Design of Chitosan-5Fu Conjugate Exhibiting Antitumor Activity

In order to provide a macromolecular prodrug of 5-fluorouracil (5FU) reducing the side effects, having an affinity for tumor cells, and exhibiting strong antitumor activity, the covalent attachments of 5FUs to chitosan and chitosamino-oligosaccharide (COS) through hexamethylene spacer groups via urea, urea bonds were carried out. The effect of prolongation of life was tested in vivo against p388 lyrnphocytic leukemia in female CDF, mice by intra-peritoneal (i.p.) transplantation/i.p. injection and the growth-inhibitory effect on Meth-A fibrosarcoma or MH-134Y heputoma was evaluated in vivo in SPF-C3H/He scl male or Balb/c male mice by subcutaneous (s.c.) implantation/intravenous (i.v.) injection. The effects of the degree of polymerization of chitosan and     

Syntheses and antitumor activities of polymers containing amino acid and 5‐fluorouracil moieties

The new monomer, 3,6‐endo‐methylene‐1,2,3,6‐tetrahydrophthalimidoethanoyl‐5‐fluorouracil (ETEFU), was synthesized from 5‐fluorouracil (5‐FU) and 3,6‐endo‐methylene‐1,2,3,6‐tetrahydophthalimidoethanoyl chloride (ETEC). Its homopolymer and copolymers with acrylic acid (AA) and vinyl acetate (VAc) were prepared by photopolymerization reactions using 2,2‐dimethoxy‐2‐phenylacetophenone (DMP) as the photoinitiator. The synthesized ETEFU and polymers were identified by FT‐IR, ¹H‐NMR, and ¹³C‐NMR spectra. The contents of ETEFU units in poly(ETEFU‐co‐AA) and poly(ETEFU‐co‐VAc) were 20 and 17 mol%, respectively. The number‐average molecular weights of the synthesized polymers determined by gel permeation chromatography (GPC) were 4,600 to 10,700 g mol⁻¹. In vitro cytotoxicities of samples were evaluated with cancer cell lines [mouse mammary carcinoma (FM3A), mouse leukemia (P388), and human histiocytic lymphoma (U937)] and a normal cell line [mouse liver cells (AC2F)]. Cytotoxicities of 5‐FU and synthesized samples against the cancer cell lines were ranked as follows: ETEFU > poly(ETEFU) > 5‐FU > poly(ETEFU‐co‐AA) > poly(ETEFU‐co‐VAc). The in vivo antitumor activities of poly(ETEFU) and poly(ETEFU‐co‐AA) against Balb/C mice bearing the sarcoma 180 tumor cells were greater than those of 5‐FU at all doses except for the activity of poly(ETEFU) at 0.8 mg/kg. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 1589–1595, 1999     

Synthesis and antitumor activity of 6-O-carboxymethyl chitin fixing 5-fluorouracils through pentamethylene, monomethylene spacer groups via amide, ester bonds.

In order to provide the water-soluble and biodegradable macromolecular prodrug of 5-fluorouracil (5FU), the fixation of 5FUs to 6-O-carboxymethyl chitin(CM-chitin) through pentamethylene, monomethylene spacer groups via amide, ester bonds was carried out. The obtained CM-chitin/5FU conjugate showed the slow release of 5FU and exhibited remarkable antitumor activity against P388 lymphocytic leukemia in mice by intraperitoneal(i.p.) implantation/i.p. injection.     

Syntheses,antitumor activities,and antiangiogenesis of a monomer and its medium molecular weight polymers: Maleimidoethanoyl‐5‐fluorouracil and its polymers

A new monomer, maleimidoethanoyl‐5‐fluorouracil (MIEFU), was synthesized by the reaction of maleimidoethanoyl chloride and 5‐fluorouracil (5‐FU). The homopolymer of MIEFU and its copolymers with acrylic acid (AA) or vinyl acetate (VAc) were prepared by photopolymerizations with 2,2‐dimethoxy‐2‐phenylacetophenone as an initiator at 25 °C for 48 h. The structures of the synthesized monomer and polymers were identified by Fourier transform infrared, ¹H NMR, and ¹³C NMR spectroscopies and elemental analysis. The contents of the MIEFU units in poly(MIEFU‐co‐AA) and poly(MIEFU‐co‐VAc) were 18 and 30 mol %, respectively. The number‐average molecular weights of the synthesized polymers, as determined by gel permeation chromatography, ranged from 4900 to 9800. The in vitro cytotoxicities of the samples against mouse mammary carcinoma (FM3A), mouse leukemia (P388), and human histiocytic lymphoma (U937) cancer cell lines decreased in the following order: 5‐FU ≥ MIEFU > poly(MIEFU) > poly(MIEFU‐co‐AA) > poly(MIEFU‐co‐VAc). The in vivo antitumor activities of the polymers against Balb/C mice bearing the sarcoma 180 tumor cells were greater than those of 5‐FU at all the doses tested. The inhibitions of the SV40 DNA replication of the samples were much greater than that of the control. The synthesized monomer and polymers showed more antiangiogenesis activity than the control. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 1247–1256, 2000     

