyrido[2,3-d]pyrimidin-
370
A. N. Zinchenko, L. V. Muzychka, O. B. Smolii et al.
8(7H)-yl]acetate (3d). Yield 0.23 g (58 %).
M.p. = 216–218 ºС. 1H NMR (400 MHz,
DMSO-d6), δ: 2.19 s (3H, CH3), 3.68 s (3H,
OCH3), 3.76 s (3H, OCH3), 5.17 s (2H, CH2),
6.94 d (2H, J 8.8 Hz, CHarom), 7.48 d (2H,
J 8.8 Hz, CHarom), 8.33 s (1H, H-5), 8.97 s (1H,
H-2), 9.63 br.s. (1H, NH), 9.73 br.s (1H, NH);
13C NMR (125 MHz, DMSO-d6), δ: 24.1
(CH3), 43.1 (CH2), 53.3 (OCH3), 55.4 (OCH3),
98.2 (C), 114.3 (2CH), 116.3 (C), 125.5 (2CH),
127.3 (CH), 132.2 (C), 150.3 (C), 156.3 (C),
156.5 (CH), 157.7 (C), 158.4 (C), 168.9 (C),
169.9 (C); MS: m/z 398 MH+. Calcd. for
C19H19N5O5: C 57.43; H 4.82; N 17.62. Found:
C 57.48; H 4.85; N 17.56.
Methyl [6-(benzoylamino)-4-[(4-methoxy-
phenyl)amino]-7-oxopyrido[2,3-d]pyrimidin-
8(7H)-yl]acetate (3e). Yield 0.27 g (59 %).
M.p. = 222–224 ºС. 1H NMR (400 MHz,
CDCl3), δ: 3.79 s (3H, OCH3), 3.82 s (3H,
OCH3), 5.31 s (2H, CH2), 6.92 d (2H, J 8.8 Hz,
CHarom), 7.44 d (2H, J 8.8 Hz, CHarom), 7.43–
7.60 m (4H, CHarom, NH), 7.90–7.92 m (2H,
CHarom), 8.43 s (1H, H-5), 9.04 s (1H, H-2),
9.29 br.s (1H, NH); MS: m/z 460 MH+. Calcd.
for C24H21N5O5: C 62.74; H 4.61; N 15.24.
Found: C 62.78; H 4.63; N 15.17.
Methyl [4-[(4-methoxyphenyl)amino]-7-
oxo-6-(pentanoylamino)pyrido[2,3-d]pyrimi-
din-8(7H)-yl]acetate (3f). Yield 0.23 g (52 %).
M.p. = 127–129 ºС. 1H NMR (400 MHz,
DMSO-d6), δ: 0.90 t (3H, J 6.8 Hz, CH3),
1.30–1.39 m (2H, CH2), 1.55–1.63 m (2H,
CH2), 3.68 s (3H, OCH3), 3.76 s (3H, OCH3),
5.17 s (2H, CH2), 6.94 d (2H, J 8.8 Hz, CHarom),
7.48 d (2H, J 8.8 Hz, CHarom), 8.33 s (1H,
H-5), 9.01 s (1H, H-2), 9.52 br.s (1H, NH),
9.75 br.s (1H, NH), the protons of the CH2
group are overlapped with water; 13C NMR
(125 MHz, DMSO-d6), δ: 13.8 (CH3), 22.3
(CH2), 27.7 (CH2), 36.2 (CH2), 43.1 (CH2),
53.0 (OCH3), 55.8 (OCH3), 98.3 (C), 114.4
(2CH), 116.0 (C), 125.2 (2CH), 127.3 (CH),
132.2 (C), 150.3 (C), 155.7 (C), 156.5 (CH),
157.7 (C), 158.4 (C), 168.9 (C), 172.8 (C);
MS: m/z 440 MH+. Calcd. for C22H25N5O5: C
60.13; H 5.73; N 15.94. Found: C 60.18; H
5.77; N 15.88.
3,4-Dimethoxy-N-[7-oxo-4-(propylamino)-
7,8-dihydropyrido[2,3-d]pyrimidin-6-yl]ben-
zamide (6a). Yield 0.20 g (54 %). M.p. =
261–263 ºС. 1H NMR (400 MHz, DMSO-d6),
δ: 0.91 t (3H, J 7.2 Hz, CH3), 1.57–1.64 m
(2H, CH2), 3.43 q (2H, J 7.2 Hz, CH2), 3.84 s
(6H, 2OCH3), 7.11 d (1H, J 8.4 Hz, CHarom),
7.52 s (1H, CHarom), 7.59 d (1H, J 8.4 Hz,
CHarom), 8.29 s (1H, H-5), 8.36 t (1H, J 6.4 Hz,
NH), 8.78 s (1H, H-2), 9.39 br.s (1H, NH),
12.67 br.s (1H, NH); MS: m/z 384 MH+. Calcd.
for C19H21N5O4: C 59.52; H 5.52; N 18.27.
