Inhibition of in vitro transcription by 2-arylidene derivatives of thiazolo[3,2-α]benzimidazol-3(2H)-one
Aim. To evaluate a series of 2-substituted thiazolo[3,2-α]benzimidazolones as potential transcription inhibitors. Methods. Compounds were tested in a model transcription system based on T7 RNA polymerase. Results. The testing revealed a number of compounds able to inhibit transcription at micromolar...
Gespeichert in:
| Datum: | 2010 |
|---|---|
| Hauptverfasser: | , , , , , , , , |
| Format: | Artikel |
| Sprache: | English |
| Veröffentlicht: |
Інститут молекулярної біології і генетики НАН України
2010
|
| Schriftenreihe: | Вiopolymers and Cell |
| Schlagworte: | |
| Online Zugang: | https://nasplib.isofts.kiev.ua/handle/123456789/154215 |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| Назва журналу: | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| Zitieren: | Inhibition of in vitro transcription by 2-arylidene derivatives of thiazolo[3,2-α]benzimidazol-3(2H)-one / L.G. Palchykovska, I.V. Alexeeva, V.V. Negrutska, Yu.K. Kostyuk, T.M. Indychenko, O.M. Kostenko, D.V. Kryvorotenko, A.D. Shved, I.Ya. Dubey // Вiopolymers and Cell. — 2010. — Т. 26, № 6. — С. 508-511. — Бібліогр.: 19 назв. — англ. |
Institution
Digital Library of Periodicals of National Academy of Sciences of Ukraine| id |
nasplib_isofts_kiev_ua-123456789-154215 |
|---|---|
| record_format |
dspace |
| spelling |
nasplib_isofts_kiev_ua-123456789-1542152025-02-09T23:25:10Z Inhibition of in vitro transcription by 2-arylidene derivatives of thiazolo[3,2-α]benzimidazol-3(2H)-one Інгібування транскрипції in vitro 2-ариліденовими похідними тіазоло[3,2-α]бензімідазол-3(2Н)-ону Ингибирование транскрипции in vitro 2-арилиденовыми производными тиазоло[3,2-α]бензимидазол-3(2Н)-она Palchykovska, L.G. Alexeeva, I.V. Negrutska, V.V. Kostyuk, Yu.K. Indychenko, T.M. Kostenko, O.M. Kryvorotenko, D.V. Shved, A.D. Dubey, I.Ya. Bioorganic Chemistry Aim. To evaluate a series of 2-substituted thiazolo[3,2-α]benzimidazolones as potential transcription inhibitors. Methods. Compounds were tested in a model transcription system based on T7 RNA polymerase. Results. The testing revealed a number of compounds able to inhibit transcription at micromolar concentrations. The most active inhibitor was dihydroxy derivative BT29 with IC50 = 1.6 μM. Conclusions. Structure-functional dependence of the activity of tested compounds as transcription inhibitors was found. The key structural feature required for their high activity is a presence of hydroxy or dialkylamino group at p- or m-position of arylidene fragment. Мета. Дослідити серію 2-заміщених тіазоло[3,2-α]бензімідазолонів як потенційних інгібіторів транскрипції. Методи. Речовини тестували в модельній системі транскрипції на основі РНК-полімерази Т7. Результати. Тестування виявило низку сполук, здатних інгібувати транскрипцію в мікромолярних концентраціях. Найактивнішим з-поміж них є дигідроксипохідне ВТ29 з IC50 = 1,6 μM. Висновки. Встановлено залежність активності вивчених речовин як інгібіторів транскрипції від їхнього структурно-функціонального стану. Ключовим фактором, що визначає їхню високу активність, є присутність гідрокси- чи діалкіламіногрупи в п- або м-положенні ариліденового фрагмента. Цель. Исследовать серию 2-замещенных тиазоло[3,2-α]бензимидазолонов как потенциальных ингибиторов транскрипции. Методы. Вещества тестировали в модельной системе транскрипции на основе РНК-полимеразы Т7. Результаты. Тестирование выявило ряд соединений, способных ингибировать транскрипцию в микромолярных концентрациях. Наиболее активным среди них является дигидрокси-производное ВТ29 с IC50 = 1,6 μM. Выводы. Установлена зависимость активности изученных веществ как ингибиторов транскрипции от их структурно-функционального состояния. Ключевым фактором, определяющим их высокую активность, является присутствие гидрокси- или диалкиламиногруппы в п- или м-положении арилиденового фрагмента. 