Syntheses,antitumor activities,and antiangiogenesis of exo‐3,6‐epoxy‐1,2,3,6‐tetrahydrophthalimidoethanoyl‐ 5‐fluorouracil and its polymers

A new monomer, exo‐3,6‐epoxy‐1,2,3,6‐tetrahydrophthalimidoethanoyl‐5‐fluorouracil (ETFU), was synthesized by the reaction of exo‐3,6‐epoxy‐1,2,3,6‐tetrahydrophthalimidoethanoyl chloride (ETPC) and 5‐fluorouracil (5‐FU). The homopolymer of ETFU and its copolymers with acrylic acid (AA) and vinyl acetate (VAc) were prepared via photopolymerizations with 2,2‐dimethoxy‐2‐phenylacetophenone at 25 °C for 48 h. The structures of the synthesized monomer and polymers were identified by Fourier transform infrared, ¹H NMR, and ¹³C NMR spectroscopy and elemental analysis. The ETFU contents in poly(ETFU‐co‐AA) and poly(ETFU‐co‐VAc) were 26 mol % and 26 mol %, respectively. The number‐average molecular weights of the polymers, as determined by gel permeation chromatography, ranged from 5600 to 17,000. The in vitro cytotoxicities of 5‐FU and the synthesized samples against mouse mammary carcinoma and human histiocytic lymphoma cancer cell lines increased in the following order: ETFU > 5‐FU > poly(ETFU‐co‐AA) > poly(ETFU) > poly(ETFU‐co‐VAc). The in vivo antitumor activities of the polymers against Balb/C mice bearing the sarcoma 180 tumor cells were greater than those of 5‐FU at all doses tested. The inhibitions of the samples for SV40 DNA replication and antiangiogenesis were much greater than the inhibition of the control. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 4272–4281, 2000     

Anticonvulsant activity and succinate dehydrogenase inhibitory property of new substituted thiobarbiturates

Eight 1-aryl-3-(2-pyridyl)thiobarbiturates were synthesized and evaluated for their anticonvulsant property and their ability to inhibit succinate dehydrogenase activity of rat brain homogenates. These substituted thiobarbiturates (100 mg./kg., i.p.) provided 20–60% protection against pentylenetetrazol-induced convulsions in albino mice. Low toxicity of these compounds was reflected by their high approximate LD₅₀ values which were found to range from 500–1000 mg./kg. All substituted thiobarbiturates (ImM) inhibited in vitro succinate dehydrogenase activity and the degree of inhibition ranged from 10–72%.     

Monte Carlo Simulation of Hyperbranched Copolymerizations in the Presence of a Multifunctional Initiator

The Monte Carlo method is applied to simulate the copolymerization of a self‐condensing vinyl monomer and a conventional vinyl monomer in the presence of a multifunctional initiator at equal rate constants. With the increase of the molar ratio of self‐condensing vinyl monomer in the monomer composition, the number average degree of polymerization decreases and the weight average degree of polymerization decreases at a lower conversion of double bonds but increases at a higher conversion of double bonds. The molecular weight distribution, PI, changes from 1.01 to 12.0 and the average degree of branching, DB, increases from 0 to 0.456. We discovered that the addition of conventional vinyl monomer can modify the ratio of multi‐arm hyperbranched macromolecules in the product, i. e., the content of macromolecules with core moiety will increase with the increase of the ratio of conventional vinyl monomer. The possibility of controlling PI and DB by changing the conversion and monomer compositions is demonstrated.     

