611 research outputs found
Synthesis of Combretastatin A-4 and 3 0 -Aminocombretastatin A-4 derivatives with Aminoacid Containing Pendants and Study of their Interaction with Tubulin and as Downregulators of the VEGF, hTERT and c-Myc Gene Expression
Natural product combretastatin A-4 (CA-4) and its nitrogenated analogue
3
0
-aminocombretastatin A-4 (AmCA-4) have shown promising antitumor activities. In this study,
a range of CA-4 and AmCA-4 derivatives containing amino acid pendants have been synthesized in
order to compare their biological actions with those of their parent compounds. Thus, inhibition of
cell proliferation on tumor cell lines HT-29, MCF-7 and A-549, as well as on the nontumor cell line
HEK-273; in vitro tubulin polymerization; mitotic cell arrest; action on the microtubule cell network
and inhibition of VEGF, hTERT, and c-Myc genes have been evaluated. Some AmCA-4 derivatives
bearing L-amino acids exhibited inhibition of cell proliferation at low nanomolar levels exceeding
the values shown by AmCA-4. Furthermore, while CA-4 and AmCA-4 derivatives do not show
significant effects on the in vitro tubulin polymerization and cell cycle arrest, some selected CA-4 and
AmCA-4 derivatives are able to cause total depolymerization of the microtubule network on A-549
cells. The best results were obtained in the inhibition of gene expression, particularly on the VEGF
gene, in which some AmCA-4 derivatives greatly exceeded the inhibition values achieved by the
parent compound
Aldol Reactions between L-Erythrulose Derivatives and Chiral α-Amino and α -Fluoro Aldehydes: Competition between Felkin–Anh and Cornforth Transition States
Both matched and mismatched diastereoselection have been observed in aldol reactions of a boron
enolate of a protected l-erythrulose derivative with several chiral α-fluoro and α-Amino aldehydes. Strict
adherence to the Felkin–Anh model for the respective transition structures does not account satisfactorily
for all the observed results, as previously observed in the case of α-oxygenatedaldehydes. In some cases,
only the Cornforth model provides a good explanation. The factors that influence this dichotomy are
discussed and a general mechanistic model is proposed for aldol reactions with a-heteroatom-substituted
aldehydes. Additional support for the model was obtained from density functional calculation
Inhibitory effect of cytotoxic stilbenes related to resveratrol on the expression of the VEGF, hTERT and c-Myc genes
A group of thirty-nine stilbene derivatives, prepared by means of Heck coupling reactions, has been investigated for their cytotoxicity, as well as for their ability to inhibit the production of the vascular endothelial growth factor (VEGF) and the activation of telomerase. The ability of these compounds to inhibit proliferation of two tumoral cell lines (HT-29 and MCF-7) and one non tumoral cell line (HEK-293) was first determined. Subsequently, we determined the capacity of the compounds to inhibit the secretion of VEGF in the aforementioned cell lines and to downregulate the expression of the VEGF, hTERT and c-Myc genes, the two latter involved in the control of the activation of telomerase. One of the synthetic stilbenes, (E)-4-(4-methoxystyryl)aniline, showed strong cytotoxicity and proved able to cause a marked decrease both in the secretion of VEGF and in the expression of the hTERT and c-Myc genes, in all cases at concentrations in the low nanomolar range
Convergent, stereoselective syntheses of the glycosidase inhibitors broussonetines D and M
The first syntheses of the polyhydroxylated alkaloids (iminosugars) broussonetines D and M
glycosidase inhibitors of the pyrrolidine class, have been performed in a convergent, stereocontrolled
way from D-serine as the chiral starting material. A cross metathesis step was one key feature of the
synthesis. The versatility of the synthetic concept chosen permits the access to many members of this
compound family, both natural ones and analogues thereo
Synthesis and evaluation of biphenyl derivatives as potential downregulators of VEGF protein secretion and telomerase-related gene expressions
A group of 47 biphenyl functionalized compounds, prepared by means of Suzuki couplings, has been
investigated for their cytotoxicity on two tumoral cell lines (HT-29 and MCF-7) and one non tumoral cell
line (HEK-293). 29 selected compounds have been investigated for their ability to inhibit the production
of the vascular endothelial growth factor (VEGF). Subsequently, the capacity of the compounds to downregulate
the expression of the VEGF, h-TERT and c-Myc genes, the two latter involved in the control of the
activation of telomerase, has also been determined.Financial support has been granted to M.C. by the Ministerio
de EconomĂa y Competitividad of Spain (project CTQ2014-
52949-P), by the ConsellerĂa d´Empresa, Universitat i Ciencia de
la Generalitat Valenciana (projects PROMETEO/2013/027 and
ACOMP/2014/ 274) and by the University Jaume I (project PI-
1B2011-37). M. S.-P. thanks the University Jaume I for a
predoctoral fellowship
