Lupane Triterpenoids—Betulin and Betulinic acid derivatives induce apoptosis in tumor cells

In the present investigation the antiproliferative activity of thirteen derivatives of betulinic acid and betulin was tested against five different tumor cell lines. The toxicity against normal human fibroblasts (WWO70327) and the mode of cell death on HT-29 (colon cancer) as well as caspase activity induced by the most active compounds, 9 (3-O-chloroacetylbetulinic acid) and 15 (28-O-chloroacetylbetulin) were determined. Investigated derivatives exerted a dose dependent antiproliferative action at micromolar concentrations toward target tumor cell lines. Treatment of HT-29 cells for 24 h with 9 and 15 induced apoptosis, as observed by dye exclusion test (trypan blue) and confirmed by the appearance of a typical ladder pattern in the DNA fragmentation assay

(18-Crown-6)potassium(I) Trichlorido[28-acetyl-3-(tris-(hydroxylmethyl)amino-ethane)betulinic ester-κN]platinum(II): Synthesis and In Vitro Antitumor Activity

Synthesis of platinum(II) conjugate with acetylated betulinic acid tris(hydroxymethyl)aminomethane ester (BATRIS) is presented (BATRISPt). HR-ESI-MS and multinuclear NMR spectroscopy, as well as elemental analysis were used for characterization of BATRISPt. Cytotoxicity (3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), crystal violet (CV), and sulforhodamine B (SRB) assays) of BA, BATRIS, BATRISPt, and cisplatin were assessed on seven different tumor cell lines: melanoma B16, colon HCT116 and DLD-1, adenocarcinoma HeLa, breast MCF-7, and anaplastic thyroid tumor 8505C and SW1736; as well as normal MRC-5 fibroblasts. Furthermore, the effect of the mentioned compounds on the apoptosis (Annexin V/PI assay) and autophagy induction (acridine orange (AO) assay) as well as caspase 3, 8, and 9 activation were investigated on the selected B16 melanoma cell line. BATRISPt showed lower activity than BA, BATRIS, or cisplatin. All tested compounds triggered apoptosis in B16 cells. Induction of autophagy was observed in B16 cells exposed only to BATRIS. On the other hand, new conjugate activates caspases 8 and 9 in B16 cells with higher impact than BATRIS or cisplatin alone

Increased betulinic acid induced cytotoxicity and radiosensitivity in glioma cells under hypoxic conditions

<p>Abstract</p> <p>Background</p> <p>Betulinic acid (BA) is a novel antineoplastic agent under evaluation for tumor therapy. Because of the selective cytotoxic effects of BA in tumor cells (including gliomas), the combination of this agent with conservative therapies (such as radiotherapy and chemotherapy) may be useful. Previously, the combination of BA with irradiation under hypoxic conditions had never been studied.</p> <p>Methods</p> <p>In this study, the effects of 3 to 30 μM BA on cytotoxicity, migration, the protein expression of PARP, survivin and HIF-1α, as well as radiosensitivity under normoxic and hypoxic conditions were analyzed in the human malignant glioma cell lines U251MG and U343MG. Cytotoxicity and radiosensitivity were analyzed with clonogenic survival assays, migration was analyzed with Boyden chamber assays (or scratch assays) and protein expression was examined with Western blot analyses.</p> <p>Results</p> <p>Under normoxic conditions, a half maximal inhibitory concentration (IC₅₀) of 23 μM was observed in U251MG cells and 24 μM was observed in U343MG cells. Under hypoxic conditions, 10 μM or 15 μM of BA showed a significantly increased cytotoxicity in U251MG cells (p = 0.004 and p = 0.01, respectively) and U343MG cells (p < 0.05 and p = 0.01, respectively). The combination of BA with radiotherapy resulted in an additive effect in the U343MG cell line under normoxic and hypoxic conditions. Weak radiation enhancement was observed in U251MG cell line after treatment with BA under normoxic conditions. Furthermore, under hypoxic conditions, the incubation with BA resulted in increased radiation enhancement. The enhancement factor, at an irradiation dose of 15 Gy after treatment with 10 or 15 μM BA, was 2.20 (p = 0.02) and 4.50 (p = 0.03), respectively. Incubation with BA led to decreased cell migration, cleavage of PARP and decreased expression levels of survivin in both cell lines. Additionally, BA treatment resulted in a reduction of HIF-1α protein under hypoxic conditions.</p> <p>Conclusion</p> <p>Our results suggest that BA is capable of improving the effects of tumor therapy in human malignant glioma cells, particularly under hypoxic conditions. Further investigations are necessary to characterize its potential as a radiosensitizer.</p

Lowering Melting Points in Asymmetrically Substituted Salen-copper(II) Complexes Exhibiting Mesomorphic Behavior. Structure of the Mesogen Cu(5-hexyloxySalen)

In comparison with their symmetrical analogues, unsymmetrically substituted Cu−Salen complexes show mesophases with lowered melting points. For terminally substituted complexes, symmetrical ones (R1 = R2) have only an SA phase, while for unsymmetrical alkoxy substitution a monotropic SE phase occurs and the melting temperature decreases with no loss in mesophase stability. Lateral substitution, when it is symmetrical (R3 = R4), lowers mesophase stability but not melting temperature, and when it is unsymmetrical, it greatly lowers both mesophase stability and melting temperature compared with the parent compound. Substitution at the imine carbon (R5, R6) also lowers chemical stability (decomposition) of the compounds. The structure of the 5-hexyloxy complex (R1 = R2 = OC6H13, R3 = R4 = R5 = H) shows the pre-mesophasic arrangement likely adopted after melting