Found: C 59.56; H 5.49; N 18.23.
N-[4-(Isobutylamino)-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl]-3,4-di-
methoxybenzamide (6b). Yield 0.21 g (53 %).
M.p. = 236–238 ºС. 1H NMR (500 MHz,
DMSO-d6), δ: 0.91 d (6H, J 6.5 Hz, 2CH3),
1.95-2.02 m (1H, CH), 3.85 s (6H, 2OCH3),
7.11 d (1H, J 8.5 Hz, CHarom), 7.53 s (1H,
CHarom), 7.59 d (1H, J 8.5 Hz, CHarom), 8.16 t
(1H, J 6.0 Hz, NH), 8.25 s (1H, H-5), 8.79 s
(1H, H-2), 9.38 br.s (1H, NH), 12.54 br.s (1H,
NH); MS: m/z 398 MH+. Calcd. for
C20H23N5O4: C 60.44; H 5.83; N 17.62. Found:
C 60.48; H 5.81; N 17.56.
N-(4-Anilino-7-oxo-7,8-dihydro py ri do-
[2,3-d]pyrimidin-6-yl)-4-methoxybenzamide
(6c). Yield 0.22 g (56 %). M.p. = 283–285 ºС.
1H NMR (400 MHz, DMSO-d6), δ: 3.85 s (3H,
371
Novel amino-substituted deriva-tives of pyrido[2,3-d]pyrimidine as inhibitors of protein kinase CK2
OCH3), 7.09–7.11 m (3H, CHarom), 7.33–
7.38 m (2H, CHarom), 7.67 d (2H, J 10.0 Hz,
CHarom), 7.96 d (2H, J 10.0 Hz, CHarom), 8.35
s (1H, H-5), 9.04 s (1H, H-2), 9.41 br.s (1H,
NH), 9.77 br.s (1H, NH), 12.77 br.s (1H, NH);
13C NMR (125 MHz, DMSO-d6), δ: 56.0
(OCH3), 91.9 (C), 114.6 (C), 117.3 (2CH),
123.1 (CH), 124.1 (C), 126.2 (2CH), 127.8
(CH), 128.0 (C), 129.4 (2CH), 129.6 (2CH),
151.3 (C), 156.6 (C), 157.1 (CH), 159.6 (C),
162.9 (C), 164.7 (C); MS: m/z 388 MH+.
Calcd. for C21H17N5O3: C 65.11; H 4.42; N
18.08. Found: C 65.14; H 4.46; N 18.03.
N-(4-Anilino-7-oxo-7,8-dihydro py ri-
do[2,3-d]pyrimidin-6-yl)-3,4-dimethoxybenza-
mide (6d). Yield 0.25 g (60 %). M.p. = 225–
227 ºС. 1H NMR (400 MHz, DMSO-d6), δ: 3.85
s (6H, 2OCH3), 7.11–7.13 m (2H, CHarom),
7.34–7.38 m (3H, CHarom), 7.55 s (1H, CHarom),
7.68 d (2H, J 8.0 Hz, CHarom), 8.36 s (1H, H-5),
9.02 s (1H, H-2), 9.46 br.s (1H, NH), 9.76 br.s
(1H, NH), 12.76 br.s (1H, NH); MS: m/z 418
MH+. Calcd. for C22H19N5O4: C 63.30; H 4.59;
N 16.78. Found: C 63.35; H 4.61; N 16.64.
3,4-Dimethoxy-N-{4-[(4-methoxyphenyl)
amino]-7-oxo-7,8-dihydropyrido[2,3-d]pyrim-
idin-6-yl}benzamide (6e). Yield 0.24 g (54 %).
M.p. = 278–280 ºС. 1H NMR (500 MHz,
DMSO-d6), δ: 3.76 s (3H, OCH3), 3.86 s (6H,
2OCH3), 6.89 d (2H, J 10.0 Hz, CHarom), 7.06 d
(1H, J 10.0 Hz, CHarom), 7.52 d (3H, J 10.0 Hz,
CHarom), 7.57 d (1H, J 10.0 Hz, CHarom), 8.25 s
(1H, H-5), 9.04 s (1H, H-2), 9.33 br.s (1H,
NH), 9.37 br.s (1H, NH), 12.68 br.s (1H, NH);
MS: m/z 448 MH+. Calcd. for C23H21N5O5:
C 61.74; H 4.73; N 15.65. Found: C 61.78;
H 4.75; N 15.62.