2010 Article Inhibition of in vitro transcription by 2-arylidene derivatives of thiazolo[3,2-α]benzimidazol-3(2H)-one / L.G. Palchykovska, I.V. Alexeeva, V.V. Negrutska, Yu.K. Kostyuk, T.M. Indychenko, O.M. Kostenko, D.V. Kryvorotenko, A.D. Shved, I.Ya. Dubey // Вiopolymers and Cell. — 2010. — Т. 26, № 6. — С. 508-511. — Бібліогр.: 19 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.00017B https://nasplib.isofts.kiev.ua/handle/123456789/154215 577.151.042:577.214.3 en Вiopolymers and Cell application/pdf Інститут молекулярної біології і генетики НАН України |
| institution |
Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| collection |
DSpace DC |
| language |
English |
| topic |
Bioorganic Chemistry Bioorganic Chemistry |
| spellingShingle |
Bioorganic Chemistry Bioorganic Chemistry Palchykovska, L.G. Alexeeva, I.V. Negrutska, V.V. Kostyuk, Yu.K. Indychenko, T.M. Kostenko, O.M. Kryvorotenko, D.V. Shved, A.D. Dubey, I.Ya. Inhibition of in vitro transcription by 2-arylidene derivatives of thiazolo[3,2-α]benzimidazol-3(2H)-one Вiopolymers and Cell |
| description |
Aim. To evaluate a series of 2-substituted thiazolo[3,2-α]benzimidazolones as potential transcription inhibitors. Methods. Compounds were tested in a model transcription system based on T7 RNA polymerase. Results. The testing revealed a number of compounds able to inhibit transcription at micromolar concentrations. The most active inhibitor was dihydroxy derivative BT29 with IC50 = 1.6 μM. Conclusions. Structure-functional dependence of the activity of tested compounds as transcription inhibitors was found. The key structural feature required for their high activity is a presence of hydroxy or dialkylamino group at p- or m-position of arylidene fragment. |
| format |
Article |
| author |
Palchykovska, L.G. Alexeeva, I.V. Negrutska, V.V. Kostyuk, Yu.K. Indychenko, T.M. Kostenko, O.M. Kryvorotenko, D.V. Shved, A.D. Dubey, I.Ya. |
| author_facet |
Palchykovska, L.G. Alexeeva, I.V. Negrutska, V.V. Kostyuk, Yu.K. Indychenko, T.M. Kostenko, O.M. Kryvorotenko, D.V. Shved, A.D. Dubey, I.Ya. |
| author_sort |
Palchykovska, L.G. |
| title |
Inhibition of in vitro transcription by 2-arylidene derivatives of thiazolo[3,2-α]benzimidazol-3(2H)-one |
| title_short |
Inhibition of in vitro transcription by 2-arylidene derivatives of thiazolo[3,2-α]benzimidazol-3(2H)-one |
| title_full |
Inhibition of in vitro transcription by 2-arylidene derivatives of thiazolo[3,2-α]benzimidazol-3(2H)-one |
| title_fullStr |
Inhibition of in vitro transcription by 2-arylidene derivatives of thiazolo[3,2-α]benzimidazol-3(2H)-one |
| title_full_unstemmed |
Inhibition of in vitro transcription by 2-arylidene derivatives of thiazolo[3,2-α]benzimidazol-3(2H)-one |
| title_sort |
inhibition of in vitro transcription by 2-arylidene derivatives of thiazolo[3,2-α]benzimidazol-3(2h)-one |
| publisher |
Інститут молекулярної біології і генетики НАН України |
| publishDate |
2010 |
| topic_facet |
Bioorganic Chemistry |
