Release characteristics of novel pH-sensitive p(HEMA-DMAEMA) hydrogels containing 3-(trimethoxy-silyl) propyl methacrylate

An amphiphilic hydrogel of poly(2-hydroxyethyl methacrylate) cross-linked with tetraethyleneglycol diacrylate (TEGDA) was synthesized to contain the hydrophobic monomer 3-(trimethoxy-silyl) propyl methacrylate (PMA) and the pH-responsive, hydrophilic monomer N',N'-dimethylaminoethyl methacrylate (DMAEMA). The gels were separately loaded with two biomolecular probes, insulin and protamine, via both physical entrapment and equilibrium imbibition methods. The release profiles for these biomolecular probes, possessing similar MW (5.7 and 4-6 kDa, respectively) but different pI's (5.3 and 10.0, respectively), were investigated with respect to variation in the pH of the bathing medium as well as the DMAEMA content, and the cross-link density of the hydrogel. Gels exhibited classical Fickian diffusion release profiles. For a typical gel composition 66:15:10:09 mol % (HEMA:DMAEMA:PMA:TEGDA), as the pH of the release media decreased from 7.3 to 4.0, the rate of release of both biomolecular probes increased. When loaded via entrapment, the insulin release rate increased ca. 4-fold (1.0-3.7 x 10(-7) cm(2) s(-1)), whereas that of protamine increased 10-fold (0.3-3.3 x 10(-7) cm(2) s(-1)). When loaded by imbibition, the insulin diffusion coefficient increased 2-fold (3.8-7.2 x 10(-7) cm(2) s(-1)), whereas that of protamine increased 3-fold (1.9-5.5 x 10(-7) cm(2) s(-1)). The reduction of pH, through its protonation of the gel network, has a more dramatic influence on protamine release, the result of its higher pI (10.0) compared to that of insulin (5.3). As the DMAEMA content of the hydrogel was increased from 0 to 20 mol %, the diffusion coefficient of protamine increased by ca. 7-fold (1.7-12.2 x 10(-7) cm(2) s(-1)), whereas that of insulin increased only ca. 2-fold (1.7-4.0 x 10(-7) cm(2) s(-1)). This differential release confirms the role of internal protonation in effecting the greater release of the protonated drug molecule. Increasing the TEGDA content from 3 to 15 mol % reduced the diffusion coefficient ca. 3-fold for insulin (1.6-0.5 x 10(-7) cm(2) s(-1)) and 5-fold for protamine (4.0-0.8 x 10(-7) cm(2) s(-1)). The final D(ip) at 15 mol % TEGDA suggests that the smaller mesh size offsets any differential release that arises from protonation. The presence of PMA in the hydrogel formulation, which contributes additional cross-links by reason of the formation of siloxane macromers, did not change the usually observed Fickian diffusion mechanism.     

Synthesis of 3-(2-aminoethylthio)propyl glycosides

Anomeric pairs of 3-(2-aminoethylthio)propyl d-galactopyranoside (4, 4a), d-glucopyranoside (5, 5a), and 2-acetamido-2-deoxy-d-glucopyranoside (6, 6a) were prepared by addition of 2-aminoethanethiol to the corresponding, anomeric, allyl glycosides. The allyl α-glycosides were prepared by refluxing the sugars with allyl alcohol in the presence of an acid catalyst; the allyl β-glycosides were prepared by the reaction of acetylated glycosyl bromides with allyl alcohol in the presence of mercuric cyanide, followed by O-deacetylation. The rate of thiol addition to the allylic group was found to be different for each glycoside.     

Synthesis and properties of thermo- and pH-sensitive poly(N-isopropylacrylamide)/polyaspartic acid IPN hydrogels

Various interpenetrating polymer network (IPN) hydrogels with sensitivity to temperature and pH were prepared by introducing the pH-sensitive polymer polyaspartic acid (PASP) hydrogel, into the poly(N-isopropylacrylamide) (PNIPAAm) hydrogel system for the purpose of improving its response rate to temperature. The morphologies and thermal behavior of the prepared IPN hydrogels were studied by both scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). The IPN hydrogels showed a large and uneven porous network structure, without showing the common PNIPAAm hydrogel structure. The paper moreover studied their swelling properties, such as temperature dependence of equilibrium swelling ratio, shrinking kinetics, re-swelling kinetics and oscillatory swelling behavior in water. The swelling experiment results revealed that IPN hydrogels exhibited much faster shrinking and re-swelling in function of the composition ratio of the two network components. These fast responsive hydrogels foster potential applications in biomedical and biotechnology fields.     

