Synthesis and Structure-Activity Relationships of Poly[(3,4-dihydro-2H-pyran)-alt-(maleic acid)] and Its Derivatives as Antitumor Agents

Poly[3,4-dihydro-2H-pyran)-alt-(maleic acid)] and its derivatives were synthesized by hydrolyses or substitution reactions of the alternating copolymers obtained by radical copolymerizations of 3,4-dihydro-2H-pyran de rivatives with maleic anhydride The polymers have different substituents in the 2-position of tetrahydropyran rings in copolymer backbone, such as, hydroxyl, methoxy, ethoxy, acetoxy, carboxyl, methoxycarbonyl, carbamoyl, for myl, hydroxymethyl, acetoxymethyl, tosyloxymethyl, and mercaptomethyl groups. The copolymers obtained by solution copolymerizations were found to have low number-average molecular weights (Mn < 2,000), while bulk copoly merizations gave copolymers with higher Mn (4,000 - 8,000). ID₅₀ values of the copolymers on normal and tumor cells (3LL and B16) in vitro and the in creased life span against B16 melanoma in vivo were measured and they dis played cytotoxicities and antitumor activities comparable to or superior to that of DIVEMA, an alternating copolymer of divinyl ether-maleic anhydride (1:2). Especially high cytotoxicities against tumor and normal cells were found by the copolymers containing methoxy, acetoxy or formyl groups in vitro and high antitumor activities were found by the copolymers having hydroxy or acetoxy groups in vivo with the increased life spans of 140 and 147%, respectively.