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Synthesis and evaluation of new peptide-linked doxorubicin conjugates as prodrugs activated by prostate-specific antigen
Medicinal Chemistry Research ( IF 2.6 ) Pub Date : 2020-06-04 , DOI: 10.1007/s00044-020-02573-w
Herve Aloysius , Longqin Hu

The targeted delivery of cytotoxic agents to prostate cancer cells via 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-Chg-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, glutaryl-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 prodrugs I–III and further improve PSA specificity, 3-aminooxypropionate was incorporated between the promoiety and Dox (prodrug IV). Despite its slower PSA cleavage rate (t1/2 value of 67 min), GABA ← mGly-Ala-Ser-Chg-Gln-NH-O-CH2-C(Me)2C(O)-14-O-Dox (IV) was equipotent (IC50 value of 0.19 μM) to prodrug I at killing PSA-producing LNCaP cells due to its ability to release free Dox through a cyclization activation mechanism. Further metabolism and PK/PD studies will be conducted to evaluate the tumor specificity of the novel Dox prodrugs (II–IV) reported herein.


中文翻译:

前列腺特异性抗原激活的新型肽连接的阿霉素偶联物的合成和评价

细胞毒性剂的靶向递送到前列腺癌细胞经由先前已经证明了前列腺特异性抗原(PSA)对肽连接的前药的选择性激活。在我们继续设计具有改善的前列腺肿瘤特异性的前药的过程中,我们开发了GABA←mGly-Ala-Ser-Chg-Gln和谷氨酰-Ser-Ala-Ser-Chg-Gln作为从已知底物序列开始具有增强的PSA特异性的促销品。戊二酰-Hyp-Ala-Ser-Chg-Gln。根据它们在血浆中的PSA裂解速率和对非PSA介导的水解的抵抗力,选择GABA←mGly-Ala-Ser-Chg-Gln和谷氨酰-Ser-Ala-Ser-Chg-Gln作为最佳蛋白质,并与阿霉素偶联(Dox)作为使用PSA的前药,使用Ser-Leu接头。与Dox前药孵育72小时后,在不产生PSA的DU145细胞中没有明显的细胞毒性。Dox前药,戊二酰-Hyp-Ala-Ser-Chg-Gln-Ser-Leu-Dox(I),戊二酰-Ser-Ala-Ser-Chg-Gln-Ser-Leu-Dox(II)和GABA←mGly-Ala-Ser-Chg-Gln-Ser-Leu-Dox(III)表现出可比的PSA裂解率( t 1/2值<23分钟),并且对产生PSA的LNCaP细胞具有细胞毒性,IC 50值分别为0.18、0.27和0.082μM。为了减轻前体药物I–III中neprilysin介导的Ser-Leu接头的水解并进一步提高PSA特异性,在成分和Dox(前体药物IV)之间掺入了3-氨氧基丙酸酯。尽管其PSA裂解速度较慢(t 1/2值为67分钟),但GABA←mGly-Ala-Ser-Chg-Gln-NH-O-CH 2 -C(Me)2 C(O)-14-O- Dox(IV)在杀死PSA产生的LNCaP细胞时与前药I等价(IC 50值为0.19μM ),因为它具有通过环化激活机制释放游离Dox的能力。将进行进一步的代谢和PK / PD研究,以评估本文报道的新型Dox前药(II–IV)的肿瘤特异性。
更新日期:2020-06-04
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