204133-80-2

Upstream product

• 7693-46-1 4-Nitrophenyl chloroformate 
• 7689-03-4 camptothecin 
• 5070-13-3 bis-(p-nitrophenyl) carbonate 

Relevant academic research and scientific papers

Bioactivation of carbamate-based 20(S)-camptothecin prodrugs

Two new prodrugs of CPT were synthesized, based on carbamate linkages between the 20-hydroxy group of CPT and a linker designed to be enzymatically removed by either Penicillin-G-Amidase or catalytic antibody 38C2. Cell growth inhibition assays showed an

New somatostatin-drug conjugates for effective targeting pancreatic cancer

Pancreatic cancer poorly responds to available drugs, and finding novel approaches to target this cancer type is of high significance. Here, based on a common property of pancreatic cancer cells to express somatostatin receptors (SSTR), we designed drug conjugates with novel somatostatin-derived cyclic peptides (SSTp) with broad selectivity towards SSTR types to facilitate drug targeting of the pancreatic cancer cells specifically. Uptake of our newly designed SSTps was facilitated by SSTRs expressed in the pancreatic cancers, including SSTR2, SSTR3, SSTR4 and SSTR5. Three major drugs were conjugated to our best SSTps that served as delivery vehicles, including Camptothecin (CPT), Combretastatin-4A (COMB) and Azatoxin (AZA). All designed drug conjugates demonstrated penetration to pancreatic cancer cell lines, and significant toxicity towards them. Furthermore, the drug conjugates specifically accumulated in tumors in the animal xenograft model, though some accumulation was also seen in kidney. Overall these findings lay the basis for development of novel drug series that could target the fatal pancreatic cancer.

Autocatalytic Morphology Transformation Platform for Targeted Drug Accumulation

The precise and highly efficient drug delivery of nanomedicines into lesions remains a critical challenge in clinical translational research. Here, an autocatalytic morphology transformation platform is presented for improving the tumor-specific accumulation of drugs by kinetic control. The in situ reorganization of prodrug from nanoparticle to β-sheet fibrous structures for targeted accumulation is based on nucleation-based growth kinetics. During multiple administrations, the autocatalytic morphology transformation can be realized for skipping slow nucleating process and constructing the bulky nanoassembly instantaneously, which has been demonstrated to induce the cumulative effect of prodrug. Furthermore, the sustained drug release from fibrous prodrug depot in the tumor site inhibits the tumor growth efficiently. The autocatalytic morphology transformation strategy in vivo offers a novel perspective for targeted delivery strategy by introducing chemical kinetics and shows great potential in disease theranostics.

Bioreduction activated prodrugs of camptothecin: Molecular design, synthesis, activation mechanism and hypoxia selective cytotoxicity

Several water-soluble derivatives (CPT3, CPT3a-d) of camptothecin (CPT) were synthesized, among which CPT3 bearing an N,N′-dimethyl-1- aminoethylcarbamate side-chain was further conjugated with reductively eliminating structural units of indolequinone, 4-nitrobenzyl alcohol and 4-nitrofuryl alcohol to produce novel prodrugs of camptothecin (CPT4-6). All CPT derivatives were of lower cytotoxicity than their parent compound of CPT. In contrast, CPT4 and CPT6 showed higher hypoxia selectivity of cytotoxicity towards tumor cells than CPT. A mechanism by which a representative prodrug CPT4 is activated in the presence of DT-diaphorase to release CPT was also discussed. The bioreduction activated CPT prodrugs including CPT4 and CPT6 are identified to be promising for application to the hypoxia targeting tumor chemotherapy. The Royal Society of Chemistry 2005.

Synthesis and biological evaluation of new camptothecin derivatives obtained by modification of position 20

The preparation and biological evaluation of a novel series of dimeric camptothecin derivatives are described. All the new compounds showed a significant ability to inhibit human tumor cell growth with IC50 values ranging from 0.03 to 12.2 μM. The interference with the activity of the nuclear enzymes topoisomerases has been demonstrated, highlighting the poison effect of one of the obtained byproducts toward topoisomerase I. A moderate antiangiogenic activity has been demonstrated for one of the obtained compounds. Moreover, the effects of four new compounds on caspases activity and ROS generation have been studied on transgenic mouse cell.