3,4-Dimethoxy-N-(7-oxo-4-piperidin-1-yl-
7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)ben-
zamide (6f). Yield 0.23 g (56 %). M.p. = 273–
275 ºС. 1H NMR (400 MHz, DMSO-d6), δ:
1.63–1.73 m (6H, 3CH2), 3.56–3.66 m (4H,
2CH2), 3.85 s (6H, 2OCH3), 7.11 d (1H,
J 8.4 Hz, CHarom), 7.50 s (1H, CHarom), 7.56 d
(1H, J 8.4 Hz, CHarom), 8.38 s (1H, H-5), 8.73 s
(1H, H-2), 9.33 br.s (1H, NH), 12.74 br.s (1H,
NH); MS: m/z 410 MH+. Calcd. for
C21H23N5O4: C 61.60; H 5.66; N 17.10. Found:
C 61.64; H 5.70; N 17.06.
N-(4-Azepan-1-yl-7-oxo-7,8-dihydro py ri-
do[2,3-d]pyrimidin-6-yl)-3,4-dimethoxyben-
zamide (6g). Yield 0.24 g (57 %). M.p. =
228–230 ºС. 1H NMR (500 MHz, DMSO-d6),
δ: 1.54–1.61 m (4H, 2CH2), 1.86–1.93 m (4H,
2CH2), 3.77–3.87 m (10H, 2OCH3, 2CH2),
7.10 d (1H, J 9.0 Hz, CHarom), 7.48 s (1H,
CHarom), 7.54 d (1H, J 9.0 Hz, CHarom), 8.27 s
(1H, H-5), 8.99 s (1H, H-2), 9.27 br.s (1H,
NH), 12.61 br.s (1H, NH); MS: m/z 424 MH+.
Calcd. for C22H25N5O4: C 62.40; H 5.95;
N 16.54. Found: C 62.43; H 5.97; N 16.50.
4-Chloropyrido[2,3-d]pyrimidin-7-amine
(7) was synthesized according to method [34].
Methyl 2-[(7-aminopyrido[2,3-d]pyrimi-
din-4-yl)amino]benzoate (8). The mixture of
pyrido[2,3-d]pyrimidine 7 (0.18 g, 1 mmol),
methyl 2-aminobenzoate (0.14 ml, 1.1 mmol)
and triethylamine (0.15 ml, 1.1 mmol) in ace-
tonitrile (2 ml) was refluxed for 7 h. The
formed precipitate was filtered and recrystal-
lized from ethanol– DMF (2:1). Yield 0.15 g
(53 %). M.p. = 174–176 ºС. 1H NMR
(400 MHz, DMSO-d6), δ: 3.78 s (3H, OCH3),
6.93 d (1H, J 9.2 Hz, H-6), 7.31 t (1H, J 8.0 Hz,
СHarom), 7.66-7.79 m (3H, NH2, CHarom),
7.97 d (1H, J 8.0 Hz, СHarom), 8.23 d (1H,
J 9.2 Hz, H-5), 8.39 d (1H, J 8.0 Hz, СHarom),
8.57 s (1H, H-2), 11.24 br.s (1H, NH); 13C
372
A. N. Zinchenko, L. V. Muzychka, O. B. Smolii et al.
NMR (125 MHz, DMSO-d6), δ: 52.8 (OCH3),
101.2 (C), 113.8 (CH), 114.0 (C), 125.3 (CH),
131.0 (CH), 133.4 (CH), 133.9 (CH), 139.0
(CH), 152.7 (C), 154.5 (C), 158.5 (CH), 159.6
(C), 162.9 (C), 167.6 (C); MS: m/z 296 MH+.
Calcd. for C15H13N5O2: C 61.06; H 4.47;
N 23.65. Found: C 61.01; H 4.44; N 23.72.
Biochemical testing
Сompounds were tested using in vitro kinase
assay [35]. Each test was done in triplicate in a
reaction volume of 30µL, containing 6 µg of
peptide substrate RRRDDDSDDD (New
England Biolabs); 10 units of recombinant hu-
man CK2 holoenzyme (New England Biolabs);
50 µM ATP and γ-labeled 32P ATP, diluted to
specific activity 100 µCi/µM; CK2 buffer (20
mM Tris-HCl, pH 7.5; 50 mM KCl; 10 mM
MgCl2) and inhibitor in varying concentrations.
