Integrin alpha V beta 3 targeted dendrimer‐rapamycin conjugate reduces fibroblast‐mediated prostate tumor progression and metastasis

Therapeutic strategies targeting both cancer cells and associated cells in the tumor microenvironment offer significant promise in cancer therapy. We previously reported that generation 5 (G5) dendrimers conjugated with cyclic‐RGD peptides target cells expressing integrin alpha V beta 3. In this study, we report a novel dendrimer conjugate modified to deliver the mammalian target of rapamycin (mTOR) inhibitor, rapamycin. In vitro analyses demonstrated that this drug conjugate, G5‐FI‐RGD‐rapamycin, binds to prostate cancer (PCa) cells and fibroblasts to inhibit mTOR signaling and VEGF expression. In addition, G5‐FI‐RGD‐rapamycin inhibits mTOR signaling in cancer cells more efficiently under proinflammatory conditions compared to free rapamycin. In vivo studies established that G5‐FI‐RGD‐rapamycin significantly inhibits fibroblast‐mediated PCa progression and metastasis. Thus, our results suggest the potential of new rapamycin‐conjugated multifunctional nanoparticles for PCa therapy.Here, we synthesized and characterized a novel dendrimer conjugate, G5‐FI‐RGD‐rapamycin. Multifunctional G5‐FI‐RGD‐rapamycin binds to PCa and fibroblasts via alpha V beta 3 integrin and significantly inhibits mTOR signaling and VEGF expression. These in vitro data were confirmed by in vivo data that G5‐FI‐RGD‐rapamycin inhibits fibroblast‐mediated PCa progression and metastasis.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146470/1/jcb26727.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146470/2/jcb26727_am.pd

Mononuclear manganese(III) complexes with imine/amine and phenolate coordination

A new tetradentate Schiff base ligand (H2L) was synthesized by condensation of diisobutyraldehyde disulfide with 2-aminophenol and hydrogenated to form the satd. analog (H2L'). In MnLX (X = Cl, N3, NCS) and the ligands have imine and phenolate ligation, which are relatively rare. MnLOAc can accept an anion like chloride, azide, or thiocyanate which replaces the acetate anion. Cond. data in DMF soln. indicate that the chloride and azide ions are strongly bonded to the metal to give neutral complexes while the thiocyanate and the acetate complexes behave as 1:1 electrolytes. Electronic absorption spectroscopic results are consistent with a 5-coordinate square-pyramidal geometry for these complexes. In DMF, all the complexes exhibit quasireversible Mn(III)/Mn(II) couple where E½values range between −0.77 and −0.89 V vs. Ag/AgCl. The Schiff base is reduced by NaBH4 to provide amine and phenolate coordination. The azide complex, Mn(L')N3 was synthesized to probe any possible shift in the Mn(III)/Mn(II) potential upon changing the 2 donor atoms from imine to amine. The E½ value for the square-pyramidal complex is −0.78 V vs. Ag/AgCl. Room temp. magnetic moment values for the complexes in the solid state lie at 4.90-5.10 µB (µ eff/µ B) indicating high-spin Mn(III) complexes. on SciFinder(R)

A convenient route to iron(III)-thiolates: synthesis and characterization of low-spin (S = ½) iron(III) complexes having the chromophore FeN<SUB>2</SUB>S<SUB>2</SUB>S<SUB>2</SUB> (S* = thioether)

Three air-stable iron(III) complexes with homoleptic hexadentate ligands with the donor set N2S*2S2 (S* = thioether, S = thiolate) have been isolated. The two thiol groups present in each ligand are initially protected as their t-butyl derivatives. When iron(III) chloride is allowed to reflux with any of these thiol-protected ligands the S¤ But linkages are cleaved forming the corresponding iron(III)-thiolates in high yields. The complexes are characterized by electronic absorption, EPR and room-temperature Mossbauer spectroscopic as well as room-temperature magnetic susceptibility studies. As the spectral data indicate each complex has a pseudo-octahedral coordination geometry around the metal ion. The effective magnetic moment values at 300 K lie in the range 2.24-2.30, corresponding to low-spin iron(III) (S =½ ) complexes with significant orbital contribution. One of the complexes exhibits a quasi-reversible FeIII/FeII couple at Ef = 1.66 V (vs S.C.E.), while another complex shows a quasi-reversible FeIV/FeIII couple at Ef = 0.86 V (vs S.C.E.)

Mononuclear Mn(III) complexes with imine/amine and phenolate coordination

767-771A new tetradentate schiff base ligand has been synthesized by condensation of di-isobutyraldehyde disulphide with 2-aminophenol. The ligand forms mononuclear Mn(III) complexes with imine and phenolate ligation, which are relatively rare. The ligand forms a mononuclear Mn(III) complex with the formula, [Mn(L)](acetate) when treated with Mn(acetate)3.2H2O under basic conditions. The resulting cationic complex can accept an anion like chloride, azide, or thiocyanate which replaces the acetate anion. Conductivity data in DMF solution indicate that the chloride and azide ions are strongly bonded to the metal to give neutral complexes while the thiocyanate and the acetate complexes behave as 1:1 electrolytes. Electronic absorption spectroscopic results are consistent with a five-coordinate square-pyramidal geometry for these complexes. In DMF, all the complexes exhibit quasi-reversible Mn(III)/Mn(II) couple where E1/2 values range between -0.77 and -0.89 V vs Ag/AgCl. The schiff base is reduced by NaBH4 to provide amine and phenolate coordination. The azide complex having the formula, [Mn(L')N3] has been synthesized to probe any possible shift in the Mn(III)/Mn(lI) potential upon changing the two donor atoms from imine to amine. The E1/2 value for the square-pyramidal complex is found to be - 0.78 V vs Ag/AgCI. Room temperature magnetic moment values for the complexes in the solid state lie in the range 4.90-5.10 B.M. (μeff/μB) indicating high-spin Mn(III) complexes

Modelling the blue protein active sites: synthesis and characterization of CuN<SUB>2</SUB>S<SUB>2</SUB> complexes showing rhombic EPR spectra and high Cu<SUP>II</SUP>/Cu<SUP>I</SUP> potential

Two new tetradentate ligands have been synthesized by Schiff base condensation oof diisobutyraldehyde disulphide with 2-mercaptoethylamine (L1) and 2-aminothiophenol (L2) respectively and then reducing the imine linkages with NaBH4 in refluxing methanol. In the free ligands the thiolate sulphur is protected with tertiary butyl groups which are cleaved in the presence of CuII-salts to give neutral CuN2S2 complexes. The copper complexes show ligand field transitions at 815 and 760 nm at room temperature which are independent of the solvents used and are consistent with a pseudotetrahedral coordination around the CuII ion. The EPR spectrum of the aliphatic thiolate in MeCN glass shows significant rhombic splitting (gx−gx = 0.09 and Ax−Ay = 60 × 10−4 cm−1) attributable to δ z2 mixing into the ground state wavefunction. For the aromatic thiolate complex, however, the EPR spectrum was not well resolved although the rhombic nature of the spectrum could easily be observed. Both the complexes exhibit well-defined cyclic responses in their cyclic voltammograms at RT and in acetonitrile for the CuII/CuI couple with E½ =0.5V vs SCE. This high positive value for the redox couple is also consistent with a coordination geomttry much distorted from planarity. The active sites of the blue protein which contain copper in distorted geomtries exhibit CuII/CuI potential in the range 300-800 mV vs NHE at pH = 7.0