AbstractDespite their impact on cancer therapy, limitations such as systemic toxicity and drug resistance are encountered with platinum-based drugs. This study explores the potential of combining PtIV-based NP with carmofur (Car) to address these issues. In this study, platinum nanoparticles (PtNPs) and Car-loaded PtNP (Car@PtNP) were synthesized and their cytotoxic and apoptotic effects on colorectal and breast cancer cells were evaluated. Following characterization of the synthesized NPs by dynamic light scattering, UV–VIS spectroscopy, FTIR, and STEM, it was found that the average size of PtNPs was 55.42 nm and the size increased to approximately 186.06 nm upon synthesis of Car@PtNP. MTT assays demonstrated that Car@PtNP exhibited higher levels of cellular toxicity than carmofur alone. While it significantly decreased cell viability in both colon and breast cancer cells, its toxicity to HUVEC cells was minimal. Treatment of MCF-7 and HCT116 cells with 50 µg ml−1 of free Car resulted in cell viabilities of 65.2% and 76.93%, respectively, whereas the viability of cells treated with Car@PtNP decreased to 49.60% and 55.47%. Flow cytometric analysis confirmed that apoptosis was increased in healthy HCT116 cells treated with Car@PtNP, with a marked increase in both early and late apoptotic cell populations. Furthermore, these results were confirmed by Hoescht and Rhodamin123 immunofluorescence staining, and significant mitochondrial dysfunction and apoptotic morphological changes were observed in treated cells. The findings underscore the promise of Car@PtNP as a novel chemotherapeutic approach, integrating the benefits of PtIV complexes and Car to enhance antitumor efficacy while mitigating the drawbacks of conventional platinum-based therapies.

01 Nov 2024·Biochemical and Biophysical Research Communications

Structural basis of main proteases of MERS-CoV bound to antineoplastic drug carmofur

Article

Author: Zhou, Xuelan ; Li, Wenwen ; Zeng, Pei ; Guo, Li ; Zhang, Jin ; Li, Jian

Recurrent epidemics of coronaviruses have posed significant threats to human life and health. The mortality rate of patients infected with the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is 35 %. The main protease (M^pro) plays a crucial role in the MERS-CoV life cycle, and M^pro exhibited a high degree of conservation among different coronaviruses. Therefore inhibition of M^pro has become an effective strategy for the development of broad-spectrum anti-coronaviral drugs. The inhibition of SARS-CoV-2 M^pro by the anti-tumor drug carmofur has been revealed, but structural studies of carmofur in complex with M^pro from other types of coronavirus have not been reported. Hence, we revealed the structure of the MERS-CoV M^pro-carmofur complex, analysed the structural basis for the binding of carmofur to MERS-CoV M^pro in detail, and compared the binding patterns of carmofur to M^pros of two different coronaviruses, MERS-CoV and SARS-CoV-2. Considering the importance of M^pros for coronavirus therapy, structural understanding of M^pro inhibition by carmofur could contribute to the design and development of novel antiviral drugs with safe and broad-spectrum efficacy.

01 Oct 2024·Inflammopharmacology

Taming the storm: potential anti-inflammatory compounds targeting SARS-CoV-2 MPro

Review

Author: Timmers, Luis Fernando Saraiva Macedo ; de Lima, Jeferson Camargo ; Goettert, Marcia Inês ; Camini, Ana Micaela ; Dahmer, Bruno Rampanelli ; Anton, Débora Bublitz

In severe COVID-19 cases, an exacerbated inflammatory response triggers a cytokine storm that can worsen the prognosis. Compounds with both antiviral and anti-inflammatory activities show promise as candidates for COVID-19 therapy, as they potentially act against the SARS-CoV-2 infection regardless of the disease stage. One of the most attractive drug targets among coronaviruses is the main protease (MPro). This enzyme is crucial for cleaving polyproteins into non-structural proteins required for viral replication. The aim of this review was to identify SARS-CoV-2 MPro inhibitors with both antiviral and anti-inflammatory properties. The interactions of the compounds within the SARS-CoV-2 MPro binding site were analyzed through molecular docking when data from crystallographic structures were unavailable. 18 compounds were selected and classified into five different superclasses. Five of them exhibit high potency against MPro: GC-376, baicalein, naringenin, heparin, and carmofur, with IC₅₀ values below 0.2 μM. The MPro inhibitors selected have the potential to alleviate lung edema and decrease cytokine release. These molecules mainly target three critical inflammatory pathways: NF-κB, JAK/STAT, and MAPK, all previously associated with COVID-19 pathogenesis. The structures of the compounds occupy the S1/S2 substrate binding subsite of the MPro. They interact with residues from the catalytic dyad (His41 and Cys145) and/or with the oxyanion hole (Gly143, Ser144, and Cys145), which are pivotal for substrate recognition. The MPro SARS-CoV-2 inhibitors with potential anti-inflammatory activities present here could be optimized for maximum efficacy and safety and be explored as potential treatment of both mild and severe COVID-19.

100 Deals associated with Carmofur

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KEGG	Wiki	ATC	Drug Bank
D01784	Carmofur	L01BC04	DB09010

R&D Status

Approved

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Indication	Country/Location	Organization	Date
Breast Cancer	China	Qilu Tianhe Pharmaceutical Co. Ltd.	01 Jan 1997
Colorectal Cancer	China	Qilu Tianhe Pharmaceutical Co. Ltd.	01 Jan 1997
Esophageal Carcinoma	China	Qilu Tianhe Pharmaceutical Co. Ltd.	01 Jan 1997
Stomach Cancer	China	Qilu Tianhe Pharmaceutical Co. Ltd.	01 Jan 1997

Developing

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	Italy	Istituto Italiano di Tecnologia	24 Apr 2013

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