| url |
https://nasplib.isofts.kiev.ua/handle/123456789/154215 |
| citation_txt |
Inhibition of in vitro transcription by 2-arylidene derivatives of thiazolo[3,2-α]benzimidazol-3(2H)-one / L.G. Palchykovska, I.V. Alexeeva, V.V. Negrutska, Yu.K. Kostyuk, T.M. Indychenko, O.M. Kostenko, D.V. Kryvorotenko, A.D. Shved, I.Ya. Dubey // Вiopolymers and Cell. — 2010. — Т. 26, № 6. — С. 508-511. — Бібліогр.: 19 назв. — англ. |
| series |
Вiopolymers and Cell |
| work_keys_str_mv |
AT palchykovskalg inhibitionofinvitrotranscriptionby2arylidenederivativesofthiazolo32αbenzimidazol32hone AT alexeevaiv inhibitionofinvitrotranscriptionby2arylidenederivativesofthiazolo32αbenzimidazol32hone AT negrutskavv inhibitionofinvitrotranscriptionby2arylidenederivativesofthiazolo32αbenzimidazol32hone AT kostyukyuk inhibitionofinvitrotranscriptionby2arylidenederivativesofthiazolo32αbenzimidazol32hone AT indychenkotm inhibitionofinvitrotranscriptionby2arylidenederivativesofthiazolo32αbenzimidazol32hone AT kostenkoom inhibitionofinvitrotranscriptionby2arylidenederivativesofthiazolo32αbenzimidazol32hone AT kryvorotenkodv inhibitionofinvitrotranscriptionby2arylidenederivativesofthiazolo32αbenzimidazol32hone AT shvedad inhibitionofinvitrotranscriptionby2arylidenederivativesofthiazolo32αbenzimidazol32hone AT dubeyiya inhibitionofinvitrotranscriptionby2arylidenederivativesofthiazolo32αbenzimidazol32hone AT palchykovskalg íngíbuvannâtranskripcííinvitro2arilídenovimipohídnimitíazolo32αbenzímídazol32nonu AT alexeevaiv íngíbuvannâtranskripcííinvitro2arilídenovimipohídnimitíazolo32αbenzímídazol32nonu AT negrutskavv íngíbuvannâtranskripcííinvitro2arilídenovimipohídnimitíazolo32αbenzímídazol32nonu AT kostyukyuk íngíbuvannâtranskripcííinvitro2arilídenovimipohídnimitíazolo32αbenzímídazol32nonu AT indychenkotm íngíbuvannâtranskripcííinvitro2arilídenovimipohídnimitíazolo32αbenzímídazol32nonu AT kostenkoom íngíbuvannâtranskripcííinvitro2arilídenovimipohídnimitíazolo32αbenzímídazol32nonu AT kryvorotenkodv íngíbuvannâtranskripcííinvitro2arilídenovimipohídnimitíazolo32αbenzímídazol32nonu AT shvedad íngíbuvannâtranskripcííinvitro2arilídenovimipohídnimitíazolo32αbenzímídazol32nonu AT dubeyiya íngíbuvannâtranskripcííinvitro2arilídenovimipohídnimitíazolo32αbenzímídazol32nonu AT palchykovskalg ingibirovanietranskripciiinvitro2arilidenovymiproizvodnymitiazolo32αbenzimidazol32nona AT alexeevaiv ingibirovanietranskripciiinvitro2arilidenovymiproizvodnymitiazolo32αbenzimidazol32nona AT negrutskavv ingibirovanietranskripciiinvitro2arilidenovymiproizvodnymitiazolo32αbenzimidazol32nona AT kostyukyuk ingibirovanietranskripciiinvitro2arilidenovymiproizvodnymitiazolo32αbenzimidazol32nona AT indychenkotm ingibirovanietranskripciiinvitro2arilidenovymiproizvodnymitiazolo32αbenzimidazol32nona AT kostenkoom ingibirovanietranskripciiinvitro2arilidenovymiproizvodnymitiazolo32αbenzimidazol32nona AT kryvorotenkodv ingibirovanietranskripciiinvitro2arilidenovymiproizvodnymitiazolo32αbenzimidazol32nona AT shvedad ingibirovanietranskripciiinvitro2arilidenovymiproizvodnymitiazolo32αbenzimidazol32nona AT dubeyiya ingibirovanietranskripciiinvitro2arilidenovymiproizvodnymitiazolo32αbenzimidazol32nona |
| first_indexed |
2025-12-01T16:56:15Z |
| last_indexed |
2025-12-01T16:56:15Z |
| _version_ |
1850325783920246784 |
| fulltext |
BIOORGANIC CHEMISTRY
Inhibition of in vitro transcription by 2-arylidene
derivatives of thiazolo[3,2-α]benzimidazol-3(2H)-one
