Miloš Sedlák

Synthesis of a new class of double-hydrophilic block copolymers with calcium binding capacity as builders and for biomimetic structure control of minerals

Small block copolymers consisting of a hydrophilic poly(ethylene glycol) block and a second, also hydrophilic, moiety which strongly interacts with alkaline earth ions were synthesized by diverse reaction sequences based on poly(ethylene glycol) monomethyl ethers (MW = 2000 and 5000 g/mol, respectively). These starting blocks were transferred to the poly(ethylene glycol) monomethyl monoglycidyl ether or to poly(ethylene glycols) with one terminal acid chloride group. Both intermediates were subsequently reacted with poly(ethyleneimine) (MW = 700 g/mol) and bromoacetic acid to yield poly(ethylene glycol)-block-poly[(N-carboxymethyl)ethyleneimine] (PEG-b-PEIPA, average MW = 3800 resp. 6800 g/mol) as a polymeric analog of EDTA. The terminal epoxy group is also convenient for the connection of simple peptide sequences. For the desired purpose of ion binding, poly(aspartic acid) (PAsp) was applied, resulting in the block copolymer PEO-b-PAsp. A simple testing procedure concerning the inhibition of calcium carbonate precipitation was applied for the prepared structures. A comparison with commercial builders for water treatment such as poly[(acrylic acid)-co-(maleic anhydride)] or poly(aspartic acid) stresses the superb calcium carbonate crystallization inhibition efficiency (up to the 20 fold) of the double hydrophilic block copolymer stabilizers.

Synthesis of double-hydrophilic block copolymers with hydrophobic moieties for the controlled crystallization of minerals.

A set of double hydrophilic block copolymers was synthesized on the basis of a branched poly(ethylene glycol)-block-poly(ethyleneimine) (PEG-b-PEI) block copolymer by polymer analogous reactions. Different hydrophobic moieties were successfully introduced as well as carboxylate, phosphonate, sulfonate and thiol groups leading to a library of only partially differing block copolymers. The analysis of the block copolymers by GPC turned out to be extremely difficult, as the muti-functional polymers tend to interact with various column materials. However, characterization of PEG-b-PEI was possible with 1 H NMR and alnalytical ultracentrigugation as well as with elemental analysis. These techniques revealed a significant amount of unbound PEG due to side reactions with PEI momoners or oligomers. The degree of the various functionalizations of PEG-b-PEI was determined by elemental analysis indicating that the sterically big phosphonic or sulfonic acid groups are only attached to the primary amino groups of the PEI block whereas the smaller thiol and carboxy groups car additionally be bound to secondary amino groups. The set of polymers was applied as additive in the crystallization of CaCO 3 yielding microparticles in all cases. Under the basic conditions of the experiment (pH > 8.5) both hydrophobically modified and unmodified polymers show almost the same influence on the CaCO 3 morphology, whereas the stabilization of the formed microparticles varies. However, the kind of functional group has a strong influce, with phosphonate and sulfonate as the substituents leading to the most significant changes in the CaCO 3 morphology.

The Separation of Racemic Crystals into Enantiomers by Chiral Block Copolymers

A series of chiral double hydrophilic block copolymers (DHBCs) was synthesized and employed as additives in the crystallization of calcium tartrate tetrahydrate (CaT). We found that appropriate polymers can slow down the formation of the thermodynamically most stable racemic crystals as well as the formation of one of the pure enantiomeric crystals so that chiral separation by crystallization occurs even when racemic crystals can be formed. In addition, the presence of DHBCs results in major modifications of crystal morphology, creating unusual morphologies of higher complexity. Our study demonstrates the potential application of chiral DHBCs in the control of chirality throughout crystallization, in particular for racemic crystal systems, and also shows that enantiomeric excess of one enantiomer can be maximized by the kinetic control of crystallization.

Highly Enantioselective Nitroaldol Reactions Catalyzed by Copper(II) Complexes Derived from Substituted 2-(Pyridin-2-yl)imidazolidin-4-one Ligands

Ten optically pure substituted 2-(pyridin-2-yl)imidazolidin-4-ones, 1a-d, 2a-4a, and 2b-4b, were prepared and characterized. The absolute configurations of individual ligands were determined by X-ray analysis or NOESY experiments. The Cu(II) complexes of the respective ligands were studied as enantioselective catalysts of the nitroaldol (Henry) reaction of aldehydes with nitromethane, giving the corresponding substituted 2-nitroalkanols. In the case of an anti arrangement of the imidazolidin-4-one ring, the obtained result was 91-96% ee, whereas in the case of syn arrangement, a significant drop to 25-27% ee was observed.

Synthesis and Characterisation of a New Amphotericin B- Methoxypoly(ethylene Glycol) Conjugate

The reaction of methoxypoly(ethylene glycol)-4-nitrophenyl carbonate with amphotericin B has been used to prepare a new conjugate of amphotericin B (mPEG-AmB). A preliminary screening of in vitro antifungal activity has suggested that mPEG-AmB possesses a similar effect and a similar spectrum of activity as the conventional amphotericin B formulated with sodium desoxycholate.

