Synthesis and evaluation of new peptide-linked doxorubicin conjugates as prodrugs activated by prostate-specific antigen

AbstractThe targeted delivery of cytotoxic agents to prostate cancer cellsvia selective activation of peptide-linked prodrugs by prostate-specific antigen (PSA) has been previously demonstrated. In our continued efforts to design prodrugs with improved prostate tumor specificity, we developed GABA  ← mGly-Ala-Ser-Chg-Gln and glutaryl-Ser-Ala-Ser-Chg-Gln as promoieties with enhanced PSA specificity starting from the known substrate sequence glutaryl-Hyp-Ala-Ser-Chg-Gln. Based on their PSA cleavage rates and resistance to non-PSA-mediated hydrolysis in plasma, GABA ← mGly-Ala-Ser-Ch g-Gln and glutaryl-Ser-Ala-Ser-Chg-Gln were selected as optimal promoieties and coupled to doxorubicin (Dox) as PSA-targeted prodrugs, using Ser-Leu linkers. Following 72-h incubations with Dox prodrugs, there was insignificant cytotoxicity in non-PSA-producing DU145 cells. The Dox prodrugs, glutary l-Hyp-Ala-Ser-Chg-Gln-Ser-Leu-Dox (I), glutaryl-Ser-Ala-Ser-Chg-Gln-Ser-Leu-Dox (II) and GABA  ← mGly-Ala-Ser-Chg-Gln-Ser-Leu-Dox (III) demonstrated comparable PSA cleavage rates (t1/2 values<23  min), and were cytotoxic against PSA-producing LNCaP cells with IC50 values of 0.18, 0.27 and 0.082  μM, respectively. To mitigate neprilysin-mediated hydrolysis of the Ser-Leu linker in prodrugsI –III and further improve PSA specificity, 3-aminooxypropionate was incorporated between the promoiety and Dox (prodrugIV). Despite its slower PSA cleavage rate (t1/2 value of 67  min), GAB...
Source: Medicinal Chemistry Research - Category: Chemistry Source Type: research