L. G. Palchykovska, I. V. Alexeeva, V. V. Negrutska, Yu. K. Kostyuk,
T. M. Indychenko, O. M. Kostenko, D. V. Kryvorotenko, A. D. Shved, I. Ya. Dubey
Institute of Molecular Biology and Genetics NAS of Ukraine
150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680
dubey@imbg.org.ua
Aim. To evaluate a series of 2-substituted thiazolo[3,2-α]benzimidazolones as potential transcription inhi-
bitors. Methods. Compounds were tested in a model transcription system based on T7 RNA polymerase.
Results. The testing revealed a number of compounds able to inhibit transcription at micromolar
concentrations. The most active inhibitor was dihydroxy derivative BT29 with IC50 = 1.6 µM. Conclusions.
Structure-functional dependence of the activity of tested compounds as transcription inhibitors was found.
The key structural feature required for their high activity is a presence of hydroxy or dialkylamino group at
p- or m-position of arylidene fragment.
Keywords: thiazolo[3,2-α]benzimidazolones, transcription inhibitors, T7 RNA polymerase.
Introduction. Transcription is a key process required
for cellular growth and replication. Specific inhibition
of this process is a way to suppress viruses, bacteria and
cancer cells. The search for novel transcription inhi-
bitors remains one of the main directions of medicinal
chemistry and drug design [1].
Molecular shape often determines the interactions
of small molecules with biological targets, and shape
complementarity is a critically important factor in the
recognition. The notion that molecules with similar 3D
shapes tend to have similar biological activity has been
fully recognized and implemented in drug discovery
[2].
The literature search revealed that many transcrip-
tion inhibitors were conjugated heteroaromatic compo-
unds with S-like molecular shape. Molecular shape
concept [2] allowed us to assume that 2-arylidene-sub-
stituted thiazolo[3,2-α]benzimidazoles, S-shaped mo-
lecules, could be inhibitors of RNA polymerases. These
structures contain rigid bent tricyclic scaffold poten-
tially able to interact with DNA thus affecting DNA-
based enzymatic systems, with a relatively flexible
arylidene fragment which can contain various sub-
stituents to ensure the efficient fitting to polymerase
target, and a number of hydrogen bonding centers. So
we designed a small library of 2-arylidene-[1,3]thiazo-
lo[3,2-α]benzimidazol-3(2H)-ones (benzimidazothia-
zolones, BT) and studied their transcription inhibition
activity. The in vitro screening was performed in a mo-
del transcription system based on bacteriophage T7
RNA polymerase (T7 RNAP).
508
ISSN 0233-7657. Biopolymers and Cell. 2010. Vol. 26. N 6. P. 508–511
Institute of Molecular Biology and Genetics NAS of Ukraine, 2010
N
N
S
O
R
BT
R – aryl, heteroaryl
The transcription performed by this small
single-subunit DNA-dependent RNA polymerase is
fast and efficient and does not require ancillary
transcription factors. Its mechanism of action has been
thoroughly studied [3, 4], and the crystal structure is
known [5] allowing the computer modeling of ligand
binding to the transcription complex. Moreover, the
structure of its active site is similar to that of other viral,
bacterial and eukaryotic polymerases [5, 6]. T7 RNAP
is thus a reliable in vitro model used for the studies of
transcription [3–6] and mechanism of action of DNA-
binding drugs [7–10]. This system was proposed in our
previous papers for the screening of nucleic acids
synthesis inhibitors [11–13].