Synthesis and hybridization properties of oligonucleotides containing (2S,3R)-9-(2,3,4-trihydroxybutyl)adenine

The synthesis and properties of oligonucleotides (ONs) containing 9-(2,3,4-trihydroxybutyl)adenine, A(C2) and A(C3), are described. The ON containing A(C2) involves the 3'-->4' and 3-->5' phosphodiester linkages in the strand, whereas that containing A(C3) possesses the 3'-->4' and 2'-->5' phosphodiester linkages. It was found that incorporation of the analogs, A(C2) or A(C3), into ONs significantly reduces the thermal and thermodynamic stabilities of the ON/DNA duplexes, but does not largely decrease the thermal and thermodynamic stabilities of the ON/RNA duplexes as compared with the case of the ON/DNA duplexes. It was revealed that the base recognition ability of A(C2) is greater than that of A(C3) in the ON/RNA duplexes.     

Synthesis of 9-[1-(substituted)-3-(phosphonomethoxy)propyl]adenine derivatives as possible antiviral agents

Acyclic N9 adenine nucleosides substituted at C-1' position were prepared by the Mitsunobu reaction of 1-tert-butyldimethylsilyl-4-pivaloylbutan-1,2,4-triol (5) with adenine. Pivaloyl hydroxyl was modified to the phosphonomethoxy derivatives, and the tert-butyldimethylsilyl hydroxyl was converted to methoxy, azido, amino, fluoro, and c-hydroxyethyl and was eliminated to give vinyl. The resulting phosphonic acids were converted to prodrugs also.     

Synthesis of 9-[1-(1 -hydroxyethyl)-3-(phosphonomethoxy)propyl]adenine and prodrug as possible antiviral agents

The appropriately protected C-1'-hydroxyethyl-3-hydroxypropyl-N9-adenine nucleoside was prepared from 1-pivaloyloxy-5-tert-butyldiphenylsilyloxy-3-pentanol and adenine through the Mitsunobu reaction. One of the terminal hydroxyls was converted to the phosphonomethoxy derivative and the prodrug.     

Synthesis and antiplasmodial activity of new N-[3-(4-{3-[(7-chloroquinolin-4-yl)amino]propyl}piperazin-1-yl)propyl]carboxamides

The parallel acylation of N-{3-[4-(3-aminopropyl)piperazin-1-yl]propyl}-7-chloroquinolin-4-amine with polymer-bound carboxylic acids opened straightforward access to novel aminoquinolines with activity against Plasmodium falciparum strains in vitro. Using this amino scaffold prepared in solution and polymer-bound carboxylic, we have synthesized a series of 29 new compounds in good to excellent yield and purity. Biological evaluation included determination of the activity against a chloroquine (CQ) sensitive strain and a CQ resistant mutant. Most of the novel structures presented here displayed activity against both strains in the lower nanomolar range, four compounds showed an at least fourfold increase in the ratio of inhibition of CQ resistant to sensitive strains over CQ itself. These results suggest that this derivatization technique is a useful method to speed up structure-activity relationship studies on aminoquinolines toward improved activity versus CQ resistant strains of P. falciparum in vitro.     

Synthesis and properties of triplex-forming oligonucleotides containing 2′-O-(2-methoxyethyl)-5-(3-aminoprop-1-ynyl)-uridine

2′-O-(2-Methoxyethyl)-5-(3-aminoprop-1-ynyl)-uridine phosphoramidite (MEPU) has been synthesized from d-ribose and 5-iodouracil and incorporated into triplex-forming oligonucleotides (TFOs) by automated solid-phase oligonucleotide synthesis. The TFOs gave very high triplex stability with their target duplexes as measured by ultraviolet/fluorescence melting and DNase I footprinting. The incorporation of MEPU into TFOs renders them resistant to degradation by serum nucleases.     

