Papers by Vassiliki Magafa
We present here a novel semi-synthetic cyclic ether fluorinated noscapine analog (CEFNA) that sho... more We present here a novel semi-synthetic cyclic ether fluorinated noscapine analog (CEFNA) that shows potent antiproliferative and anticancer activity in both hormone-responsive (MCF-7) and hormone non-responsive (MDA-MB-231) breast cancer cells. Interestingly, it is also effective against MCF-7/Adr, an adriamycin-resistant variant of MCF-7 cells. Immunofluorescence experiments showed numerous micronuclei, indicative of apoptotic cell death triggered by this novel analog. Mechanistically, CEFNA exerts a strong antimitotic effect as revealed by cell-cycle studies that show a dose-dependent increase in G2/M population preceding a rising sub-G1 population, suggesting apoptosis.
Amino Acids, Nov 3, 2009
We report the solid phase synthesis and some pharmacological properties of 24 oxytocin (OT) analo... more We report the solid phase synthesis and some pharmacological properties of 24 oxytocin (OT) analogues. Basic modifications at position 9 (introduction of L-or D-b-(2-thienyl)-alanine [L-or D-Thi], or L-or D-3-Pyridylalanine [L-or D-3-Pal]) were combined with D-tyrosine(OEthyl) [D-Tyr(Et)] or D-1-naphthylalanine [D-1-Nal] in position 2 and b-mercaptopropionic acid (Mpa) in position 1 modifications in altogether 14 analogues. Additionally, 8 analogues having a-aminoisobutyric acid [Aib] or D-1,2,3,4-tetrahydroisoquinoline-3carboxylic acid (D-Tic) or diethylglycine (Deg) in position 9 and D-Tyr(Et) or D-1-Nal or D-Tic in position 2 and Mpa or Pen (bb-dimethylcysteine) in position 1 were prepared. Two of these analogues have one more modification in position 6, i.e. Pen. Furthermore, two analogues having Mpa in position 1 and D-Tyr(Et) or D-1-Nal in position 2 were prepared for comparison purposes. The analogues were tested for rat uterotonic activity in vitro, in the rat pressor assay and for binding affinity to human OT receptor. The analogue having the highest anti-oxytocic activity was [Mpa 1 , D-Tyr(Et) 2 , Deg 9 ]OT (pA 2 = 8.68 ± 0.26); this analogue was also selective.
The preparation of graphite intercalation compounds (GICÕs) of three perfluorinated alkylsulfonat... more The preparation of graphite intercalation compounds (GICÕs) of three perfluorinated alkylsulfonate anions, C 10 F 21 SO 3 À , C 2 F 5 OC 2 F 4 SO 3 À and C 2 F 5 (C 6 F 10)SO 3 À is described for the first time. Pure stage 2 GICÕs are obtained by chemical oxidation of graphite with K 2 MnF 6 in a solution containing hydrofluoric and nitric acids for 72 h. One-dimensional electron density maps derived from powder diffraction data are fit to obtain models for the intercalate gallery structures: the structure models provide details on anion concentrations, orientations, and conformations. In all cases, anion bilayers are observed with anion sulfonate headgroups oriented towards graphene sheets. Compared with structures calculated for the isolated anions, the intercalated anion conformations show changes in dihedral angles, involving rotations about CC or CO bonds. For the GIC containing C 2 F 5 (C 6 F 10)SO 3 À , the anion conformation change is related to the more efficient packing of anions in the intercalate gallery.
Bioorganic & Medicinal Chemistry, 2016
Nowadays, AT1 receptor (AT1R) antagonists (ARBs) constitute the one of the most prevalent classes... more Nowadays, AT1 receptor (AT1R) antagonists (ARBs) constitute the one of the most prevalent classes of antihypertensive drugs that modulate the renin-angiotensin system (RAS). Their main uses include also treatment of diabetic nephropathy (kidney damage due to diabetes) and congestive heart failure. Towards this direction, our study has been focused on the discovery of novel agents bearing different scaffolds which may evolve as a new class of AT1 receptor antagonists. To fulfill this aim, a combination of computational approaches and biological assays were implemented. Particularly, a pharmacophore model was established and served as a 3D search query to screen the ChEMBL15 database. The reliability and accuracy of virtual screening results were improved by using molecular docking studies. In total, 4 compounds with completely diverse chemical scaffolds from potential ARBs, were picked and tested for their binding affinity to AT1 receptor. Results revealed high nanomolar to micromolar affinity (IC50) for all the compounds. Especially, compound 4 exhibited a binding affinity of 199nM. Molecular dynamics simulations were utilized in an effort to provide a molecular basis of their binding to AT1R in accordance to their biological activities.