Materials and Methods. T7 RNA polymerase and
other components of the in vitro transcription reaction
were purchased from «Fermentas» (Lithuania).
2-Arylidene-[1,3]thiazolo[3,2-α]benzimidazol-3(2H)-
ones were prepared by three-step protocol based on me-
thods [14, 15] (details will be published elsewhere).
In vitro transcription assay. The screening was per-
formed according to our protocol [11]. Reaction pro-
ducts were separated by electrophoresis in 1.2 %
agarose gel. Gels stained with ethidium bromide were
photographed with FujiFilm FinePix S5600 digital
camera, and images were processed using TotallLab
1.10 software.
Inhibition activity was determined by comparing
the amount of RNA produced in test reactions with that
in a control (no inhibitor). IC50 and IC90 values (con-
centrations required for 50 and 90 % inhibition) were
obtained from the concentration-activity plots. At least
3 independent experiments were performed for each
compound. Standard deviations were below 10 %, ex-
cept for BT23 where higher spread of data was ob-
served (± 15 %).
Results and Discussion. Thiazolo[3,2-α]benzimi-
dazoles have a wide range of biological activity [16].
Among 2-arylidene-[1,3]thiazolo[3,2-α]benzimidazol-
3(2H)-ones were found antihelmintics [14], antibacte-
rial agents [16], inhibitors of ubiquitin ligase [17] and
other enzymes, and they may be used for the treatment
of viral and inflammatory diseases, neurological disor-
ders and cancer. In addition, some isosteric thiazolo[3,
4-α]benzimidazoles inhibit enteroviruses [18] and tu-
mors [19].
A series of 29 BT compounds containing aromatic
and heteroaromatic arylidene fragments with halogen,
hydroxy, alkoxy and dialkylamino substituents at va-
rious positions were synthesized. The testing was per-
formed in an assay system involving T7 RNA poly-
merase. RNA was produced by T7 RNAP from linea-
rized DNA template (pTZ19R plasmid containing T7
promoter and a 341 b. p. insert from which RNA trans-
cript is synthesized).
All compounds were preliminary tested at the con-
centration of 25 µg/ml (70–80 µM, depending on the
structure). In vitro transcription assay revealed the in-
hibition of transcription by most BT compounds. The
results allowed us to evaluate the influence of arylidene
substituent structure on biological activity. Six com-
pounds (Table), that completely inhibited polymerase
509
INHIBITION OF IN VITRO TRANSCRIPTION BY 2-ARYLIDENE DERIVATIVES
Compound R IC90, µg/ml IC50, µg/ml IC90, М IC50, М
ВТ11 16.0 8.0 5.4⋅10–5 2.7⋅10–5
ВТ15 15.0 3.3 4.6⋅10–5 1.0⋅10–5
ВТ16 12.5 2.8 4.4⋅10–5 9.8⋅10–6
ВТ19 10.6 4.2 3.0⋅10–5 1.2⋅10–5
ВТ23 14.1 6.4 4.8⋅10–5 2.2⋅10–5
ВТ29 0.7 0.5 2.3⋅10–6 1.6⋅10–6
Transcription inhibition activity of thiazolobenzimidazolone derivatives in T7 RNA polymerase assay
OH
O
O
S
NEt2
OH
OH
OH
at 25 µg/ml (inhibition above 99 %), were selected for
further investigation.