Incubation time was 20 min at 30oC. The reac-
tion was stopped by adding an equal volume of
10 % o-phosphoric acid and the reaction mixture
was loaded onto 20-mm discs of phosphocel-
lulose paper (Whatman). Disks were washed
three times with 1 % o-phosphoric acid solution,
air-dried at room temperature, and counted by
the Cherenkov method in a beta-counter (LKB).
As a negative control an equal volume of DMSO
was added to the reaction mixture. Percent in-
hibition was calculated as ratio of substrate-in-
corporated radioactivity in the presence of in-
hibitor to the radioactivity incorporated in con-
trol reactions, i.e. in the absence of inhibitor.
Serial dilutions of inhibitor stock solution were
used to determine its IC50 concentration.
Molecular docking
Preparation of ligand and receptor molecules.
Ligands were prepared by MGL Tools 1.5.6
[36] and Vega ZZ (command line) [37]. The
catalytic subunit of protein kinase CK2 com-
plex with a stable analogue of ATP (PDB code
3NSZ) was used as a target for docking [38].
Water molecules, ions, and ligands were re-
moved from the PDB file. The receptor was
prepared using MGL Tools and AutoGrid.
Hydrogen atoms were removed from nonpolar
atoms. The incoming formats of receptor and
ligands data were converted into PDBQT-
format with Vega ZZ in AUTODOCK force
field.
Flexible docking. Autodock 4.2.6 programs
package was used for the receptor-based fle-
xib le docking [36]. Parameters for docking
calculation were set as described previously
[39]. Autodock results were scored with
Autodock scoring function and visual analysis
of the best-scored complexes was performed
using Discovery Studio Visualizer 4.0 (http://
accelrys.com/).
Results and discussion
To identify new inhibitors of protein kinase
CK2 among pyrido[2,3-d]pyrimidines, the
receptor-based virtual screening of the virtual
library (3408 pyridopyrimidine derivatives)
was carried out. The molecular docking of
ligands was performed with AutoDock 4.2.6
program targeting ATP-binding site of CK2.
The most promising 14 compounds which had
the best estimated binding energies were se-
lected for further synthesis and biochemical
evaluation.
4,6-Dichloropyrimidin-5-carbaldehyde 1
was chosen as the initial compound for syn-
thesis of pyrido[2,3-d]pyrimidine derivatives
containing aminogroups in positions 4 and 6
of core heterocycle (Scheme 1). Owing to
373
Novel amino-substituted deriva-tives of pyrido[2,3-d]pyrimidine as inhibitors of protein kinase CK2
interaction of aldehyde 1 with glycine methyl
ester in methanol in the presence of triethyl-
amine, intromolecular cyclization with follow-
ing formation of 6-amino-4-chloro-
7-oxopyrido[2,3-d]pyrimidine 2 takes place.
Therefore, replacement of the chlorine atom
with the aliphatic amines fragments in the
compound 2 and the reaction of acylation lead
to the formation of the target products 3.
In order to synthesize pyrido[2,3-d]pyrimi-
dine derivatives 6, 8 as an initial reagent it was
utilized 4-amino-6-chloropyrimidin-5-carbal-
dehyde (Scheme 2). 6-Amino-4-chloro-7-
oxopyrido[2,3-d]pyrimidine 5 was obtained by
reaction of aldehyde 4 with glycine methyl
ester in the presence of triethylamine.
7-Aminopyrido[2,3-d]pyrimidine 7 was synthe-
sized via Wittig reaction. Products of cyclization
N
N
Cl
Cl
H
O
N
N
Cl
O
N O
NH2
OMe
NR1R2
N
N
O
N O
N
H
R
O
OMe
R1R2NH, Et3N
, Et3NNH2 O
OMe
1
R1R2N = MeNH (3a); EtNH (3b); MeO(CH2)2NH (3c); 4-MeOC6H4NH (3d,e,f).
R = Me (3d); n-Bu (3f); CH(Et)2 (3c); Ph (3a,e); 2-FC6H4 (3b).
, MeCN
, MeCN
1)
MeOH
HCl.
2 3 a-f
RC(O)Cl, Et3N2)
Scheme 1. Synthesis of amino-substituted pyrido[2,3-d]pyrimidin-7-ones derivatives 3.