Synthesis and antitumor activity of 5-[1-(3-(dimethylamino)propyl)-5-halogenated-2-oxoindolin-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamides

We report herein the design and synthesis of novel 1-[3-(dimethylamino)propyl]indolin-2-one derivatives based on the structural features of Sunitinib, a known multitargeted receptor tyrosine kinase inhibitor, and TMP-20, a previously discovered compound with good antitumor activity in our lab. These newly synthesized derivatives were evaluated for in vitro activity against five human cancer cell lines and VEGF/bFGF-stimulated HUVECs. Results revealed that all of the target compounds 1a-p show potent antitumor activity, compounds 1e-h (IC₅₀’s: 0.45-5.08 μM) are more active than Sunitinib (IC₅₀’s: 1.35-6.61 μM), and the most active compound 1h (IC₅₀: 0.47-3.11 μM) is 2.1-4.6-fold more potent than Sunitinib against all five cancer cell lines. In addition, like Sunitinib, 1a-p have higher selectivity on VEGF-stimulated HUVEC other than bFGF-stimulated HUVEC.     

Synthesis and QSAR studies on hypotensive 1-[3-(4-substituted phenylthio) propyl]-4-(substituted phenyl) piperazines

A series of 1-[3-(4-substituted phenylthio) propyl]-4-(substituted phenyl) piperazines has been synthesized and evaluated for hypotensive activity. The QSAR studies indicate that resonance and hydrophobic parameters of the aryl substituents are important for hypotensive activity. The similar role of resonance parameter in describing the variance of 5-HT(2A) receptor binding affinities of these compounds suggests a possible role of 5-HT(2A) receptors in mediating the hypotensive action of title compounds.     

3-(1H-imidazol-4-yl)propyl]guanidines containing furoxan moieties: a new class of H3-antagonists endowed with NO-donor properties

Synthesis and pharmacological characterisation of a series of products obtained by coupling the H(3)-antagonist SKF 91486 through appropriate spacers with the NO-donor 3-phenylfuroxan-4-yloxy and 3-benzenesulfonylfuroxan-4-yloxy moieties, as well as with the corresponding furazan substructures, devoid of NO-donating properties, are reported. All the products were tested for their H(3)-antagonistic and H(2)-agonistic properties on electrically-stimulated guinea-pig ileum segments and guinea-pig papillary muscle, respectively. The whole series of compounds displayed good H(3)-antagonist behaviour and feeble partial H(2)-agonist activity. Among furoxan derivatives, the benzenesulfonyl hybrid 28, a good NO-donor, triggered a dual NO-dependent muscle relaxation and H(3)-antagonistic effect on guinea-pig intestine.     

Synthesis and properties of carboxymethylchitosan hydrogels modified with poly(ester-urethane)

Preparation and properties of carboxymethylchitosan (CMC) modified with polyurethane (PU) containing poly(ethylene adipate) (PEA) as a soft segment is described. Urethane prepolymer was first synthesized by the reaction of PEA with an excess of 1,6-hexamethylene diisocyanate (HDI) to terminate its ends with isocyanate functional groups, followed by chain extension reaction using ethylene glycol as a chain extender. Its chemical structure was characterized by ¹H NMR and FTIR, molecular weight by GPC, and thermal behavior by DSC. To prepare PU-modified CMC (CMC-PU), 1–60 wt% of PU were introduced into the CMC solution of THF:H₂O mixture (50:50 v/v) in the presence of 10 wt% of hexamethylene-1,6-di-(aminocarboxysulfonate) (HDA) to increase network density. Formation of the network structure was confirmed by investigating percent crosslinking and water swelling properties of CMC-PU compared to CMC network without PU. When percent of PU increased from 1 to 60 wt%, percent crosslinking of CMC-PU gradually increased up to 82%, whereas equilibrium water content (EWC) dropped and retained at 1000%. SEM showed microphase separation of PU (10–50 μm) thoroughly dispersed in CMC surface and in the bulk. In addition, CMC-PU exhibited a slight enhancement in toughness properties. Cytotoxicity and biocompatibility tests indicated that CMC-PU was non-toxic.     