Detailed study of the activity-concentration depen-
dence of these compounds allowed determining their
IC90 and IC50 values. A series of reactions with T7
RNAP was carried out with 2-fold inhibitor dilution at
each next step. Five independent experiments were
performed with all these BT compounds at each tested
concentration. The activity plots were built by calcu-
lating the RNA product yield as a function of inhibitor
concentration (Figure). IC90 and IC50 values were found
from the plots by extrapolation. As can be seen from
Figure, derivative BT29 demonstrated a very high
activity and completely inhibited transcription at con-
centration below 1 µg/ml. An additional set of reac-
tions at lower concentrations was performed to find that
its IC50 is 1.6 µM. The other five compounds have IC50
in the range of 10–27 µM (Table).
Local deviation from linearity of the plot was ob-
served for the compound BT19 that appeared as se-
eming enzyme stimulation at the concentration range of
2–3 µg/ml (Figure). A similar effect was reported for
T7 RNA polymerase inhibition by pyrrolo[2,1-c][1,
4]benzodiazepines [8], although the authors were unab-
le to provide any explanation.
We suppose that this deviation may indicate the
presence of two binding sites for BT19 on the poly-
merase or its complex with DNA template, or two dis-
tinct binding modes. Mechanism of this effect will be
the subject of the future study.
The analysis of experimental data revealed that the
activity of BT compounds depended on the structure of
arylidene fragment. The presence of halogen or mul-
tiple methoxy substituents in arylidene fragment signi-
ficantly decreases the activity as compared to un-
substituted derivative (R = Ph, 94 % inhibition at
25 µg/ml)). The activity of compounds with heteroaryl
moiety depends on its nature. Thiophen derivative
almost totally inhibits RNA synthesis at 25 µg/ml, whi-
le 3- and 4-pyridyl derivatives are inactive; only 2-py-
ridyl derivative has noticeable activity (86 % inhibition
at 25 µg/ml). Structure-activity relationship data sug-
gest that the key feature of the most active compounds
is the presence at p- or m-position of arylidene ring (but
not at o-position) of either ОН, alkoxy or dialkylamino
group, i. e. functions able to form hydrogen and donor-
acceptor bonds. The introduction of both о- and п-ОН
substituents into the structure of ВТ29 led to the dra-
matic increase of inhibitory activity.
Conclusions. A number of 2-aryliden-[1,3]thia-
zolo[3,2-α]benzimidazol-3(2H)-ones efficiently inhi-
bit transcription in the T7 RNAP-based in vitro assay at
micromolar concentrations. The dihydroxy derivative
BT29 is the most active polymerase inhibitor with IC50
1.6 µM. The structure of this compound will be further
optimized using computer modeling to develop more
efficient inhibitors. In our opinion, high activity of BT
compounds in vitro allows to consider them potential
antiviral drugs.
Л. Г. Паль чи ко вська, І. В. Алeксєєва, В. В. Нег руць ка,
Ю. К. Кос тюк, Т. М. Інди чен ко, О. М. Кос тен ко,
Д. В. Кри во ро тен ко, А. Д. Швед, І. Я. Ду бей
Інгібу ван ня транс крипції in vitro 2-ариліде но ви ми похідни ми
тіазо ло[3,2-α]бензіміда зол-3(2Н)-ону
Ре зю ме
Мета. Дослідити серію 2-заміще них тіазо ло[3,2-α]бензіміда -
зо лонів як по тенційних інгібіторів транс крипції. Ме то ди. Ре -
чо ви ни тес ту ва ли в мо дельній сис темі транс крипції на основі
РНК-поліме ра зи Т7. Ре зуль та ти. Тес ту ван ня ви я ви ло низ ку
спо лук, здат них інгібу ва ти транс крипцію в мікро мо ляр них
кон цен траціях. На йак тивнішим з-поміж них є дигідрок си -
похідне ВТ29 з IC50 = 1,6 µM. Вис нов ки. Вста нов ле но за -
лежність ак тив ності вив че них ре чо вин як інгібіторів транс-
крипції від їхньо го струк тур но-функціональ но го стану. Клю -
чо вим фак то ром, що виз на чає їхню ви со ку ак тивність, є при -
сутність гідрок си- чи діалкіламіног ру пи в п- або м-по ло женні
ариліде но во го фраг мен та.