New Principles in Metallomesogen Structure-magnetism Correlations

Whereas binuclear salicylaldimine complexes and their mononuclear parents are waxlike solids with long chain N-substituents, they are liquid crystalline (mesogenic) when such substituent chains are placed on both the ligand rings and the N-atoms. The structure of the non-mesogenic binuclears is determined via X-ray crystallography, and via the strength of magnetic coupling for the mesogenic ones. In the non-mesogenic binuclears the central metal environments have a marked distortion towards tetrahedral (\u3e36°; scale 0° for planar, 90° for tetrahedral), while in the mesogenic ones, the stronger magnetic coupling indicates that this is closer to planar (25°)

Synthesis and Mesogenic Properties of Binuclear Copper (II) Complexes Derived from Salicylaldimine Schiff Bases

The synthesis and mesomorphic (liquid crystal) properties of new binuclear dihalocopper(II) complexes derived from N- and ring-substituted salicylaldimine Schiff bases are reported, together with the mesomorphic properties of their monomeric precursor complexes. with just N-substituents both the dichlorodicopper(II) binuclear complexes and their mononuclear analogues are waxy solids with melting points that increase with their N-chain length. However, with both N- and ring-substituents in the 4-positions, the mononuclear and binuclear complexes are each liquid crystalline or mesogenic, except in case of the mononuclear complexes where the N-substituent is straight chain alkyl. The other mononuclear complexes exhibit a variety of liquid crystal phases: smectic A, C, and E (SA, SC, and SE, respectively). The liquid crystal phase SA is observed in the binuclears with shorter chain N-substituents p-R−O−C6H4− and shorter chain ring-substituents. The chain lengths were increased until the phase behavior expanded to a further form SC in the case of an N-substituent p-C14H29O−C6H4− and a −OC12H25 ring substituent. This points the way toward achieving multiphase behavior with these binuclear systems. The Cu−Br analogues of the binuclear complexes behave similarly but with significant qualitative differences, specifically lower mesophase stability and higher melting temperatures. The structures of the nonmesogenic binuclears ([Cu(N-dodecylSal)X]2, X = Cl, Br) were determined with the aid of X-ray crystallography. These are prototypes for the structures of the binuclear complexes and especially for the shape of the central Cu2O2 X2 core in the binuclears: distorted planar coordination about the copper with distortion toward tetrahedral measured by a characteristic twist angle τ (0° planar; 90° tetrahedral). The binuclear complexes also show magnetic coupling which can be used to estimate the geometry. For [Cu(N-dodecylSal)X]2 τ \u3e 36°, which corresponds to weaker coupling than observed in the mesogenic binuclears where a stronger magnetic coupling indicates a geometry closer to planar (τ = 25°). The mesophases were characterized by differential scanning calorimetry (DSC) analysis and optical polarized microscopy

Small structural changes of pentacyclic lupane type triterpenoid derivatives lead to significant differences in their anticancer properties

In the present investigations five new derivatives of betulinic and betulonic acid were synthesized and the effect of this structural variations on anticancer activity was studied and discussed. The antiproliferative activity of betulinic and betulonic acid derivatives was studied against eight tumor cell lines of different histogenic origin. The derivatives exerted a dose dependent antiproliferative action at micromolar concentrations toward target tumor cell lines. The apoptotic mode of cell death on colon cancer cell line HT-29 was induced by the most active compounds 5, 2-amino-3-hydroxy-2-(hydroxymethyl)propyl (3-O-acetyl)betulinate, and 9, 2-amino-3-hydroxy-2-(hydroxymethyl)propyl betulonate. Treatment of HT-29 cells with 5 and 9 induced apoptosis, as observed by dye exclusion test (trypan blue) and by the appearance of a typical ladder pattern in the DNA fragmentation assay and FITC annexin V assay. Cell cycle perturbations caused by compound 5 are also presented

Effects of Ligand Substituents (F for H; OR for R) on Mesogenic Properties of M(Salen) Derivatives (M = Cu, Ni, VO). New Fluoro-substituted Complexes and Crystal Structure of the Mesogen Ni(5-hexylSalen)

The preparation of new metallomesogens containing fluoro-substituted bis(salicylaldehyde) ethylenediimine (Salen) ligands is reported for the complexes of copper(II), nickel(II), and oxovanadium(IV), in which substitution for individual atoms is shown to have a dramatic effect on packing and mesogenic properties. In other mesogens, fluoro substitution reduces melting points or extends the mesogenic range, or both. By contrast, in the title compounds the melting points are lowered by up to 50°C, while the mesogenicity is eliminated or drastically reduced in range by fluorination, presumed to exert its influence through the dipolar effect. When the alkoxy O atom in Ni(5-(hexyloxy)Salen) is replaced with CH 2, the structure changes dramatically from roughly planar to an irregular S-shape, but mesogenic properties are retained. The crystal structure of (5-n-hexylSalen)Ni shows it to be an S-shaped molecule with especially dramatic bending at the n-hexyl chains from their phenyl rings (58, 85°). Crystal data: C 28H 38N 2O 2Ni, space group P1, a = 12.640(2) Å, b = 16.872(2) Å, c = 6.650(2) Å, α = 98.54(3)°, β = 92.89(3)°, γ = 71.43(1)°, Z = 2, R = 5.44%, R w = 5.96% for 1612 observed unique reflections. © 1995 American Chemical Society

Metals in Medicine

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