Novel multitarget inhibitors with antiangiogenic and immunomodulator properties
By means of docking studies, seventeen compounds T.1-T17 have been designed and evaluated as multitarget inhibitors of VEGFR-2 and PD-L1 proteins in order to overcome resistance phenomena offered by cancer. All these designed molecules display a urea moiety as a common structural feature and eight of them (T.1-T8) further contain a 1,2,3-triazol moiety. The antiproliferative activity of these molecules on several tumor cell lines (HT-29, MCF-7, HeLa, A549, HL-60), on the endothelial cell line HMEC-1 and on the non-tumor cell line HEK-293 has been determined. The urea derivatives were also evaluated for their antiangiogenic properties, whereby their ability to inhibit tubulogenesis and kinase activity employing flow cytometry, ELISA, immunofluorescence and western blot techniques was measured. In addition, these techniques were also employed to investigate the immunomodulator action of the synthetic compounds on the inhibition of PD-L1 and c-Myc proteins. Compound T.2, 1-(3-chlorophenyl)-3-(2-(4-(4-methoxybenzyl)-1H-1,2,3-triazol-1-yl)ethyl)urea, has shown similar results to sorafenib in both down-regulation of VEGFR-2 and inhibition of the kinase activity of this receptor. Furthermore, compound T.14, (E)-1-(4-chlorophenyl)-3-(3-(4-methoxystyryl)phenyl)urea, improves the effect of T.2 as regards tube formation of endothelial cells and inhibition of VEGFR-2 tyrosine kinase activity. In addition, T.14 improves the effect of the experimental drug BMS-8 in the inhibition of PD-L1 and c-Myc proteins
Double diastereoselection in anti aldol reactions mediated by dicyclohexylchloroborane between an L-erythrulose derivative and chiral aldehydes
Anti aldol reactions of an L-erythrulose derivative with several α-chiral aldehydes mediated by
dicyclohexylboron chloride are examined. Good yields and stereoselectivities are observed. The results
are best explained when the reactions are assumed to occur via boat-like transition states with
minimization of 1,3-allylic strain and avoidance of syn pentane interactions
Synthesis of combretastatin A-4 O-alkyl derivatives and evaluation of their cytotoxic, antiangiogenic and antitelomerase activity
We here report the synthesis and biological evaluation of several combretastatin A-4 derivatives alkylated at the phenol hydroxyl group. Some of these derivatives contain an (E)-arylalkene fragment reminiscent of that present in some natural stilbenes like resveratrol. The cytotoxicities towards one human healthy kidney embryonic and two tumoral cell lines were determined. In addition, the ability of these compounds to inhibit the production of the vascular endothelial growth factor (VEGF) was measured. Finally, the expression of genes controlling the production of telomerase was measured. Some of the compounds were found to have an activity comparable or higher than that of combretastatin A-4 in at least one of the aforementioned biological properties. The compounds with the (E)-arylalkene fragment were in general terms more active than the simple O-alkyl derivatives. However, no clear structure/activity correlations were perceived when comparing the observed compound activities across the three biological properties. This points out the existence of marked differences between the mechanisms responsible for their cytotoxicity
Synthesis and biological evaluation of carbamates derived from aminocombretastatin A-4 as vascular disrupting agents
A series of t wenty-six carbamates derived from aminocombretastatin A- 4 (AmCA-4 ) were syn thesized
and evaluated for their capacity to affect cell proliferation, tubulin polymerization, mitotic cell arrest,
microtubule network organization, apoptos is and endothelial tubular structures in vitro. The anti-
pro liferative activity of the synthetic carbamates was measured on several human tumor cell lines
(i.e. HT-29, MCF-7, HeLa, A-549, MDA-MB-231, H L-60) as well as on the endothelial cell line HMEC-1
and the non-tumor cell line H EK-293. The compounds showed anti-proliferative activity in the
nanomolar range thereby exceeding by far the activity of combretastatin A-4 (CA-4 ) and, in some cases,
the activity of AmCA-4. The most active compounds proved to be the carbamates bearing chloro,
bromo or methoxy groups in the meta position of the phenyl ring. Moreover, all carbamates inhibited
in vitro tubulin polymerization, in a similar manne r to that of CA-4 and Am CA-4 by interacting with
the colchicine binding site in tubulin. The synthetic carbamates proved as active as AmCA-4 in causing
mitotic arrest, as asses sed in A549 human lung cancer cells, and disruption of the microtubule ce llular
network. Some selected carbamates induced apoptosis at concentrations as low as 10 nM, being more
active than AmCA-4. Final ly, these selected carbamates displayed a vascular disrupting activity on
endothelial cells in a dose-dependent manner. In conclusion, our data indicate that carbamates derived
from aminocombretastatin A-4 represent interesting lead compounds for the design of vascular dis-
rupting agent
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