Sea Urchin Embryo Model As a Reliable in Vivo Phenotypic
Screen to Characterize Selective Antimitotic Molecules. Comparative
evaluation of Combretapyrazoles, -isoxazoles, -1,2,3-triazoles, and
-pyrroles as Tubulin-Binding Agents
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Posted on 2018-12-06 - 13:33
A series
of both novel and reported combretastatin analogues, including
diarylpyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles, were
synthesized via improved protocols to evaluate their antimitotic antitubulin
activity using in vivo sea urchin embryo assay and a panel of human
cancer cells. A systematic comparative structure–activity relationship
studies of these compounds were conducted. Pyrazoles 1i and 1p, isoxazole 3a, and triazole 7b were found to be the most potent antimitotics across all
tested compounds causing cleavage alteration of the sea urchin embryo
at 1, 0.25, 1, and 0.5 nM, respectively. These agents exhibited comparable
cytotoxicity against human cancer cells. Structure–activity
relationship studies revealed that compounds substituted with 3,4,5-trimethoxyphenyl
ring A and 4-methoxyphenyl ring B displayed the highest activity.
3-Hydroxy group in the ring B was essential for the antiproliferative
activity in the diarylisoxazole series, whereas it was not required
for potency of diarylpyrazoles. Isoxazoles 3 with 3,4,5-trimethoxy-substituted
ring A and 3-hydroxy-4-methoxy-substituted ring B were more active
than the respective pyrazoles 1. Of the azoles substituted
with the same set of other aryl pharmacophores, diarylpyrazoles 1, 4,5-diarylisoxazoles 3, and 4,5-diaryl-1,2,3-triazoles 7 displayed similar strongest antimitotic antitubulin effect
followed by 3,4-diarylisoxazoles 5, 1,5-diaryl-1,2,3-triazoles 8, and pyrroles 10 that showed the lowest activity.
Introduction of the amino group into the heterocyclic core decreased
the antimitotic antitubulin effect of pyrazoles, triazoles, and to
a lesser degree of 4,5-diarylisoxazoles, whereas potency of the respective
3,4-diarylisoxazoles was increased.
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Semenova, Marina
N.; Demchuk, Dmitry V.; Tsyganov, Dmitry V.; Chernysheva, Natalia B.; Samet, Alexander V.; Silyanova, Eugenia A.; et al. (2018). Sea Urchin Embryo Model As a Reliable in Vivo Phenotypic
Screen to Characterize Selective Antimitotic Molecules. Comparative
evaluation of Combretapyrazoles, -isoxazoles, -1,2,3-triazoles, and
-pyrroles as Tubulin-Binding Agents. ACS Publications. Collection. https://doi.org/10.1021/acscombsci.8b00113
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AUTHORS (13)
MS
Marina
N. Semenova
DD
Dmitry V. Demchuk
DT
Dmitry V. Tsyganov
NC
Natalia B. Chernysheva
AS
Alexander V. Samet
ES
Eugenia A. Silyanova
VK
Victor P. Kislyi
AM
Anna S. Maksimenko
AV
Alexander E. Varakutin
LK
Leonid D. Konyushkin
MR
Mikhail M. Raihstat
AK
Alex S. Kiselyov
VS
Victor V. Semenov
KEYWORDS
Pyrazoles 1 i3- hydroxy -4-methoxy ring Bantimitotic antitubulin activitysea Urchin Embryo Modelcompoundcancer cellsseriesisoxazolepyrrolevivo sea urchin embryo assayVivo Phenotypic Screentriazole 7 brelationshipsea urchin embryo3- Hydroxy groupdiaryldiarylisoxazole4- methoxyphenyl ring Bdiarylpyrazolepyrazoleantimitotic antitubulin effectpotency