A designed cyclic peptide based on Trastuzumab used to construct peptide-drug conjugates for its HER2-targeting ability

Human epidermal growth factor receptor 2 (HER2) has been recognized as an important therapeutic target for its overexpression in many cancers. Trastuzumab is a monoclonal antibody targeting HER2, which has been approved by FDA to treat HER2-positive cancer. In this research, cyclic peptide Cyclo-GCGPep1 was designed based on the binding mode between antibody and HER2 protein in silico, which has been confirmed possessing good affinity with HER2. Cyclo-GCGPep1 was also used to construct peptide-drug conjugates with Camptothecin. Biological evaluations demonstrated that Conjugate 1 has a good antiproliferative activity on SK-BR-3 and NCI-N87 cells. Conjugate 1 retained the pro-apoptotic and Topo I inhibitory ability of Camptothecin. Meanwhile, it has good targeting ability towards HER2-positive cells with the help of Cyclo-GCGPep1. It also has better permeability in the tumor spheroid model than Camptothecin. In summary, the design of cyclic peptide derived from antibody is of significance for the discovery of targeting peptides and Conjugate 1 is expected as a good therapeutic agent for HER2-positive cancers.

Oligosaccharide-camptothecin conjugates as potential antineoplastic drugs: Design, synthesis and biological evaluation

Thirty novel 20 (S)–O-linked camptothecin (CPT) glycoconjugates were synthesized. They showed more potent in vitro cytotoxicities over irinotecan, but very weak direct topoisomerase I (Topo I) inhibition was observed at 100.0 μM. Oligosaccharide types, length of a PEG linker and acetyl groups exerted obvious effects on cytotoxicity, selectivity, water solubility and stability of the newly synthesized CPT glycoconjugates. Construct 40, with a bleomycin (BLM) disaccharide linked to diethylene glycol in the introduced ester moiety, demonstrated a superior antitumor activity and a distinct selectivity compared to CPT. No toxicity was detectable in animal acute toxicity intravenously (160 mg/kg). Collectively, attachment of oligosaccharides with tumor targeting to 20 (S)–OH of CPT could offer a solution to the daunting problems posed by current Topo I poisons.

Amplified Self-Immolative Release of Small Molecules by Spatial Isolation of Reactive Groups on DNA-Minimal Architectures

Triggering the release of small molecules in response to unique biomarkers is important for applications in drug delivery and biodetection. Due to low quantities of biomarker, amplifying release is necessary to gain appreciable responses. Nucleic acids have been used for both their biomarker-recognition properties and as stimuli, notably in amplified small-molecule release by nucleic-acid-templated catalysis (NATC). The multiple components and reversibility of NATC, however, make it difficult to apply in vivo. Herein, we report the use of the hybridization chain reaction (HCR) for the amplified, conditional release of small molecules from standalone nanodevices. We couple HCR with a DNA-templated reaction resulting in the amplified, immolative release of small molecules. We integrate the HCR components into single nanodevices as DNA tracks and spherical nucleic acids, spatially isolating reactive groups until triggering. This could be applied to biosensing, imaging, and drug delivery.

Camptothecin sugar derivative and preparation method and application thereof

The invention relates to a camptothecin sugar derivative and a preparation method and application thereof, and belongs to the field of biological medicines. The structural formula of the camptothecinsugar derivative is shown in formula (I) in specification. The camptothecin sugar derivative can obviously improve the stability and water solubility of camptothecin and 10-hydroxycamptothecin, and has different sensitivities to different tumor cells. Especially when the chain link n equals to 1, the camptothecin sugar derivative of the invention can significantly increase the selectivity to tumorcells.

PRODRUG COMPOSITIONS, PRODRUG NANOPARTICLES, AND METHODS OF USE THEREOF

The present invention encompasses prodrug compositions, nanoparticles comprising one or more prodrugs, and methods of use thereof.