Syntheses and antitumor activities of medium molecular weight polymers containing α-ethoxy-exo-3,6-epoxy-1,2,3,6-tetrahydrophthaloyl-5-fluorouracil

The new monomer, α-ethoxy-exo-3,6-epoxy-1,2,3,6-tetrahydrophthaloyl-5-fluorouracil (EETFU), was synthesized from 5-fluorouracil (5-FU) and α-ethoxy-exo-3,6-epoxy-1,2,3,6-tetrahydrophthaloyl chloride. Its homopolymer and copolymers with acrylic acid (AA) and vinyl acetate (VAc) were synthesized by photopolymerizations using 2,2-dimethoxy-2-phenylaceto-phenone. The synthesized samples were characterized by FT-IR, ¹H-NMR and ¹³C-NMR spectroscopes, elemental analysis, and gel permeation chromatography. The EETFU contents in poly(EETFU-co-AA) and poly(EETFU-co-VAc) were 40 and 37 mol %, respectively. The number average molecular weights were in range from 8,400 to 10,300. The in vitro cytotoxicities of synthesized samples were evaluated against mouse mammary carcinoma (FM3A), mouse leukemia (P388), and human histiocytic lymphoma (U937) as cancer cell lines and mouse liver cells (AC2F) as a normal cell line. The range of IC₅₀ values obtained from the in vitro test for synthesized samples were 0.03–0.16 µg/mL against cancer cell lines. The in vitro cytotoxicities of polymers were beter than 5-FU. The in vivo antitumor activities of synthesized monomer and polymers were also investigated by mice bearing the sarcoma 180 tumor cells. The in vivo antitumor activities of the synthesized monomer and polymers were greater than those of 5-FU at corresponding dosage concentrations. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 2619–2627, 1999     

Free-ionic polymerization of isobutyl vinyl ether by radiation

Radiation-induced free-ionic polymerization of isobutyl vinyl ether in bulk system has been studied by dilatometry and electrical conductivity measurement. Some refinements in kinetic treatment of estimate the propagation rate constant k_p from the rate of polymerization and steady-state conductivity were attempted. Polymerization of superdried monomer which gave a half-power dose-rate dependence of R_p was carried out at 0, 25, and 50°C. The k_p value obtained at 25°C and an activation energy for propagation were estimated as 1.2 ± 0.4 × 10⁵ I./mole-sec and 9.6 ± 2.8 kcal/mole, respectively. In isobutyl vinyl ether, a propagation reaction in free-ionic mechanism was found to be characterized with a high frequency factor and presumably higher activation energy, compared with ion-pair mechanism. Discussions were also made as to several contrasting behaviors between the polymerization of alkyl vinyl ethers and other vinyl monomers as styrene both in free-ion and ion-pair mechanisms.     

Synthesis of casein-G-poly(vinyl acetate). II

Poly(vinyl acetate) was graft-copolymerized onto casein in the presence of potassium peroxydisulfate-ascorbic acid. The effect of synthetic variables on the rates of conversion of monomer (R_p), graft copolymerization (R_g), and homopolymerization (R_h), percent grafting, and grafting efficiency were investigated and the results, compared with the system initiated by peroxydisulfate alone.     

Photopolymerization with the use of titanocene dichoride as sensitizer

Titanocene dichloride sensitized photopolymerization of vinyl ethers and styrene but did not polymerize methyl methacrylate and vinyl acetate. In the case of 2-chloroethyl vinyl ether, polymerization started rapidly some time after the color of the liquid had changed from orange to green. Polymerization was also achieved by heating the monomer at 60°C after stopping the irradiation at the end of the induction period. On the basis of the reactivity of the monomers and the effect of additives, polymerization is considered to proceed cationically. In case of the polymerization of styrene, conversion increased linearly with time. The k/k_t value of 6.3 × 10^?5l./mole-sec obtained for the polymerization of styrene agrees well with the value reported for radical polymerization. The agreement of the value and ineffective inhibition of polymerization in the presence of pyridine indicates the polymerization follows a radical mechanism. Copolymerization of styrene (M₁) and 2-chloroethyl vinyl ether (M₂) proceeded radically, and the reactivity ratios were r₁ = 2.5 and r₂ = 0.6.     

Reactivity ratios for copolymerization of vinyl chloride with 2-methylpentyl vinyl brassylate by computerized linearization

A computerized version of the Fineman-Ross linearization procedure was used to determine reactivity ratios for copolymerization of vinyl chloride (monomer 1) and 2-methylpentyl vinyl brassylate (monomer 2). From differential refractometry data for the products of low-conversion copolymerization, the procedure gave r₁ = 1.06 and r₂ = 0.234. The ratios computed from chlorine contents of the same products were r₁ = 1.10 and r₂ = 0.239. The polarity factor (e₂) and general monomer reactivity (Q₂) calculated for monomer 2 from these ratios were, respectively, ?0.95 to ?0.98 and 0.032–0.033. The interquartile range for the copolymerization of a mixture of 60% monomer 1 and 40% monomer 2 was 1.4%. These values suggest that from suitable proportions of reactants, sufficiently homogeneous distribution of monomers can be achieved in copolymers of vinyl chloride and 2-methylpentyl vinyl brassylate to offer the possibility of effective internal plasticization.     

