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Molecules (Basel, Switzerland) Oct 2021Mosquito-borne viruses including dengue, Zika, and Chikungunya viruses, and parasites such as malaria and endanger health and economic security around the globe, and...
Mosquito-borne viruses including dengue, Zika, and Chikungunya viruses, and parasites such as malaria and endanger health and economic security around the globe, and emerging mosquito-borne pathogens have pandemic potential. However, the rapid spread of insecticide resistance threatens our ability to control mosquito vectors. Larvae of were screened with the Medicines for Malaria Venture Pandemic Response Box, an open-source compound library, using INVAPP, an invertebrate automated phenotyping platform suited to high-throughput chemical screening of larval motility. We identified rubitecan (a synthetic derivative of camptothecin) as a hit compound that reduced larval motility. Both rubitecan and camptothecin displayed concentration dependent reduction in larval motility with estimated EC of 25.5 ± 5.0 µM and 22.3 ± 5.4 µM, respectively. We extended our investigation to adult mosquitoes and found that camptothecin increased lethality when delivered in a blood meal to adults at 100 µM and 10 µM, and completely blocked egg laying when fed at 100 µM. Camptothecin and its derivatives are inhibitors of topoisomerase I, have known activity against several agricultural pests, and are also approved for the treatment of several cancers. Crucially, they can inhibit Zika virus replication in human cells, so there is potential for dual targeting of both the vector and an important arbovirus that it carries.
Topics: Aedes; Animals; Antiviral Agents; Camptothecin; Drug Discovery; Female; High-Throughput Screening Assays; Humans; Insecticide Resistance; Insecticides; Larva; Mosquito Vectors; Motor Activity; Pandemics; Topoisomerase I Inhibitors; Vector Borne Diseases; Virus Replication; Zika Virus
PubMed: 34684807
DOI: 10.3390/molecules26206226 -
Biochemical and Biophysical Research... Apr 2021In the present study the role of poly(ADP)ribosylation on rubitecan induced caspase dependent cell death was evaluated. We show that Top1 poisoning by rubitecan induces...
In the present study the role of poly(ADP)ribosylation on rubitecan induced caspase dependent cell death was evaluated. We show that Top1 poisoning by rubitecan induces caspase mediated apoptosis which was reduced by PARP inhibitor olaparib in zebrafish embryo. Collectively our data introduces zebrafish as a valuable model for PARP related biomedical research.
Topics: Animals; Apoptosis; Camptothecin; Caspase 3; DNA Topoisomerases, Type I; Drug Synergism; Phthalazines; Piperazines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Topoisomerase I Inhibitors; Zebrafish
PubMed: 33706100
DOI: 10.1016/j.bbrc.2021.03.005 -
European Journal of Pharmacology May 20229-nitrocamptothecin (9-NC), an active derivative of camptothecin (CPT), demonstrated antitumor effect on experimental tumors in mice by topoisomerase I (Topo I)...
9-Nitro-20(S)-carbonate-camptothecin (NCP4), a novel prodrug of 9-nitrocamptothecin (9-NC), exhibits potent chemotherapeutic efficacy and improved safety against hepatocarcinoma.
9-nitrocamptothecin (9-NC), an active derivative of camptothecin (CPT), demonstrated antitumor effect on experimental tumors in mice by topoisomerase I (Topo I) inhibition. However, under human physiological conditions, the rapid opening of lactone ring of 9-NC resulting in the formation of inactive and high toxic carboxylate limited its clinical efficacy. Therefore, strategies aimed to maintain the active closed-lactone form of 9-NC in the plasma were developed, such as prodrugs. In our study, 9-nitro-20(S)-carbonate-camptothecin (NCP4), a novel prodrug of 9-NC, was designed and synthesized. A preclinical evaluation of the chemotherapeutic potential of NCP4 was performed in vitro and in vivo. In cytotoxicity assay against six human cancer cells, the cytotoxic effect of NCP4 was slightly weaker than 9-NC. In addition, our data showed that 9-NC can be converted from NCP4 in vivo, and that the intracellular conversion of NCP4 to its active metabolites was correlated well with its cytotoxicity, demonstrating that NCP4 could serve as a prodrug of 9-NC. In human hepatoma Bel-7402 xenografts, NCP4 by intravenous injection showed more potent antitumor efficacy than 9-NC. Mechanistically, NCP4 induced cell apoptosis by increasing the expressions of caspase-3 and Bax in tumor tissues. In human hepatoma Hep G2 xenografts, NCP4 by oral administration significantly inhibited tumor growth. Importantly, the toxic effect of NCP4 on mice was much lower than 9-NC, demonstrating improved safety of NCP4. Overall, our study indicated that NCP4 would be a promising anticancer candidate and worthy of further investigation.
