Neung-Ju Lee

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.

Syntheses and biological activities of α-methoxy-3,6-endo-methylene-1,2,3,6-tetrahydrophthaloyl-5-fluorouracil and its polymers

The new monomer, α-methoxy-3,6-endo-methylene-1,2,3,6-tetrahydrophthaloyl-5-fluorouracil (MMTFU), was synthesized from 5-fluorouracil (5-FU) and α-methoxy-3,6-endo-methylene-1,2,3,6-tetrahydrophthaloyl chloride (MMTC). Poly(α-methoxy-3,6-endo-methylene-1,2,3,6-tetrahydrophthaloyl-5-fluorouracil) [poly(MMTFU)], poly(α-methoxy-3,6-endo-methylene-1,2,3,6-tetrahydrophthaloyl-5-fluorouracil-co-acrylicco-AA), and poly(α-methoxy-3,6-endo-methylene-1,2,3,6-tetrahydrophthaloyl-5-fluorouracil-co-vinyl acetate) [poly(MMTFU-co-VAc)] were synthesized by photopolymerizations using 2,2-dimethoxy-2-phenylacetophenone (DMP) as the photoinitiator. The synthesized MMTFU and the polymers were identified by FT-IR, 1H-NMR, and 13C-NMR spectroscopies. The contents of MMTFU in poly(MMTFU-co-AA) and poly(MMTFU-co-VAc) determined by elemental analysis were 63 and 57 mol %, respectively. The number average molecular weights and polydispersity indices of synthesized polymers determined with GPC were in range of 7,700–19,100 and 1.6–2.7. The in vitro cytotoxicities of samples were evaluated with 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 cytotoxicities of 5-FU and synthesized samples against cancer cell lines increased in following orders: 5-FU > MMTFU > poly(MMTFU) > poly(MMTFU-co-AA) > poly(MMTFU-co-VAc). The in vivo antitumor activities of the synthesized samples against mice bearing the sarcoma 180 tumor cell line were evaluated. The in vivo antitumor activities of the polymers were greater than that of 5-FU at a dose of 80 mg/kg.

Syntheses and biological activities of α‐methoxy‐exo‐3,6‐epoxy‐1,2,3,6‐tetrahydrophthaloyl‐5‐fluorouracil and its polymers

The new monomer, α-methoxy-exo-3,6-epoxy-1,2,3,6-tetrahydrophthaloyl-5-fluorouracil (METFU), was synthesized by the reaction of 5-fluorouracil (5-FU) and exo-3,6-epoxy-1,2,3,6-tetrahydrophthalic anhydride (ETA) in order to prepare polymers containing 5-FU moiety. Poly(α-methoxy-exo-3,6-epoxy-1,2,3,6-tetrahydrophthaloyl-5-fluorouracil) [poly(METFU)], poly(α-methoxy-exo-3,6-epoxy-1,2,3,6-tetrahydrophthaloyl-5-fluorouraci-co-acrylic acid) [poly(METFU-co-AA)], and poly(α-methoxy-exo-3,6-epoxy-1,2,3,6-tetrahydrophthaloyl-5-fluorouracil-co-vinyl acetate) [poly(METFU-co- VAc)] were synthesized by photopolymerizations using 2,2-dimethoxy-2-phenylacetophenone (DMP) as an initiator. The synthesized METFU and the polymers were identified by FTIR and 1H-NMR spectroscopies. The contents of METFU in poly(METFU-co-AA) and poly(METFU-co-VAc) determined by elemental analysis were 52 and 60 mol %, respectively. The average molecular weights and polydispersity indices determined with GPC were as follows: Mn = 9,400, Mw = 11,400 Mw/Mn = 1.21 for poly(METFU), Mn = 14,400, Mw = 26,800, Mw/Mn = 1.86 for poly(METFU-co-AA), and Mn = 23,100, Mw = 33,000, Mw/Mn = 1.43 for poly(METFU-co-VAc). The in vitro cytotoxicities of samples were evaluated with 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 in vivo antitumor activities of synthesized polymers against mice bearing the sarcoma 180 tumor cell line were greater than those of 5-FU at concentrations of 0.8 and 80 mg/kg.

