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

Abstract

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. © 1998 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 36: 1625–1632, 1998

Synthesis and antitumour activity of medium molecular weight phthalimide polymers of camptothecin

“…The average molecular weights and polydispersity indices of the polymers are listed in Table 1. The number average molecular weights ( M n ) of the polymers we synthesized using a previously reported method21–25 ranged from 12 100 to 18 300 g mol −1 and molecular weight distributions ( M w / M n ) were 1.83–1.93. The polymers met the minimum chain length requirement to exhibit antitumour activity based on Ottenbrite's findings 27.…”

“…Such polymers have been found in our laboratories to be efficient carriers of 5‐fluorouracil (5‐FU), retaining the antitumour activity while decreasing the toxicity of the parent molecule. Moreover, tetrahydrophthalic‐acid‐based polymers showed a strong antitumour activity against cancer cell lines,21–24 while they displayed very low toxicity against normal cells 25…”

Synthesis and biological activity of phthalimide‐based polymers containing 5‐fluorouracil

“…Ottenbrite34 reported that polymers having molecular weight of 10 000–30 000 g mol −1 exhibit optimal biological activity. The polymer that we synthesized using a previously reported method,25–32 met the minimum chain length requirement to exhibit antitumour activity based on Ottenbrite's findings.…”

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

“…Ottenbrite et al 13 reported that medium molecular weight polymers of 10 000–30 000 play a significant role in biological activity. Therefore, we controlled the molecular weights of the polymers by using the photopolymerization method on the basis of our previous studies,18–21 and the molecular weights of the polymers obtained were in a reasonable range to exhibit antitumour activity.…”