N
N
Cl
H
O
, Et3N N
N N
H
O
NH2
Cl
O
OMe R1R2NH, Et3N
NR1R2
N
N N
H
O
N
H
R
O
N
N
Cl
N NH2
NR3R4
N
N N NH2
R3R4NH, Et3N
, MeOH
HCl∙H2N , MeCN
, MeCN
4
5
7 8
6 a-g
1)
2)
, MeCN
Ph3P=CH-CN
Et3N, MeCN
RC(O)Cl, Et3N
R1R2N = n-PrNH (6a); i-BuNH (6b); PhNH (6c,d); 4-MeOC6H4NH (6e); (CH2)5N (6f); (CH2)6N (6g).
R = 4-MeOC6H4 (6c); 3,4-(MeO2)C6H3 (6a,b,d-g); R3R4N = 2-MeOC(O)C6H4NH (8).
NH2
Scheme 2. Synthesis of pyrido[2,3-d]pyrimidine derivatives 6, 8.
374
A. N. Zinchenko, L. V. Muzychka, O. B. Smolii et al.
5 and 7 were shown to be convenient synthons
for the preparation of new 4-amino-substituted
pyrido[2,3-d]pyrimidine derivatives 6, 8.
The structures of synthesized compounds
were proven by elemental analysis, 1Н and 13С
NMR data and LCMS methods.
14 pyrido[2,3-d]pyrimidine derivatives
were synthesized and their effect on the en-
zyme activity was investigated. In vitro ex-
periments revealed that 2 compounds inhibit
the activity of protein kinase CK2 (Fig. 1).
The complex of compound 6c with the ATP-
acceptor site of protein kinase CK2 obtained
with molecular docking shows that the
pyrido[2,3-d]pyrimidine heterocycle of com-
pound 6c is located in the adenine pocket of
the ATP-binding site (Fig. 2). The hydrogen
bond with the hinge region is formed between
the NH-group of heterocycle and the carbonyl
group of the amino acid residue Val116. The
substituent at the position 6 of heterocycle is
directed into deep pocket of the ATP-binding
site and forms stacking with Phe113. The sub-
stituent at the position 4 of heterocycle resides
in the ribose pocket of the ATP-binding site
and forms hydrophobic contact with Leu45.
In case of compound 8, pyrido[2,3-d]py-
rimidine heterocycle is located mirrored and
deeper in the ATP acceptor site in comparison
with compound 6c (Fig. 3). The hydrogen bond
interactions with the hinge region of CK2 oc-
cur between the backbone NH and carboxyl
oxygen of Val116 and N-atom at position 6 of
heterocycle and the amino group at position 7
of pyrido[2,3-d]pyrimidine. The substituent at
position 4 of heterocycle is directed into deep
pocket of the ATP binding site and forms stack-
ing with Phe113 and additional hydrogen bond
with Lys68. A higher activity of compound 8
(IC50 = 6 μM) compared to compound 6c
(IC50 = 19,5 μM) can be explained by its tigh-
ter interaction with CK2.
There are some ways of chemical optimiza-
tion of pyrido[2,3-d]pyrimidines to increase
their activity toward protein kinase CK2.
Taking into account the similarity of binding
mode of compound 8 with binding modes of
flavones and thienopyrimidines obtained ear-
lier [17,40,41] the introduction of hydrophobic
groups, in particular, methyl, ethyl, phenyl or
halogens (Br or Cl), into the position 5 of
pyrido[2,3-d]pyrimidine can significanly in-
crease the inhibitory activity of its derivatives.
Also, improvement can be achieved by substi-
tuting 2-aminobenzoic acid methyl ester to
2-aminobenzoic acid or especially 3-amino-
benzoic acid at position 4 of heterocycle. Such
replacement will allow pyridopyrimidine de-
rivatives to form ion bonds with Lys68 that
N
N N
H
O
N
H
O
NH
OMe
N
N N NH2
NH
O
OMe
86 c
IC50 = 19,5µM IC50 = 6 µM
N
N N
H
O
N
H
O
NH
OMe
N
N N NH2
NH
O
OMe
86 c
IC50 = 19,5µM IC50 = 6 µM
Fig. 1. Struc-
tures and IC50
values of
pyrido[2,3-d]
pyrimidine de-
rivatives.
375
Novel amino-substituted deriva-tives of pyrido[2,3-d]pyrimidine as inhibitors of protein kinase CK2
will significantly enhance their interaction with
the ATP acceptor site of protein kinase CK2.
