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 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

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.)

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

Synthesis of cryptands having tritopic receptor sites by [2+3] Schiff base condensation using Cs(I) ion as the template

Synthesis of two tritopic receptors L<SUP>1</SUP> and L<SUP>2</SUP> by [2+3] Schiff base condensation of trialdehyde 1 or 2 and 1,2-diaminobenzene followed by reduction with NaBH<SUB>4</SUB> are reported. The reactions undergo smoothly in presence of Cs(I) ion as the template

Synthesis and studies of Cu(II)-thiolato complexes: bioinorganic perspectives

Ligation of thiolate sulfur to copper at the active sites of quite a number of copper proteins has been established either by X-ray crystallographic and/or by spectroscopic studies. In addition, for Cu(II)-substituted metalloproteins, the presence of Cu(II)-thiolate bonding at the active sites could be established spectroscopically. Cu(II)-thiolate bonding in different enzymes is not always very similar. Obviously, the bioinorganic significance of Cu(II)-thiolate bonding is enormous and has attracted a lot of attention to synthesize model Cu(II)-thiolato complexes as electronic structural analogues of the active sites of these biomolecules. The present review deals with (i) nature of Cu(II)-thiolate bonding present in different metalloproteins, (ii) difficulties involved in the synthesis of Cu(II)-thiolates and ways to surmount them, (iii) characterization of the Cu(II)-thiolate bonding by electronic and EPR spectroscopic techniques and (iv) electron transfer properties of the Cu(II)-thiolato complexes by cyclic voltammetric studies. The properties of the Cu(II)-thiolato complexes have been discussed as possible models for the active site(s) of copper proteins

Syntheses and X-ray structures of mixed-ligand salicylaldehyde complexes of Mn(III), Fe(III), and Cu(II) ions: reactivity of the Mn(III) complex toward primary monoamines and catalytic epoxidation of olefins by the Cu(II) complex

The Schiff base (L), synthesized from 2-(dimethylamino)ethylamine and salicylaldehyde acts as a tridentate ligand. This ligand, when stirred with 1 equiv of KOH in methanol, undergoes partial hydrolysis of the imine bond. This solution readily takes up Mn(II)/Mn(III) acetate or Fe(III) chloride/perchlorate to form mixed-ligand Mn(III) or Fe(III) complexes, respectively. The neutral dark brown complex, [Mn(L-H)(NCS){o-(CHO)C6H4O-}] (1), crystallizes in the presence of thiocyanate in the orthorhombic space group Pbca with a = 15.271(8), b = 19.522(7), c = 13.213(7) &#197; Z = 8; R = 0.060; and Rw = 0.062. The coordination geometry around Mn(III) ion is distorted octahedral with donation from one L-H, one salicylaldehyde and, one thiocyanate ligand. With Fe(III), the dark red complex isolated in the solid state is found to be a neutral &#181;-oxo Fe(III) dimer with the formula [{o-(CHO)C6H4O-}(L-H)Fe]2O (3). The structure of 3 has been solved and successfully refined in the monoclinic space group C2/c with a = 18.558(7), b = 11.231(5), c = 16.943(6) &#197;; &#946; = 95.81(3)&#176;; Z = 4; R = 0.052; and Rw = 0.055. Each of the Fe(III) ions is hexadentate with donation from one L-H and one salicylaldehyde besides the bridged O atom. The Fe(III)-O-Fe(III) angle is found to be 166.05(4)&#176;, which is well within the normal range observed for monobridged Fe(III)-O-Fe(III) complexes. Due to structural trans effects, the coordination geometry around each metal center is distorted from the ideal octahedral geometry. Cu(II) makes the neutral complex, [Cu(L-H){o-(CHO)C6H4O-}] (2) when L, salicylaldehyde, and a Cu(II) salt are allowed to react in equimolar quantities in the presence of excess of KOH. It crystallizes in the monoclinic space group C2/c with a = 18.077(4), b = 11.514(2), c = 16.716(4) &#197;; &#946; = 93.66(2)&#176;; Z = 8; R = 0.057; and Rw = 0.061. The coordination geometry around Cu(II) is square pyramidal where, out of the four equatorial donors, three are provided by the Schiff base L and the fourth one by the phenolate O of the salicylaldehyde group. The Cu(II) ion is 0.170(5) &#197; above the equatorial plane and is bonded axially to the O atom of the carbonyl group of the salicylaldehyde. The bound salicylaldehyde in the Mn(III) complex 1 readily reacts with the reagents 2-aminophenol, 2-aminothiophenol, or 2-aminoethanol to form mononuclear, neutral Mn(III) complexes 4-6, respectively, with the general formula,[Mn(L-H)(L'-2H)]. The Schiff base L' is formed by condensation of the bound salicylaldehyde in 1 with the amino group of the added reagent. Complex 4 is low-spin (&#956;eff/&#956;B = 3.01; S = 1) at 300 K, which is quite rare. It also exhibits a pseudoreversible Mn(IV)/Mn(III) couple with E&#189; = 0.54 V (vs SCE) in DMF. All the other Mn complexes are high-spin (&#181; eff/&#181; B range, 4.89-4.94; S = 2) at 300 K. The &#956;eff/&#956;B number for 2 is 1.93 and for 3 is 1.84. Complex 2 shows catalytic activity in the oxidation of olefins to epoxides in the presence of 2-methylpropanal and molecular oxygen