Synthesis and antitumor activity of α-1,4-polygalactosamine and N-acetyl- α-1,4-polygalactosamine immobilized 5-fluorouracils through hexamethylene spacer groups via urea, urea bonds

Abstract

In order to provide a macromolecular prodrug of 5-fluorouracil (5FU) with reduced side-effects, having an affinity for tumor cells and exhibiting strong antitumor activity, the covalent attachment of 5FUs to α-1,4-polygalactosamine (PGA), N-acetyl- α-1,4-polygalactosamine (NAPGA) and their oligomers (GOS, NAGOS) through hexamethylene spacer groups via urea, urea bonds was carried out. The survival effect against p388 lymphocytic leukemia in female CDF1 mice by intraperitoneal (ip) transplantation/ip injection in vivo and the growth-inhibitory effect on Meth-A fibrosarcoma in male BALB/c SPF mice by subcutaneous (sc) implantation/intravenous (iv) injection in vivo were evaluated. The effects of the degree of substitution of 5FU based on the number of galactosamine groups and the degree of N-acetylation ofamino groups of PGA based on the number of galactosamine groups on prolongation of life were investigated. The PGA/5FU and NAPGA/5FU conjugates exhibited strong survival effects against p388 lympbocytic leukemia and the GOS/5FU conjugate showed significant growth-inhibitory effect on Meth-A fibrosarcoma. The obtained PGA/5FU, NAPGA/5FU, GOS/5FU and NAGOS/5FU conjugates did not display any acute toxicity even in the high dose ranges.