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The regio-selective synthesis of 10-hydroxy camptothecin norcantharidin conjugates and their biological activity evaluation in vitro.

ABSTRACT: A series of conjugates of 10-hydroxy camptothecin (HCPT) with functionalized norcantharidin derivatives were regio-selectively synthesized in the condition of (3-dimethylaminopropyl) ethyl-carbodiimide monohydrochloride in a moderate yield. The synthesized conjugate HCPT pro-drugs can also suppress cancer cell growth in vitro. These conjugated pro-drug constructs possess therapeutic potential as novel bi-functional conjugate platforms for cancer treatment.

SUBMITTER: Zhao CK

PROVIDER: S-EPMC6030274 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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The regio-selective synthesis of 10-hydroxy camptothecin norcantharidin conjugates and their biological activity evaluation <i>in vitro</i>.

Zhao Chang K CK Li Chan C Wang Xian H XH Bao Yu J YJ Yang Fu H FH Huang Mei M

Royal Society open science 20180613 6

A series of conjugates of 10-hydroxy camptothecin (HCPT) with functionalized norcantharidin derivatives were regio-selectively synthesized in the condition of (3-dimethylaminopropyl) ethyl-carbodiimide monohydrochloride in a moderate yield. The synthesized conjugate HCPT pro-drugs can also suppress cancer cell growth <i>in vitro</i>. These conjugated pro-drug constructs possess therapeutic potential as novel bi-functional conjugate platforms for cancer treatment. ...[more]

PMID: 30110459

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Project description:Clinical applications of camptothecin (CPT) have been heavily hindered due to its non-targeted toxicity, active lactone ring instability, and poor water solubility. Targeted drug delivery systems may offer the possibility to overcome the above issues as reported. In this research, a series of prostate-specific membrane antigen (PSMA)-activated CPT prodrugs were designed and synthesized by coupling water-soluble pentapeptide, a PSMA hydrolyzing substrate, to CPT through an appropriate linker. The cytotoxicity of CPT prodrugs was masked temporarily until they were hydrolyzed by the PSMA present within the tumor sites, which restored cytotoxicity. The in vitro selective cytotoxic activities of the prodrugs were evaluated against PSMA-expressing human prostate cancer cells LNCaP-FGC and non-PSMA-expressing cancer cells HepG2, Hela, MCF-7, DU145, PC-3 and normal cells MDCK, LO2 by standard methylthiazol tetrazolium (MTT) assay. Most of the newly synthesized CPT prodrugs showed excellent selective toxicity to PSMA-producing prostate cancer cells LNCaP-FGC with improved water solubility. From among the library, CPT-HT-J-ZL12 showed the best cytotoxic selectivity between the PSMA-expressing and the non-PSMA-expressing cancer cells. For example, the cytotoxicity of CPT-HT-J-ZL12 (IC50 = 1.00 ± 0.20 µM) against LNCaP-FGC (PSMA⁺) was 40-fold, 40-fold, 21-fold, 5-fold and 40-fold, respectively, higher than that against the non-PSMA-expressing cells HepG2 (IC50 > 40.00 µM), Hela (IC50 > 40.00 µM), MCF-7 (IC50 = 21.68 ± 4.96 µM), DU145 (IC50 = 5.40 ± 1.22 µM), PC-3 (IC50 = 42.96 ± 3.69 µM) cells. Moreover, CPT-HT-J-ZL12 exhibited low cytotoxicity (IC50 > 40 μM) towards MDCK and LO2 cells. The cellular uptake experiment demonstrated the superior PSMA-targeting ability of the CPT-HT-J-ZL12, which was significantly accumulated in LNCaP-FGC (PSMA⁺), while it was minimized in HepG2 (PSMA-) cells. Further cell apoptosis analyses indicated that it showed a dramatically higher apoptosis-inducing activity in LNCaP-FGC (PSMA⁺) cells than in HepG2 (PSMA-) cells. Cell cycle analysis indicated that CPT-HT-J-ZL12 could induce cell cycle arrest at the S phase.

Dataset Information

The regio-selective synthesis of 10-hydroxy camptothecin norcantharidin conjugates and their biological activity evaluation in vitro.

Publications

The regio-selective synthesis of 10-hydroxy camptothecin norcantharidin conjugates and their biological activity evaluation <i>in vitro</i>.

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