Syntheses and biological activities of N-alaninylmaleimide and its polymers

Abstract A new monomer, N-alaninylmaleimide (AMI), was synthesized by the reaction of maleic anhydride and β-alanine. Poly(N-alaninylmaleimide) [poly(AMI)], poly(N-alaninylmaleimide-co-methacrylic acid) [poly-(AMI-co-MA)], and poly(N-alaninylmaleimide-co-vinyl acetate) [poly-(AMI-co-VAc)] were synthesized by photopolymerizations. The synthesized AMI and its polymers were characterized by IR and 1H-NMR spectroscopies, elemental analysis, and gel permeation chromatography (GPC). The average molecular weights as determined by GPC were is follows: M n = 4200, M w = 4300, M w/M n = 1.02 for poly(AMI); M n = 4000, M w = 4100, M w/M n = 1.03 for poly(AMI-co-MA); and M n = 21,500, M w = 23,300, M w/M n = 1.08 for poly(AMI-co-VAc). In-vitro cytotoxicities of polymers against mouse mammary carcinoma (FM-3A/s), mouse leukemia (P-388/s), and human histiocytic lymphoma (U-937/s) cell lines were lower than those of AMI. The in-vivo antitumor activities of polymers against sarcoma 180 cells were greater than those of 5-...

Synthesis and biological activities of polymers containing exo‐3,6‐epoxy‐1,2,3,6‐tetrahydrophthalic glycinyl imide

The monomer, exo-3,6-epoxy-1,2,3,6-tetrahydrophthalic glycinyl imide(ETGI), was prepared by the Diels-Alder reaction of N-glycinylmaleimide and furan. Poly(ETGI), poly(ETGI-co-methacrylic acid)[poly(ETGI-co-MA)] and poly(ETGI-co-vinylacetate)[poly(ETGI-co-VAc)] were synthesized by photoinitiated homopolymerization of ETGI or copolymerizations of ETGI with MA and VAc. Synthesized ETGI, poly(ETGI), poly(ETGI-co-MA), and poly(ETGI-co-VAc) were characterized by IR and 1H-NMR spectroscopies, elemental analysis, and gel permeation chromatography. The in vitro cytotoxicities of ETGI, poly(ETGI), poly(ETGI-co-MA), and poly(ETGI-co-VAc) were evaluated using K-562 human leukemia cells and HeLa cells. In vitro cytotoxicity of monomer and polymers at a concentration of 1.0 mg/mL against K-562 human leukemia cells increased in the following order:poly(ETGI-co-MA) > poly(ETGI-co-VAc) > poly(ETGI) > Etgi. The cytotoxicities of copolymers against HeLa cells are less cytotoxic than ETGI at a dosage of 0.02, 1.0, and 5.0 mg/mL. The copolymers were very effective at any dosage tested. The in vivo antitumor activities of ETGI, poly(ETGI), poly(ETGI-co-MA), and poly(ETGI-co-VAc) were also evaluated against mice bearing sarcoma 180. In vivoantitumor activity of monomer and polymers at a dosage of 80 mg/kg increased in the following order: ETGI > poly(ETGI-co-VAc) > poly(ETGI-co-MA) > poly(ETGI) > 5-fluorouracil (5-FU).ETGI and polymers containing ETGI showed higher antitumor activity than 5-FU at any dosage tested.

Synthesis and biological activity of medium molecular weight polymers containing 3,6‐endo‐methylene‐1,2,3,6‐tetrahydrophthalimidobutanoyl‐5‐fluorouracil

A new monomer, 3,6-endo-methylene-1,2,3,6-tetrahydrophthalimidobutanoyl-5-fluorouracil (ETBFU), was synthesized by reaction of 3,6-endo-methylene-1,2,3,6-tetrahydrophthalimidobutanoyl chloride and 5-fluorouracil. The homopolymer of ETBFU and its copolymers with acrylic acid (AA) or vinyl acetate (VAc) were prepared by photopolymerization using 2,2-dimethoxy-2-phenylacetophenone as an initiator at 25 °C. The synthesized ETBFU and its polymers were identified by FTIR, 1H NMR and 13C NMR spectroscopies. The ETBFU content in poly(ETBFU-co-AA) and poly(ETBFU-co-VAc) was 43 and 14 mol%, respectively. The apparent number-average molecular weight (Mn) of the polymers determined by GPC ranged from 8400 to 11 300. The in vitro cytotoxicity of the samples against mouse mammary carcinoma (FM3A), mouse leukaemia (P388), and human histiocytic lymphoma (U937) cancer cell lines decreased in the order 5-FU ≥ ETBFU > poly(ETBFU) > poly(ETBFU-co-AA) > poly(ETBFU-co-VAc). The in vivo antitumour activity of the polymers against Balb/C mice bearing sarcoma 180 tumour cells was greater than that of 5-fluorouracil at all doses tested. © 2000 Society of Chemical Industry

