Synthesis, Evaluation of Chemical Reactivity, and Murine Antineoplastic Activity of 2-Hydroxy-5-(3,4-dichlorophenyl)-6,7-bis(hydroxymethyl)-2,3-dihydro-1H-pyrrolizine Bis(2-propylcarbamate) and 2-Acyloxy Derivatives as Potential Water-Soluble Prodrugs

2-Hydroxy-5-(3,4-dichlorophenyl)-6,7-bis(hydroxymethyI)-2,3-dihydro-1H-pyrrolizine bis(2-propylcarbamate) (11) was prepared in a multistep synthesis. The 2-hydroxy group was used to prepare ester prodrugs 14 and 15, and the antineoplastic activities of 11, 14, and 15a were compared to 1 (the 2-deoxy analogue of 11) in murine P388 lymphocytic leukemia and B16 melanocarcinoma. The alcohol 11 showed comparable activity to 1, while 14 was less active and 15a showed very low activity. The hydrolytic rates of 1, 11, 14, 15a, and 15b were compared, and it was found that the two carbamate moieties were much more susceptible toward hydrolysis than the C-2 esters. The salts 15a and 15b exhibited good water solubility, 3.0 X 10-2 and 3.88 X 10-2 M, respectively.