510
PALCHYKOVSKA L. G. et al.
0 2 4 6 8 10 12 14
0
20
40
60
80
100
Inhibitor concentration, µg/ml
1
2
3
4
5
6
The effect of inhibitor concentration on the efficiency of RNA syn-
thesis in vitro (error bars are not shown (see the text)): 1 – BT11; 2 –
BT23; 3 – BT19; 4 – BT15; 5 – BT16; 6 – BT29
Клю чові сло ва: тіазо ло[3,2-α]бензіміда зо ло ни, інгібітори
транс крипції, РНК-поліме ра за Т7.
Л. И. Паль чи ков ская, И. В. Алeксеева, В. В. Нег руц кая,
Ю. К. Кос тюк, Т. Н. Инди чен ко, А. Н. Кос тен ко,
Д. В. Кри во ро тен ко, А. Д. Швед, И. Я. Ду бей
Инги би ро ва ние транс крип ции in vitro 2-ари ли де но вы ми про из -
вод ны ми ти а зо ло[3,2-α]бен зи ми да зол-3(2Н)-она
Ре зю ме
Цель. Иссле до вать се рию 2-за ме щен ных ти а зо ло[3,2-α]бенз-
ими да зо ло нов как по тен ци аль ных ин ги би то ров транс крип ции.
Ме то ды. Ве щес тва тес ти ро ва ли в мо дель ной сис те ме транс -
крип ции на осно ве РНК-по ли ме ра зы Т7. Ре зуль та ты. Тес ти -
ро ва ние вы я ви ло ряд со е ди не ний, спо соб ных ин ги би ро вать
транс крип цию в мик ро мо ляр ных кон цен тра ци ях. На и бо лее ак -
тив ным сре ди них яв ля ет ся ди гид рок си-про из вод ное ВТ29 с
IC50 = 1,6 µM. Вы во ды. Уста нов ле на за ви си мость ак тив нос ти
из учен ных ве ществ как ин ги би то ров транс крип ции от их
структур но-функ ци о наль но го со сто я ния. Клю че вым фак то -
ром, опре де ля ю щим их вы со кую ак тив ность, яв ля ет ся при су -
тствие гид рок си- или ди ал ки ла ми ног руп пы в п- или м-по-
ло же нии ари ли де но во го фраг мен та.
Клю че вые сло ва: ти а зо ло[3,2-α]бен зи ми да зо ло ны, ин ги би -
то ры транс крип ции, РНК-по ли ме ра за Т7.
REFERENCES
1. Jung D., Choi Y., Uesugi M. Small organic molecules that
modulate gene transcription // Drug Discov. Today.–2006.–
11, N 9–10.–P. 452-457.
2. Ebalunode J. O., Weifan Z. Molecular shape technologies in
drug discovery: methods and applications // Curr. Top. Med.
Chem.–2010.–10, N 6.–P. 669–679.
3. Tunitskaya V. L., Kochetkov S. N. Structural-functional ana-
lysis of bacteriophage T7 RNA polymerase // Biochemistry
(Moscow).–2002.–67, N 10.–P. 1124–1135.
4. Kennedy W. P., Momand J. R., Yin Y. W. Mechanism for de
novo RNA synthesis and initiating nucleotide specificity by
T7 RNA polymerase // J. Mol. Biol.–2007.–370, N 2.–P. 256–
268.
5. Sousa R., Chung Y. J., Rose J. P., Wang B.-C. Crystal structu-
re of bacteriophage T7 RNA polymerase at 3.3 C resolution //
Nature.–1993.–364, N 6438.–P. 593–599.
6. McAllister W. T., Raskin C. A. The phage RNA polymerases
are related to DNA polymerases and reverse transcriptases //
Mol. Microbiol.–1993.–10, N 1.–P. 1–6.
