A new spacer group derived from arylmalonaldehydes for glucuronylated prodrugs

https://doi.org/10.1016/S0960-894X(98)00454-5Get rights and content

Abstract

A new glucuronylated prodrug of doxorubicin, potentially useful for ADEPT or PMT cancer chemotherapy, has been prepared from 4-methyl phenyl malonaldehyde. The enol ether spacer, linked via a carbamate to the 3′-amino group of doxorubicin is rapidly cleaved after β-glucuronidase (E coli) catalyzed hydrolysis at pH 7.2 and 37°C.

A new glucuronylated prodrug of doxorubicin, potentially useful for ADEPT or PMT cancer chemotherapy, has been prepared from 4-methyl phenyl malonaldehyde. The enol ether spacer, linked via a carbamate to the 3′-amino group of doxorubicin is rapidly cleaved by β-glucuronidase (E coli) at pH 7.2 and 37°C.

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    We hypothesized that a methyl ester of DOX-GA3, DOX-mGA3, would be more lipophilic than DOX-GA3 and of better use in enzyme prodrug therapy. The methyl ester of other methylated glucuronide prodrugs has been reported to be hydrolyzed by carboxylesterases [12,13]. When administered in vivo, the methyl group of DOX-mGA3 might be removed by carboxylesterase activity in plasma to yield the original DOX-GA3 prodrug, which could in turn be activated by human β-glucuronidase (Fig. 1).

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