Conclusion
A convenient approach to the synthesis of the new
pyrido[2,3-d]pyrimidine derivatives containing
amino groups in positions 4, 6 and 7 of hetero-
cyclic system has been developed. The results of
biochemical research have shown the perspective
of the search for protein kinase CK2 inhibitors
among pyrido[2,3-d]pyrimidines derivatives.
Methyl 2-[(7-amino py ri do[2,3-d]pyrimidin-4-yl)
amino]benzoate and N-(4-anilino-7-oxo-7,8-
dihydropy ri do[2,3-d]pyrimidin-6-yl)-3,4-dime-
thoxybenzamide were determined to inhibit ki-
nase CK2 in IC50 6 and 19,5 μМ respectively.
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Синтез та біологічна оцінка нових
амінозаміщених похідних піридо[2,3-d]
піримідину як інгібіторів протеїнкінази CK2
Г. М. Зінченкo, Л. В. Музичкa, O. Б. Смолій,
В. Г. Бджолa, М. В. Протопопов, С. М. Ярмолюк
Мета. Пошук нових інгібіторів протеїнкінази СК2
людини в ряду нових амінозаміщених похідних
піридо[2,3-d]піримідину. Методи: органічний синтез,
аналітичні та спектральні методи, молекулярний до-
кінг, біохімічне тестування in vitro. Результати.
Розроблено методи синтезу нових похідних
піридо[2,3-d]піримідину з різноманітними аміногру-
пами в положеннях 4, 6, 7 гетероциклу. Серед синте-
зованих похідних піридо[2,3-d]піримідину виявлено
дві сполуки, що інгібують кіназу СК2 в мікромолярних
концентраціях. Висновки. Синтезовано нові
піридо[2,3-d]піримідин-7-они, котрі містять аміногру-
пи в положеннях 4, 6 гетероциклічної системи, а також
4-амінозаміщені похідні піридо[2,3-d]піримідин-7-
аміну. Досліджено інгібувальну активність похідних
піридо[2,3-d]піримідину та запропоновано напрями
хімічної оптимізації. Встановлено, що метил 2-[(7-амі-
нопіридо[2,3-d]піримідин-4-іл)aмінo]бензоат та N-(4-
aнілінo-7-oксo-7,8-дигідропіридо [2,3-d]піримідин-6-
іл)-3,4-диметоксибензамід інгібують протеїнкіназу СК2
з ІС50 6 та 19,5 μМ відповідно.
К л юч ов і с л ов а: похідні піридо[2,3-d]піримідину,
синтез, протеїнкіназа СК2, інгібувальна активність.
Синтез и биологическая оценка новых
аминозамещенных производных пиридо[2,3-d]
пиримидина в качестве ингибиторов
протеинкиназы CK2
А. Н. Зинченкo, Л. В. Музычкa, О. Б. Смолий,
В. Г. Бджола, Н. В. Протопопов, С. Н. Ярмолюк
Цель. Поиск новых ингибиторов протеинкиназы СК2
человека в ряде новых аминозамещенных производных
пиридо[2,3-d]пиримидина. Методы: органический
синтез, аналитические и спектральные методы, моле-
кулярный докинг, биохимическое тестирование in vitro.
Результаты. Разработаны методы синтеза новых про-
изводных пиридо[2,3-d]пиримидина с различными
аминогруппами в положениях 4, 6, 7 гетероцикла.
Среди синтезированных производных пиридо[2,3-d]
пиримидина обнаружено два соединения, ингибиру-
ющие киназу СК2 в микромолярных концентрациях.
Выводы. Синтезированы новые пиридо[2,3-d]пири-
мидин-7-оны, содержащие аминогруппы в положени-
ях 4, 6 гетероциклической системы, а также 4-амино-
замещенные производные пиридо[2,3-d]пирими-
дин-7-амина. Исследована ингибирующая активность
производных пиридо[2,3-d]пиримидина и предложены
направления химической оптимизации. Установлено,
что метил-2-[(7-аминопиридо[2,3-d]пиримидин-4-ил)
амин]бензоат и N-(4-анилин-7-оксо-7,8-дигидропи ри-
до[2,3-d]пиримидин-6-ил)-3,4-диметоксибензамид
ингибируют протеинкиназу СК2 с IC50 6 и 19,5 μМ
соответственно.
К л юч е в ы е с л ов а: производные пиридо[2,3-d]
пиримидина, синтез, протеинкиназа СК2, ингибирую-
щая активность.
Received 12.08.2017
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