7. White R. J., Phillips D. R. Sequence-dependent termination of
bacteriophage T7 transcription in vitro by DNA-binding
drugs // Biochemistry.–1989.–28, N 10.–P. 4277–4283.
8. Puvvada M. S., Forrow S. A., Hartley J. A., Stephenson P.,
Gibson I., Jenkins T. C., Thurston D. E. Inhibition of bacte-
riophage T7 RNA polymerase in vitro transcription by DNA-
binding pyrrolo[2,1-c][1,4]benzodiazepines // Biochemist-
ry.–1997.–36, N 9.–P. 2478–2484.
9. Piestrzeniewich M., Studzian K., Wilmanska D., Pluciennic-
zak G., Gniazdowski M. Effect of DNA-interacting drugs on
phage T7 RNA polymerase // Acta Biochim. Pol.–1998.–45,
N 1.–P. 127–132.
10. Chen X., Gao F., Zhou Z.-X., Yang W.-Y., Gao L.-T., Ji L.-N.
Effect of ancillary ligands on the topoisomerases II and trans-
cription inhibition activity of polypyridyl ruthenium(II)
complexes // J. Inorg. Biochem.–2010.–104, N 5.–P. 576–
582.
11. Palchykovska L. G., Alexeeva I. V., Kostina V. G., Platonov
M. O., Negrutska V. V., Deriabin O. M., Tarasov O. A., Shved
A. D. New amides of phenazine-1-carboxylic acid: antimic-
robial activity and structure-activity relationship // Ukr.
Biochem. J.–2008.–80, N 3.–P. 140–147.
12. Stankiewicz-Drogon А., Palchykovska L. G., Kostina V. G.,
Alexeeva I. V., Shved A. D., Boguszewska-Chachulska A. M.
New acridone-4-carboxylic acid derivatives as potential
inhibitors of Hepatitis C virus infection // Bioorg. Med.
Chem.–2008.–16, N 19.–P. 8846–8852.
13. Palchykovska L. G., Alexeeva I. V., Platonov M. O., Kostenko
O. M., Usenko L. S., Negrutska V. V., Shved A. D. New 1,
2,4-triazine bearing compounds: molecular modeling, syn-
thesis and biotesting // Biopolym. Cell.–2009.–25, N 6.–
P. 491–499.
14. Mavrova A. T., Anichina K. K., Vuchev D. I., Tsenov J. A.,
Kondeva M. S., Micheva M. K. Synthesis and antitrichinello-
sis activity of some 2-substituted-[1,3]thiazolo[3,2-α]benz-
imidazol-3(2H)-ones // Bioorg. Med. Chem.–2005.–13,
N 19.–P. 5550–5559.
15. Al-Rashood K. A., Abdel-Aziz H. A. Thiazolo[3,2-α]benzimi-
dazoles: synthetic strategies, chemical transformations and
biological activities // Molecules.–2010.–15, N 6.–P. 3775–
3815.
16. Pat. UK Application GB2376944.–31.12.2002. Polycyclic
heterocyclic compounds and their therapeutic use / N. M.
Allanson, B. W. Leslie, S. Thomson.
17. Pat. USA. Application 20070015768.–01.18.2007. Ubiquitin
ligase inhibitors and methods related thereto / I. Alroy, Sh.
Tuvia, Y. Reiss, O. Levi-Hacham.
18. Leyssen P., De Clercq E., Neyts J. Molecular strategies to in-
hibit the replication of RNA viruses // Antivir. Res.–2008.–
78, N 1.–P. 9–25.
19. Chimirri A., Monforte P., Musumeci L., Rao A., Zappala M.,
Monforte A.-M. Synthesis and antitumour activity of 1H,3H-
thiazolo[3,4-α]benzimidazole derivatives // Arch. Pharm.–
2001.–334, N 6.–P. 203–208.
UDC 577.151.042:577.214.3
Received 10.06.2010
511
INHIBITION OF IN VITRO TRANSCRIPTION BY 2-ARYLIDENE DERIVATIVES
|