Amphiphilic polymethacrylates as crosslinked polymer precursors obtained by free‐radical monomethacrylate/dimethacrylate copolymerizations

As an extension of our work on the elucidation of the mechanism and control of 3‐dimensional network formation in the free‐radical crosslinking polymerization and copolymerization of multivinyl compounds with the aim to molecularly design vinyl‐type network polymers, novel amphiphilic polymers were prepared as crosslinked polymer precursors. Thus, benzyl methacrylate, a nonpolar monomer, was copolymerized radically with 5 mol % of triicosaethylene glycol dimethacrylate [CH₂C(CH₃)CO(OCH₂CH₂)₂₃OCOC(CH₃)CH₂], a polar monomer, in the presence of lauryl mercaptan as a chain transfer agent. The resulting prepolymers (i.e., vinyl‐type network‐polymer precursors or amphiphilic polymers) were characterized mainly by viscometry using t‐butylbenzene (t‐BB) and a t‐BB/MeOH (80/20) mixture as solvents. The viscosities in the t‐BB/MeOH (80/20) mixture were quite high compared with those in t‐BB, and completely reversed concentration dependencies were observed in the solvents. These are discussed by considering the difference in conformation and the shrinkage of polar, flexible polyoxyethylene units or the entanglement of nonpolar, rigid primary chains. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 4396–4402, 2000     

Molecular engineering of liquid crystal polymers by living polymerization. II. Living cationic polymerization of 11-[(4-cyano-4′-biphenyl) oxy] undecanyl vinyl ether and the mesomorphic behavior of the resulting polymers

The synthesis and living cationic polymerization of 11-[(4-cyano-4′-biphenyl)oxy]-undecanyl vinyl ether ( 6 – 11 ) are described. The mesomorphic phase behavior of poly( 6 – 11 ) with different degrees of polymerization was compared to that of 6 – 11 and of 11-[(4-cyano-4′-biphenyl) oxy] undecanyl ethyl ether ( 8 – 11 ) which is the model compound of the monomeric structural unit of poly( 6 – 11 ). 6 – 11 displays a monotropic S_A and a monotropic nematic mesophase while 8 – 11 an enantiotropic S_A mesophase. Poly( 6 – 11 ) with low degrees of polymerization exhibits an enantiotropic S_A mesophase. Poly( 6 – 8 ) with high degrees of polymerization displays an enantiotropic S_X (i. e., an unidentified smectic phase) and an enantiotropic S_C mesophase. These results demonstrate that the transformation of the nematic mesophase of the monomer into a smectic mesophase after polymerization, occurs at the level of monomeric structural unit.     

Copolymerization of ethylene with a homologous series of vinyl esters

The effect of the alkyl group on the relative reactivity of a homologous series of vinyl esters (2) has been studied with ethylene (1) as reference monomer, tert-butyl alcohol as solvent, at 62°C and 35 kg/cm². The experimental method was based on frequent measurement of the monomer feed composition throughout the copolymerization reaction by means of quantitative gas-chromatographic analysis. Highly accurate monomer reactivity ratios were estimated in a statistically justified manner by a nonlinear least-squares method applied to the integrated copolymer equation. The reactivity of the vinyl ester monomers towards an ethylene radical increased with decreasing electron-with-drawing ability of the ester group. All vinyl ester radicals considered turned out to have the same preference for their own monomer over ethylene (constant r₂ = 1.50). Reactivity ratios are discussed in terms of the Q–e scheme and the Taft relation. It appeared that chiefly polar factors contribute to the observed relative reactivity, while probably resonance stabilization only plays a minor part. Steric hindrance seems to impair monomer reactivity, only from vinyl pivalate on. Relative reactivities of the vinyl esters are compared with literature values, where other reference monomers have been used.     

Synthesis of optically active polynucleotide analogs with poly(vinyl alcohol)s as backbones and adenine and 5-bromouracil derivatives as pendants

The optically active polynucleotide analogs were prepared by grafting nucleic acid base derivatives onto poly(vinyl alcohol). The (R)-ethyl 2-(5-bromouracil-1-yl)propanoate was obtained either by reaction of 5-bromouracil sodium salt with (S)-ethyl 2-[(methylsulfonyl)oxy]propanoate or reaction of 5-bromouracil with (S)-ethyl lactate in the presence of triphenyl phosphine and diethyl azodicarboxylate. Subsequent hydrolysis of the ester is aqueous acid provided the optically pure (R)-bromouracilypropanoic acid. The monomer model compounds were prepared by an esterification reaction of the pendant groups with 3-pentyl alcohol in the presence of dicyclohexylcarbodiimide and a catalytic amount of 4-pyrrolidinopyridine. Poly(vinyl alcohol) underwent reaction with the (R)-bromouracilylpropanoic acid or the (R)-adeninylpropanoic acid in the presence of dicyclohexylcarbodiimide and a catalytic amount of 4-pyrrolidinopyridine. The resulting polymers were optically active and percents grafting were almost quantitative.     