Enantioselective Henry Reaction Catalyzed By Supported Transition Metal Complexes

Abstract: This present mini-review summarizes the recently published development and trends concerning catalysts based on immobi-lized complexes of transition metals which are designated for asymmetric Henry reaction. The paper presents examples of originally ho-mogeneous catalysts which were anchored to organic carriers (such as dendrimers, polymers) or inorganic materials. The catalysts based on organic carriers are classified and discussed in accordance to their solubility in reaction medium. In the case of inorganic materials, the discussed catalysts were anchored to different types of surface of micro- and nano-particles. The discussion concerns the effect of immo-bilization of catalysts on the overall reaction yield, enantioselectivity, possible recycling, and the effect of recycling on the above-mentioned parameters. Keywords: Enantioselective catalysis, Henry reaction, nitroaldol reaction, recyclable catalysts, solid supported catalyst, transition metal complexes. 1. INTRODUCTION

Synthesis of Substituted 2-Benzoylaminothiobenzamides and Their Ring Closure to Substituted 2-Phenylquinazoline-4-thiones

Acylation of 2-aminothiobenzamide or 2-methylaminothiobenzamide with substituted benzoyl chlorides has been used to synthesise the corresponding 2-benzoyl-aminothiobenzamides whose subsequent sodium methoxide-catalysed ring closure gives the corresponding quinazoline-4-thiones. These compounds were characterised by means of their 1H- and 13C-NMR spectra. The preferred tautomeric form of selected compounds has been discussed on the basis of their 13C-NMR, IR and Raman spectra. It has been found that in the given medium 1-methyl-quinazoline-4-thiones undergo a replacement of the sulphur substituent by oxygen giving 1-methyl-quinazoline-4-ones. In strong acid media, 2-benzoylaminothiobenzamide is cyclised through its sulphur atom to give 2-phenylbenzo[d-1,3]thiazin-4-one.

New targeting system for antimycotic drugs: β-Glucosidase sensitive Amphotericin B–star poly(ethylene glycol) conjugate

A new targeting potentially intravenous conjugate Amphotericin B (AMB)-star poly(ethylene glycol) (sPEG) (M=25,160) has been synthesized and characterized. It contains a beta-d-glucopyranoside molecular switch which is sensitive to beta-glucosidases (E.C.3.2.1.21). The beta-glucosidase-catalyzed release of AMB from the polymeric carrier was proved in vitro by means of spectrophotometry and HPLC.

Prednisolone-α-cyclodextrin-star poly(ethylene glycol) polypseudorotaxane with delayed pH-sensitivity as a targeted drug delivery system

The acylation of prednisolone 20-hydrazone with star poly(ethylene glycol) tetracarboxylic acid (M = 20,000) has been used to prepare the corresponding pH-sensitive conjugate. With α-cyclodextrin, this conjugate forms a polypseudorotaxane, which was characterised by means of (1)H NMR spectra, powder X-ray diffraction patterns and STM microscopy. The rate of acid-catalysed hydrolysis of the conjugate was studied under in vitro conditions in model media of hydrochloric acid solutions, phosphate and acetate buffers (pH 2-5.8). The acid-catalysed hydrolysis (at pH 2) of the polypseudorotaxane was ca 3.5 times slower than that of the original conjugate. After 1h in this medium, 86% of the covalently attached prednisolone remained unchanged. The prepared polypseudorotaxane represents a promising peroral transport system of prednisolone with a pH-sensitive linker with delayed acid-catalysed hydrolysis thanks to protection at the molecular level using α-cyclodextrin.

Kinetic evidence for the coexistence of zwitterionic (T+/-), neutral (T0) and anionic (T-) intermediates during rearrangement of S-(2-oxotetrahydrofuran-3-yl)-N-(4-methoxyphenyl)isothiuronium bromide to 5-(2-hydroxyethyl)-2-(4-methoxyphenylimino)-1,3-thiazolidin-4-one.

The kinetics and mechanism of rearrangement of S-(2-oxotetrahydrofuran-3-yl)-N-(4-methoxyphenyl)isothiuronium bromide (1) into 5-(2-hydroxyethyl)-2-[(4-methoxyphenyl)imino]-1,3-thiazolidin-4-one have been studied under pseudo-first-order reaction conditions in aqueous buffer solutions and in diluted HCl at 25 degrees C. Multiple breaks in the pH profile establish the formation of three different kinetically detectable intermediates T(+/-), T(0), and T(-). Treatment of 1 (pK(a) = 6.7) with base produces reactive isothiourea, which undergoes cyclization to give T(+/-) (rate limiting step at pH < 0.5). Intermediate T(+/-) then undergoes either general acid-catalyzed, concerted (alpha = -0.47) breakdown to 2 (rls at pH 2-3) or a water-mediated proton switch to T(0) which is followed by its general acid-catalyzed breakdown (pH 3-6). The last reaction pathway involves the formation of T(-) either from T(+/-) or from T(0) (pH > 6). The first possibility seems to be more likely because it is in accordance with kinetics observed in basic amine buffers, where the nonlinear increase of the k(obs) with the c(Buffer) changes to a linear increase as a general base-catalyzed pathway is introduced. Coexistence of all three kinetically detectable intermediates is very rare and is possibly due to relatively enhanced stability of these intermediates necessitating participation of an acid for progression to products.