European journal of medicinal chemistry, Jun 1, 2007
We report the solid-phase synthesis and some pharmacological properties of twenty oxytocin (OT) a... more We report the solid-phase synthesis and some pharmacological properties of twenty oxytocin (OT) analogues. Basic modifications at position 7 (introduction of a-aminoisobutyric acid [Aib], L-or D-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid [L/D-Tic], L-at -butylglycine [Gly(Bu t)] and pipecolic acid [Pip]) were combined with D-Tyr(Et) 2 , L/D-(pEt)Phe 2 , D-Tic 2 , and Mpa 1 modifications and their various combinations in a total of 14 analogues. Additionally, two analogues having one more modification in position 3, i.e. Gly(Bu t), and three analogues having glycine in position 9 substituted by D-Tic or Aib, were prepared. The analogues were tested for rat uterotonic activity in vitro, in the rat pressor assay and for binding affinity to human OT receptor. The analogue having the highest antioxytocic activity was [Mpa 1 , D-Tyr(Et) 2 , D-Tic 7 , Aib 9 ]OT having pA 2 ¼ 8.31 AE 0.19; this analogue was also selective.
Collection Symposium Series, 2005
We report the synthesis in liquid phase of a tetrapeptide Boc-Cys 1 (Acm)-Gly 2 -Ala 3 -Cys 4 (Ac... more We report the synthesis in liquid phase of a tetrapeptide Boc-Cys 1 (Acm)-Gly 2 -Ala 3 -Cys 4 (Acm)-OMe (CGAC) that contains the cysteine-rich region encountered in many metallo-proteins. Interactions of this peptide with Hg (II) have been investigated bythe one- and two-dimensional 1 H NMR technique. In dimethylsulphoxide the complexation produces significant perturbation in the 1 H NMR spectra and the results suggest that mercury chelates the two sulphur atoms of the tetrapeptide
Collection Symposium Series, 2003
The synthesis of new OT analogues bearing the following modifications: L-ŕ-t-butylglycine [Gly(Bu... more The synthesis of new OT analogues bearing the following modifications: L-ŕ-t-butylglycine [Gly(Bu')] at positions 8 and 9, D-Cys and D-Tyr(Et) at positions 6 and 2, respectively, and Mpa or Pen at position 1 have been described
Acta Chemica Scandinavica, 1995
Biopolymers, 2015
Amyloid deposits to the islets of Langerhans are responsible for the gradual loss of pancreatic b... more Amyloid deposits to the islets of Langerhans are responsible for the gradual loss of pancreatic b-cells leading to type II diabetes mellitus. Human mature islet amyloid polypeptide (hIAPP), a 37-residue pancreatic hormone, has been identified as the primary component of amyloid fibrils forming these deposits. Several individual segments along the entire sequence length of hIAPP have been nominated as regions with increased amyloidogenic potential, such as regions 8-20, 20-29, and 30-37. A smaller fragment of the 8-20 region, spanning residues 8-16 of hIAPP has been associated with the formation of early transient a-helical dimers that promote fibrillogenesis and also as a core part of hIAPP amyloid fibrils. Utilizing our aggregation propensity prediction tools AmylPred and AmylPred2, we have identified the high aggregation propensity of the 8-16 segment of hIAPP. A peptide analog corresponding to this segment was chemically synthesized and its amyloidogenic properties were validated using electron microscopy, X-ray fiber diffraction, ATR FT-IR spectroscopy, and polarized microscopy. Additionally, two peptides introducing point mutations L12R and L12P, respectively, to the 8-16 segment, were chemically synthesized. Both mutations disrupt the a-helical properties of the 8-16 region and lower its amyloidogenic potential, which was confirmed experimentally. Finally, cytotoxicity assays indicate that the 8-16 segment of hIAPP shows enhanced cytotoxicity, which is relieved by the L12R mutation but not by the L12P mutation. Our results indicate that the chameleon properties and the high aggregation propensity of the 8-16 region may significantly contribute to the formation of amyloid fibrils and the overall cytotoxic effect of hIAPP. V
