Abstract
7-Ethyl-10-hydroxycamptothecin (SN38) and vorinostat (SAHA) are quite promising combination therapy agents applied to the clinical treatment of cancer. In this study, we designed and synthesized a series of novel SN38-SAHA co-prodrugs, which were conjugated by four different amino acids including glycine, alanine, aminobutyric acid, and 6-aminocaproic acid. The hydrolytic reconversion rate to SN38 and SAHA critically depended on the carbon chain length, which were evaluated in PBS (pH 6.0/7.4) and plasma (human/mouse). With decreasing amino acid chain length, the hydrolytic reconversion rate increased gradually. The in vitro cytotoxicity test was evaluated by the sulforhodamine B (SRB) assay on the human lung adenocarcinoma cell line A549 and human colorectal cancer cell line HCT116. With the evaluation of stability and in vitro cytotoxicity, an appropriate linker was found, and the active drug can be released efficiently from compound 3a, which exhibited strong antiproliferative activity in A549 and HCT-116 cell lines correspondingly. These results indicated that the well-designed co-prodrug 3a and this kind of strategy can be a promising approach for anticancer therapy.
Highlights
By combining with the Topo I-DNA covalent conjugate, the camptothecin analogue forms a ternary complex that blocks the repolymerization of the DNA strands during their replication leading to the cell apoptosis eventually.[3−5] SN-38 is about 100- to 1000-fold more potent than irinotecan, its clinical application is limited by its poor solubility and nonspecific toxicity.[1]
Many efforts have been made to develop prodrugs of SN-38 such as polymer, albumin, and immune conjugates,[6,7] and a number of these prodrugs have reached different stages of preclinical or clinical trials.[8−11] It has been suggested that cells arrested in G2/M by camptothecin were most sensitive to subsequent addition of histone deacetylase inhibitors (HDACIs).[12,13]
The weakness leads to the loosening of the chromosome structure and disturbs transcriptional machinery, which could cause cell apoptosis .16−19 Several HDACIs exhibit little or no anticancer effects in preclinical studies, and some are in clinical studies either as single agents[16,20,21] or in combination with conventional chemotherapy
Summary
7-Ethyl-10-hydroxycamptothecin (SN-38), as a highly active topoisomerase (Topo) I inhibitor, is the active metabolic product of its prodrug irinotecan (CPT-11) commercially available as Camptosar.[1,2] By combining with the Topo I-DNA covalent conjugate, the camptothecin analogue forms a ternary complex that blocks the repolymerization of the DNA strands during their replication leading to the cell apoptosis eventually.[3−5] SN-38 is about 100- to 1000-fold more potent than irinotecan, its clinical application is limited by its poor solubility and nonspecific toxicity.[1]. Suberoylanilide hydroxamic acid (SAHA, vorinostat), which is an oral HDACI approved by the FDA as a treatment for cutaneous T-cell lymphoma (CTCL), has shown strong anticancer effects in some sensitive cell lines.[22,23] Despite promising clinical effects reported, SAHA is not efficient for the treatment of solid cancers.[20,24] SAHA has been used for drug combinations with other traditional chemotherapeutic drugs like gemcitabine and camptothecin against solid cancers to exert more cytotoxicity.[25−27] In addition, SAHA has a tendency to hydrolyze to the corresponding carboxylic acid derivative quickly in plasma, which is completely inactive.[28,29] For this kind of situation, it is necessary to improve the stability of SAHA through structural modification or other means while in clinical use To overcome these obstacles, SAHA has been designed in various forms, such as clickable pH-responsive prodrug,[30] selective enzymatic. Our hypothesis of the release mechanism is that the carbonic ester between the amino acid and SAHA could be hydrolyzed or enzymatically hydrolyzed at first
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