Get e-Alerts Abstract A prosztatitis hátterében, we report on the synthesis, enzymatic stability, and antitumor activity of novel bioconjugates containing the chemotherapeutic agent daunorubicin attached through an oxime bond to various gonadotropin-releasing hormone-III GnRH-III derivatives.
In order to increase the enzymatic stability of the bioconjugates in particular against chymotrypsin4Ser was replaced by N-Me-Ser or Lys Ac. A compound in which 4Lys was not acetylated was also prepared, with the aim Prostate Me 22 investigating the influence of the free ε-amino group on the biochemical properties. The in Prostate Me 22 cytostatic effect of the bioconjugates was determined on MCF-7 human breast, HT human colon, and LNCaP human prostate cancer cells by 3- 4,5-dimethylthiazolyl -2,5-diphenyltetrazolium bromide assay.
The results showed that 1 all synthesized bioconjugates had in vitro cytostatic effect, 2 they were stable in human serum at least for 24 h, and 3 they were hydrolyzed in the presence of lysosomal homogenate. All compounds were stable in the presence of 1 pepsin and 2 trypsin except for the 4Lys containing Prostate Me 22.
In the presence of chymotrypsin, all bioconjugates were digested; the degradation rate strongly depending on their structure. The bioconjugates in which 4Ser was replaced by N-Me-Ser or Lys Ac had the highest enzymatic stability, making them potential candidates for oral administration. In vivo tumor growth inhibitory effect of two selected bioconjugates was evaluated on orthotopically developed C26 murine colon carcinoma bearing mice.
The results indicated that the compound containing Lys Ac in position 4 had significantly higher antitumor activity than the parent bioconjugate.