Chemistry and Anticancer Activity of Hybrid Molecules and Derivatives based on 5-Fluorouracil

Cardona‐G, Wilson; Herrera-R, Angie; Wilson, Castrillón-L; Ramírez-Malule, Howard

doi:10.2174/0929867328666210211164314

Cited by 14 publications

(11 citation statements)

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“…However, this compound not only exhibits a short half-life and low selectivity but also different grades of toxicity including neurological, gastrointestinal disorders and myelosuppression, among others, which leads to dose limitation and treatment discontinuation [ 2 ]. For these reasons, this molecule has been extensively modified to obtain conjugates and hybrid molecules, which may improve its therapeutic potential and selectivity, leading to a decrease in side effects [ 3 ]. In addition, several natural products have been evaluated since they exhibit a plethora of biological activities in different in vitro and in vivo models.…”

Section: Introductionmentioning

confidence: 99%

“…Finally, hybrid F was evaluated on SW480 cells, and the results showed that 48 h post-treatment with 300 µM it displayed significant activity over SW480 cells, causing a significant reduction in cell viability (40.49%), in a time- and concentration-dependent manner [ 18 ]. Many other examples of hybrid molecules based on 5-FU conjugated with both natural and synthetic compounds, together with their biological activities on different models of cancer, were summarized by Cardona et al, 2021 [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Chemopreventive Potential of 5-FU/Genistein Hybrids on Colorectal Cancer Cells

et al. 2022

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A series of 5-FU-Genistein hybrids were synthesized and their structures were elucidated by spectroscopic analysis. The chemopreventive potential of these compounds was evaluated in human colon adenocarcinoma cells (SW480 and SW620) and non-malignant cell lines (HaCaT and CHO-K1). Hybrid 4a displayed cytotoxicity against SW480 and SW620 cells with IC50 values of 62.73 ± 7.26 µM and 50.58 ± 1.33 µM, respectively; compound 4g induced cytotoxicity in SW620 cells with an IC50 value of 36.84 ± 0.71 µM. These compounds were even more selective than genistein alone, the reference drug (5-FU) and the equimolar mixture of genistein plus 5-FU. In addition, hybrids 4a and 4g induced time- and concentration-dependent antiproliferative activity and cell cycle arrest at the S-phase and G2/M. It was also observed that hybrid 4a induced apoptosis in SW620 cells probably triggered by the extrinsic pathway in response to the activation of p53, as evidenced by the increase in the levels of caspases 3/8 and the tumor suppressor protein (Tp53). Molecular docking studies suggest that the most active compound 4a would bind efficiently to proapoptotic human caspases 3/8 and human Tp53, which in turn could provide valuable information on the biochemical mechanism for the in vitro cytotoxic response of this compound in SW620 colon carcinoma cell lines. On the other hand, molecular dynamics (MD) studies provided strong evidence of the conformational stability of the complex between caspase-3 and hybrid 4a obtained throughout 100 ns all-atom MD simulation. Molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) analyses of the complex with caspase-3 showed that the interaction between the ligand and the target protein is stable. Altogether, the results suggest that the active hybrids, mainly compound 4a, might act by modulating caspase-3 activity in a colorectal cancer model, making it a privileged scaffold that could be used in future investigations.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and Chemopreventive Potential of 5-FU/Genistein Hybrids on Colorectal Cancer Cells

et al. 2022

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“…In this sense, the use of hybrid compounds has emerged as a promising strategy in medicinal chemistry and drug discovery research. This design is based on the covalent linking of two molecules with individual intrinsic pharmacological activity [ 21 , 22 ]. The combination of two pharmacophores with different biological activities, probably acting on different targets, could confer a dual activity to the molecule [ 23 , 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Proapoptotic Effect and Molecular Docking Analysis of Curcumin–Resveratrol Hybrids in Colorectal Cancer Chemoprevention