Synthesis, swelling behavior, and biocompatibility of novel physically cross-linked polyurethane-block-poly(glycerol methacrylate) hydrogels

Physically cross-linked novel block copolymer hydrogels with tunable hydrophilic properties for biomedical applications were synthesized by controlled radical polymerization of polyurethane macroiniferter and (2,2-dimethyl-1,3-dioxolane) methyl methacrylate. The block copolymers were converted to hydrogels by the selective hydrolysis of poly[(2,2-dimethyl-1,3-dioxolane) methyl methacrylate] block to poly(glycerol methacrylate). The block copolymerization has been monitored by monomer conversion and molecular weight increase as a function of time. It was observed that the polymerization proceeded with a characteristic "living" behavior where both monomer conversion and molecular weight increased linearly, with increasing reaction time. The resulting hydrogels were investigated for their equilibrium water content (EWC), dynamic water contact angles, swelling kinetics, thermodynamic interaction parameters, plasma protein adsorption, and platelet adhesion. Similar to our previous mechanically responsive hydrogels (Mequanint, K.; Sheardown, H. J. Biomater. Sci. Polym. Ed. 2005, 10, 1303-1318), the present results indicated that block copolymer hydrogels have excellent hydrophilicity and swelling behavior with improved modulus of elasticity. The equilibrium swelling was affected by the hydrolysis time, block length of poly(glycerol methacrylate), temperature, and the presence of soluble salts. Fibrinogen adsorption and platelet adhesion were significantly lower for the hydrogels than for the control polyurethane, whereas albumin adsorption increased for the hydrogels in proportion to the contents of poly(glycerol methacrylate). These hydrogels have potential in a number of biomedical applications such as drug delivery and scaffolds for tissue engineering.     

Synthesis and characterization of pH-sensitive conjugate of isoniazid - methoxypoly(ethylene glycol)-b-poly(l-lysine)

The present paper deals with the preparation and characterization of a conjugate of isoniazid (INH) with the block copolymer methoxypoly(ethylene glycol)-b-poly(l-lysine) (mPEG-b-PLL). The structure of the conjugate (mPEG-b-PLL-INH) was verified by means of (1)H NMR, GPC, infrared spectroscopy, elemental analysis and powder X-ray diffraction. The conjugate contains six l-lysine units with five INH molecules, which are attached by means of pH-sensitive amidine bond. Under in vitro conditions, the conjugate is hydrolyzed and isoniazid is released (pH 4; 37°C; t(1/2) ≈10h).     

Synthesis and characterization of chondroitin sulfate–methacrylate hydrogels

The various degree of methacrylate (MA) substitution on chondroitin sulfate (CS) was prepared by reacting chondroitin sulfate with methacrylic anhydride (MAA) in the presence of sodium hydroxide (NaOH) as a base. The effects of reaction time, reaction temperature, MAA concentration, and NaOH amount on the substitution degree of CS-MA were tested. The confirmation of the CS-MA chemical structure was carried out by ¹H-NMR, ¹³C-NMR, FTIR and the degree of MA substituent on CS was calculated from the ratios of two peak intensities corresponding to methyl groups on methacrylate and chondroitin sulfate, respectively. Hydrogels were prepared by free radical polymerization of CS-MA precursors with or without acrylic acid (AA). CS-MA hydrogels were easily broken into small pieces during swelling study. However, CS-MA-AA hydrogels remained completely and showed a range of swelling ratio from 200 to 390% and exhibited an increase in swelling ratio with a decreasing degree of MA substitution. The thermal degradability observed with a TGA explained the unstableness of these hydrogels in comparison with the pure CS. The surface morphology conducted by SEM exhibited a porous structure after swelling.     