Letters in Peptide Science, 2001
The nonapeptide Leuprorelin, one of the LHRH agonists, was studied by means of 2D nuclear magneti... more The nonapeptide Leuprorelin, one of the LHRH agonists, was studied by means of 2D nuclear magnetic resonance spectroscopy and molecular modeling. NOESY spectra in aqueous/deuterated methanol solution (50% H 2 O/CD 3 OD) at low temperature (268 K) revealed short-range nOe connectivities (i, i+1), characteristic of flexibility of the molecule. The H N-H N sequential connectivities observed provide evidence that the sequence has the propensity to form a bend involving residues 5 and 6 and the N-terminal segment. The α-proton chemical shifts compared to random coil and additional data from the amide proton temperature coefficients support this assumption. One long-range nOe cross peak between H α 2-H NEth is indicative of proximity between C-and N-termini.
Anticancer research
Luteinizing hormone-releasing hormone (LHRH or GnRH) is not only produced by hypothalamus, but al... more Luteinizing hormone-releasing hormone (LHRH or GnRH) is not only produced by hypothalamus, but also by other normal and cancer tissues. GnRH peptide agonists and antagonists inhibit the proliferation of breast cancer cells, but their effect on the expression of metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) has not been studied despite the fact that growth and invasiveness of breast cancer cells in adjacent and distant sites is associated with the expression of MMPs. In the present study, the effects of [D-Leu6, desGly10]GnRH-NHEt (commercially available) and [D-Tic3, Deg6, desGlyl0]GnRH-NHEt on gene expression of MMPs and TIMPs in the breast cancer cell line MCF-7 were examined with semi-quantitative RT-PCR. Results showed that incubation of MCF-7 cells with 30 microM of the synthetic GnRH analogues for 48 h in serum-containing medium resulted in a decrease of MMP-9 expression and increase in MT1- and MT2-MMP mRNA levels. Furthermore, both synthetic analogues induced...
European Journal of Biochemistry, 2003
Conformational analysis of angiotensin I (AI) and II (AII) peptides has been performed through 2D... more Conformational analysis of angiotensin I (AI) and II (AII) peptides has been performed through 2D 1H-NMR spectroscopy in dimethylsulfoxide and 2,2,2-trifluoroethanol/H2O. The solution structural models of AI and AII have been determined in dimethylsulfoxide using NOE distance and 3JHNHalpha coupling constants. Finally, the AI family of models resulting from restrained energy minimization (REM) refinement, exhibits pairwise rmsd values for the family ensemble 0.26 +/- 0.13 A, 1.05 +/- 0.23 A, for backbone and heavy atoms, respectively, and the distance penalty function is calculated at 0.075 +/- 0.006 A2. Comparable results have been afforded for AII ensemble (rmsd values 0.30 +/- 0.22 A, 1.38 +/- 0.48 A for backbone and heavy atoms, respectively; distance penalty function is 0.029 +/- 0.003 A2). The two peptides demonstrate similar N-terminal and different C-terminal conformation as a consequence of the presence/absence of the His9-Leu10 dipeptide, which plays an important role in the different biological function of the two peptides. Other conformational variations focused on the side-chain orientation of aromatic residues, which constitute a biologically relevant hydrophobic core and whose inter-residue contacts are strong in dimethylsulfoxide and are retained even in mixed organic-aqueous media. Detailed analysis of the peptide structural features attempts to elucidate the conformational role of the C-terminal dipeptide to the different binding affinity of AI and AII towards the AT1 receptor and sets the basis for understanding the factors that might govern free- or bound-depended AII structural differentiation.
Journal of Peptide Science, 2008
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Papers by Vassiliki Magafa