et al. 2022

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Different hybrids based on curcumin and resveratrol were previously synthesized and characterized by spectroscopic techniques. The most active molecules (3a, 3e, 3i, and 3k) were evaluated in vitro as an approach to determine the possible mechanism of action of the hybrids. The results indicated that the evaluated curcumin/resveratrol hybrids induce mitochondrial instability in SW620 and SW480 cells. Moreover, these molecules caused a loss in membrane integrity, suggesting an apoptotic process mediated by caspases after the treatment with compounds 3i (SW480) and 3k (SW620). In addition, the results suggest that the mechanism of action of the hybrids could be independent of the p53 status. Furthermore, hybrids 3e and 3i caused G0/G1 phase arrest, which highlights the potential of these molecules not only as cytotoxic but also as cytostatic compounds. Hybrids 3e and 3i caused a negative modulation of the matrix metalloproteinase 7 (MMP7) on SW480 cells. These curcumin resveratrol hybrids could be potential candidates for further investigations in the search for potential chemopreventive agents, even in those cases with resistance to conventional chemotherapy because of the lack of p53 expression or function. Molecular docking simulations showed that compounds 3e, 3i, and 3k bind efficiently to proapoptotic human caspases 3/7 proteins, as well as human MMP-7 and p53, which, in turn, could explain at the molecular level the in vitro cytotoxic effect of these compounds in SW480 and SW620 colon cancer cell lines.

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“…Therefore, the use of hybrid compounds has emerged as promising strategy in medicinal chemistry and drug discovery research, since these compounds combine two distinct biologically active molecules into one entity that can act on different targets, displaying a dual effect [24][25][26][27][28]. We have previously reported on the biological activity of different hybrids based on S-allyl cysteine ester-caffeic acid amides, using a colon cancer cell line.…”

Section: Introductionmentioning

confidence: 99%

Colorectal Cancer Chemoprevention by S-Allyl Cysteine–Caffeic Acid Hybrids: In Vitro Biological Activity and In Silico Studies

et al. 2022

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Conventional chemotherapy for colorectal cancer (CRC) gives only a small increase in patient survival, since it is often diagnosed at late stages, when the tumor has disseminated to other organs. Moreover, it is common to observe that malignant cells may acquire resistance to conventional chemotherapies through different mechanisms, including reducing drug activation or accumulation (by enhancing efflux), inducing alterations in molecular targets, and inhibiting the DNA damage response, among other strategies. Considering these facts, the discovery of new molecules with therapeutic potential has become an invaluable tool in chemoprevention. In this context, we previously evaluated two hybrids (SAC-CAFA-MET and SAC-CAFA-PENT) that exhibited selective cytotoxicity against SW480 cells, with better results than the conventional chemotherapeutic agent (5-fluorouracil; 5-FU). Here, we investigated the possible mechanisms of these molecules in greater depth, to identify whether they could be valuable therapeutic scaffolds in the search for new molecules with chemopreventive potential for the treatment of CRC. Both compounds reduced ROS formation, which could be related to antioxidant effects. Further evaluations showed that SAC-CAFA-MET induces cell death independent of caspases and the tumor-suppressor protein p53, but probably mediated by the negative regulation of the pro-apoptotic Bcl-2. In addition, the lack of activation of caspase-8 and the positive regulation of caspase-3 induced by SAC-CAFA-PENT suggest that this compound acts through an apoptotic mechanism, probably initiated by intrinsic pathways. Furthermore, the downregulation of IL-6 by SAC-CAFA-PENT suggests that it also induces a significant anti-inflammatory process. In addition, docking studies would suggest caspase-3 modulation as the primary mechanism by which SAC-CAFA-PENT elicits apoptosis in SW480human colorectal adenocarcinoma cells. Meanwhile, density functional theory (DFT) calculations suggest that both hybrids would produce effects in the modulation of ROS in SW480 cells via the hydrogen atom transfer (HAT) pathway. The present work notes that SAC-CAFA-MET and SAC-CAFA-PENT could be potential candidates for further investigations in the search for potential chemopreventive agents.

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Chemistry and Anticancer Activity of Hybrid Molecules and Derivatives based on 5-Fluorouracil

Cited by 14 publications

References 0 publications

Synthesis and Chemopreventive Potential of 5-FU/Genistein Hybrids on Colorectal Cancer Cells

Synthesis and Chemopreventive Potential of 5-FU/Genistein Hybrids on Colorectal Cancer Cells

Proapoptotic Effect and Molecular Docking Analysis of Curcumin–Resveratrol Hybrids in Colorectal Cancer Chemoprevention

Colorectal Cancer Chemoprevention by S-Allyl Cysteine–Caffeic Acid Hybrids: In Vitro Biological Activity and In Silico Studies

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