Synthesis and decoloring properties of sodium humate/poly (N-isopropylacrylamide) hydrogels

A series of novel sodium humate/poly(N-isopropylacrylamide) (SH/PNIPA) hydrogels were synthesized by solution polymerization. The swelling and decoloring properties of SH/PNIPA hydrogels were also examined. Experiment results show that there exist hydrogen-bonding interactions between SH and PNIPA in the SH/PNIPA hydrogels network, which are not strong enough to disrupt the aggregation of dehydrated PNIPA chains at phase transition temperature, leading to the same volume phase transition temperature as pure PNIPA hydrogel. The adsorption and desorption of methylene blue (MB) for the hydrogels were influenced by temperature, initial MB concentration and SH amount. Low temperature favors the adsorption and desorption of MB. Appropriate SH amount of the hydrogels is crucial for the adsorption and desorption of MB. The maximum adsorption capacity was 10.8 mg MB per gram of SH/PNIPA gel.     

Synthesis of N6-substituted 9-[3-(phosphonomethoxy)propyl]adenine derivatives as possible antiviral agents

A number of N6-substituted 9-[3-(phosphonomethoxy)propyl]adenine derivatives having hydroxymethyl at C-1' position were prepared from the appropriate 6-chloroadenine derivative. The syntheses of the corresponding prodrugs of these compounds are also reported. These compounds showed poor activity against HCV in replicon assay.     

Synthesis of nucleotide derivatives containing 1-(4-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzamido)-2,3-propanediol for photoaffinity modification of proteins and nucleic acid

1-(4-(3-(Trifluoromethyl)-3H-diazirin-3-yl)benzamido)-3-O-(4,4'- dimethoxytrityl)-2,3-propanediol phosphoramidite was synthesized and used as a modified unit in the automatic synthesis of oligodeoxyribonucleotides. Pentadecathymidylates with various numbers of 2,3-propanediol moieties substituted with aryl(trifluoromethyl)diazirinyl (ATFMD) were obtained, and the thermal stability of their duplexes with (dA)15 were studied. One ATFMD-propanediol residue was shown to reduce the thermal stability of the duplex by 8-9 degrees C. The irradiation of the ATFMD-containing duplexes by UV light with the wavelength of 350 nm was found to cause the cross-linking reaction of the ATFMD-containing strand with the complementary strand and the formation of the cross-linked duplexes. The photomodification efficiency was independent of the oligonucleotide sequence, with each ATFMD group providing for 5% cross-linking. The irradiation of an ATFMD-containing duplex, a substrate of the HIV-1 integrase, in the presence of this enzyme resulted in the covalent DNA-protein complex. The oligonucleotides with the 1-(4-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzamido)-2,3-propanediol moiety in their chains can be used for the photoaffinity modification of both nucleic acids and proteins that recognize them. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2002, vol. 28, no. 4; see also http://www.maik.ru.     

Synthesis of N-phenyl-N-(3-(piperidin-1-yl)propyl)benzofuran-2-carboxamides as new selective ligands for sigma receptors

Novel benzofuran-2-carboxamide ligands, which are selective for sigma receptors, have been synthesized via a microwave-assisted Perkin rearrangement reaction and a modified Finkelstein halogen-exchange used to facilitate N-alkylation. The ligands synthesized are the 3-methyl-N-phenyl-N-(3-(piperidin-1-yl)propyl)benzofuran-2-carboxamides (KSCM-1, KSCM-5 and KSCM-11). The benzofuran-2-carboxamide structure was N-arylated and N-alkylated to include both N-phenyl and N-(3-(piperidin-1-yl)propyl substituents, respectively. These new carboxamides exhibit high affinity at the sigma-1 receptor with K_i values ranging from 7.8 to 34 nM. Ligand KSCM-1 with two methoxy substituents at C-5 and C-6 of the benzofuran ring, and K_i = 27.5 nM at sigma-1 was found to be more selective for sigma-1 over sigma-2.     

Synthesis and anti-inflammatory activity of some novel 3-phenyl-N-[3-(4-phenylpiperazin-1yl)propyl]-1H-pyrazole-5-carboxamide derivatives

A new series of 3-phenyl-N-[3-(4-phenylpiperazin-1yl)propyl]-1H-pyrazole-5-carboxamide derivatives were synthesized and investigated their anti-inflammatory activities using carrageenan-induced rat paw edema model in vivo. All the synthesized compounds were found to be potent anti-inflammatory agents.