Syntheses and antitumor activities of monomer and medium molecular weight polymers. III. 3,6-endo-methylene-1,2,3,6-tetrahydrophthalimidopropanoyl-5-fluorouracil and its polymers

The new monomer, 3,6-endo-methylene-1,2,3,6-tetrahydrophthalimidopropanoyl-5-fluorouracil (ETPFU), was synthesized by the reaction of 5-fluorouracil (5-FU) and 3,6-endo-methylene-1,2,3,6-tetrahydrophthalimidopropanoyl chloride (ETPC). The homopolymer of ETPFU and its copolymers with acrylic acid (AA) and vinyl acetate (VAc) were prepared by photopolymerizations. The synthesized ETPFU and polymers were identified by Fourier transfer infrared (FTIR), ¹H nuclear magnetic resonance (NMR), and ¹³C-NMR spectroscopies. The contents of ETPFU units in poly(ETPFU-co-AA) and poly(ETPFU-co-VAc) were 26 and 32 mol %, respectively. The number average molecular weights of the synthesized polymers determined by gel permeation chromatography (GPC) were in range from 8,800 to 10,700. The in vitro cytotoxicities of the samples were evaluated with mouse mammary carcinoma (FM3A), mouse leukemia (P388), and human histiocytic lymphoma (U937) as a cancer cell line and mouse liver cells (AC2F) as a normal cell line. The in vivo antitumor activities of polymers against Balb/c mice bearing the sarcoma 180 tumor cells were greater than those of 5-FU at all doses tested. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 2113–2120, 1999     

Cobalt‐Mediated Radical Polymerization of Vinyl Acetate in Miniemulsion: Very Fast Formation of Stable Poly(vinyl acetate) Latexes at Low Temperature

Summary: Poly(vinyl acetate) macroinitiators end‐capped by a Co(acac)₂ complex (PVAc–Co(acac)₂), prepared in bulk by cobalt‐mediated radical polymerization (CMRP), are used for the controlled radical polymerization of vinyl acetate in miniemulsion to give high‐molecular‐weight polymers and high monomer conversion. Stable poly(vinyl acetate) latexes with solid contents ranging from 25 to 30 wt.‐% are prepared within unusually short reaction times (∼1 h) at low temperatures (0–30 °C).

SEC chromatograms for the PVAc–Co(acac)₂ macroinitiator and PVAc latex obtained under ultrasonication for 6 min at 0 °C (79% monomer conversion).     

Radiation-induced copolymerization of tetrafluoroethylene with vinyl ethers

Radiation-induced copolymerization of tetrafluoroethylene with various vinyl ethers has been studied. It was found that tetrafluoroethylene can be copolymerized with vinyl ethers to give alternating copolymers over a wide range of the initial monomer concentration in the monomer mixture. The monomer reactivity ratios were determined for the copolymerization of tetrafluoroethylene with n-butyl vinyl ether as 0.005 (r_TFE) and 0.0015 (r_NBVE). The rate of copolymerization is extremely high and has a maximum at an equimolar concentration of two monomers. The alternating structure of the copolymers was confirmed by the analysis of NMR spectra. Some thermal properties of the copolymers were measured by DSC and DTA.     

Solvation effect in thermal decomposition of 2,2′-azoisobutyronitrile on the N,N-dimethylformamide/methyl methacrylate system

The thermal decomposition rate constant of AIBN (??_d) in N,N-dimethylformamide (DMF)/methyl methacrylate (MM) mixtures of various compositions at 60°C is studied. The ??_d value is 6.45 × 10^?4min^?1 for pure DMF and 7.20 × 10^?1 min^?1 for pure methyl methacrylate. The ??_d values of DMF/MM mixtures were found to be dependent on the mixture composition. This dependence is not a linear function of the monomer mole fraction, but has a minimum at ca. 20 30 mol% of MM. The relationship between the AIBN decomposition rate constant and the monomer mole fraction was interpreted on the basis of solvation of the initiator molecules. © 1995 John Wiley & Sons, Inc.