Topics: Animals; Antineoplastic Agents; Camptothecin; Carbonates; Carcinoma, Hepatocellular; Humans; Lactones; Liver Neoplasms; Mice; Prodrugs
PubMed: 35305999
DOI: 10.1016/j.ejphar.2022.174898 -
Journal of Pharmaceutical and... Feb 20209-Nitrocamptothecin-20-O-propionate (CZ112) and 9-Nitrocamptothecin (9NC) are the bioactive derivatives of camptothecin (CPT), an alkaloid isolated from Camptotheca...
9-Nitrocamptothecin-20-O-propionate (CZ112) and 9-Nitrocamptothecin (9NC) are the bioactive derivatives of camptothecin (CPT), an alkaloid isolated from Camptotheca acuminata, and have been confirmed to possess high anti-cancer properties. In the present study, 9NC was identified as the major metabolite of CZ112 in rat plasma through HPLC/photodiode array detection (PDA) and liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. A highly sensitive LC-MS/MS method was developed and validated for the simultaneous analysis of CZ112 and 9NC in rat plasma, and camptothecin-20-O-acetate (CZ44) was used as an internal standard (IS). The calibration curves were linear (r > 0.999) over concentrations from 2.5 to 320 ng/mL for both CZ112 and 9NC. The method had an accuracy of 96.7-109.6%, and the intra- and inter-day precision (RSD%) were 10.9% or less for CZ112 and 9NC. The stability data showed no significant degradation occurred under the experimental conditions. This method was successfully applied to the pharmacokinetic study of CZ112 and its metabolite 9NC in rat plasma after intravenous and intragastric administration. The oral bioavailability of CZ112 was 6.2 ± 3.3% (n = 6).
Topics: Animals; Antineoplastic Agents; Biological Availability; Camptothecin; Chromatography, Liquid; Male; Prodrugs; Rats; Rats, Wistar; Tandem Mass Spectrometry
PubMed: 31848079
DOI: 10.1016/j.jpba.2019.112963 -
Journal of Biomolecular Structure &... May 2021In December 2019, COVID-19 epidemic was described in Wuhan, China, and the infection has spread widely affecting hundreds of thousands. Herein, an effort was made to...
In December 2019, COVID-19 epidemic was described in Wuhan, China, and the infection has spread widely affecting hundreds of thousands. Herein, an effort was made to identify commercially available drugs in order to repurpose them against coronavirus by the means of structure-based virtual screening. In addition, ZINC15 library was used to identify novel leads against main proteases. Human TMPRSS2 3D structure was first generated using homology modeling approach. Our molecular docking study showed four potential inhibitors against Mpro enzyme, two available drugs (Talampicillin and Lurasidone) and two novel drug-like compounds (ZINC000000702323 and ZINC000012481889). Moreover, four promising inhibitors were identified against TMPRSS2; Rubitecan and Loprazolam drugs, and compounds ZINC000015988935 and ZINC000103558522. ADMET profile showed that the hits from our study are safe and drug-like compounds. Furthermore, molecular dynamic (MD) simulation and binding free energy calculation using the MM-PBSA method was performed to calculate the interaction energy of the top-ranked drugs.Communicated by Ramaswamy H. Sarma.
Topics: COVID-19; Cysteine Endopeptidases; Drug Repositioning; Humans; Molecular Docking Simulation; Peptide Hydrolases; Pharmaceutical Preparations; Protease Inhibitors; SARS-CoV-2; Viral Nonstructural Proteins
PubMed: 32306862
DOI: 10.1080/07391102.2020.1758791