Synthesis and biological activity of medium molecular weight polymers of camptothecin

A new monomer, 3,6-endo-methylene-1,2,3,6-tetrahydrophthalimidohexanoylcamptothecin (ETHCPT) was synthesized from 3,6-endo-methylene-1,2,3,6-tetrahydrophthalimidohexanoic acid. Its homopolymer and copolymer with acrylic acid (AA) were synthesized and spectroscopically characterized. The ETHCPT content in poly(ETHCPT-coAA) obtained by elemental analysis was 37 wt.%. The number-average molecular weights of the polymers determined by gel permeation chromatography were as follows: Mn ¼ 9700 for poly(ETHCPT), Mn ¼ 25 500 for poly(ETHCPT-coAA). The IC50 value of ETHCPT and its polymers against cancer cells was much larger than that of CPT. The in vivo antitumor activity of all polymers in Balb/C mice bearing the sarcoma 180 tumor cell line was greater than that of CPT at a dose of 100 mg/kg. 2002 Elsevier Science Ltd. All rights reserved.

Synthesis of copolymers from 3,5‐dioxo‐4,10‐dioxatricyclo‐[5.2.02,6]dec‐8‐ene and vinyl monomers by photopolymerization and their biological activities

Photocopolymerizations of 3,5-dioxo-4,10-dioxatricyclo[5.2.0 2,6 ]dec-8-ene (DDTD) with methacrylic acid (MA) acrylamide (AAm) and vinyl pyrrolidone (VP) were carried out in 2-butanone using dimethoxy benzoin (DMB) as an initiator at 25°C. The structures of the polymers obtained from photopolymerizations of corresponding monomer pairs were confirmed to be poly(DDTD-co-MA), poly(DDTD-co-AAm) and poly(DDTD-co-VP) by 1 H NMR and 13 C NMR spectroscopies, and the average molecular weights were determined by gel permeation chromatography (GPC). The weight average molecular weights (M w ) of the polymers were in the range 9500-17 300. The polymers were soluble in water, dimethyl sulphoxide (DMSO) and dimethyl formamide (DMF). The contents of DDTD units in the copolymers were 19, 37 and 45%. The in vitro cytotoxicities of the polymers were evaluated using mouse mammary carcinoma (FM-3A), mouse leukaemia (P-388) and human histiocytic lymphoma (U-937) cell lines. The in vivo antitumour activities of the polymers were estimated by the survival time of sarcoma 180 tumour-bearing mice. The in vivo antitumour activities of the polymers were greater than those of 5-fluorouracil (5-FU) and monomeric DDTD at a dose of 0.8 mg kg -1 . Poly(DDTD-co-AAm) and poly(DDTD-co-VP) showed higher antitumour activity than 5-FU and monomeric DDTD at all doses tested.

Synthesis and antitumour and antiangiogenesis activity of polymers containing methacryloyl‐2‐oxy‐1,2,3‐propane tricarboxylic acid

A new monomer, methacryloyl-2-oxy-1,2,3-propane tricarboxylic acid (MTCA), was synthesized from citric acid and methacrylic anhydride. Poly(methacryloyl-2-oxy-1,2,3-propane tricarboxylic acid) and poly(methacryloyl-2-oxy-1,2,3-propane tricarboxylic acid)-co-(maleic anhydride) were prepared by radical polymerizations. Terpoly(methacryloyl-2-oxy-1,2,3-propane tricarboxylic acid–maleic anhydride–furan) was obtained by in situ terpolymerization of MTCA and exo-3,6-epoxy-1,2,3,6-tetrahydrophthalic anhydride. The synthesized samples were identified by FTIR, 1H NMR and 13C NMR spectroscopies. The number-average molecular weights of the fractionated polymers determined by GPC were in the range 14 900–16 600 and polydispersity indices were less than 1.14. The in vitro IC50 values of the monomer and polymers against cancer and normal cell lines were much higher than those of 5-fluorouracil (5-FU). The in vivo antitumour activities of the synthesized samples at a dosage of 0.8 mg kg−1 against mice bearing the sarcoma 180 tumour cell line decreased in the order terpoly(MTCA-MAH-FUR) > poly(MTCA-co-MAH) > poly(MTCA) > MTCA > 5-FU. The synthesized samples inhibited DNA replication and angiogenetic activity more than did 5-FU. © 2001 Society of Chemical Industry