Synthesis, Characterization, Theoretical and Experimental Anticancer Evaluation of Novel Cocrystals of 5-Fluorouracil and Schiff Bases against SW480 Colorectal Carcinoma (original) (raw)
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Crystal Growth & Design, 2020
5-Fluorouracil (5-FU) being a mainstream anticancer drug is under keen and detailed investigation for prodrugs formulations in order to minimize the associated side effects. Cocrystallization of 5-FU is an innovative technique for the synthesis of 5-FU prodrugs to improve its anticancer effectiveness. The present study is based on the synthesis of 5-FU supramolecular synthons with four coformers: succinic acid, cinnamic acid, malic acid, and benzoic acid utilizing acetone as a solvent. Solid state grinding followed by a slow evaporation solution method was applied. Colorless clear crystals were obtained in all the cases. The cocrystal formation was supported with the help of Fourier transform infrared (FTIR) spectroscopy and powder X-ray diffraction (PXRD). Through FTIR, the main peaks of interest in the spectrum of 5-FU were N−H (3409.02 cm −1) and carbonyl group (1647.80 cm −1), which were prominently shifted in all spectra of the cocrystals demonstrating the replacement as well as the development of already present interactions with the new ones. For 5-FU−cinnamic acid cocrystals, the anticipated peaks were observed at 1673.13 cm −1 (−CO) and 3566.89 cm −1 (N−H) manifesting a significant change in comparison to 5-FU. Furthermore, with the help of PXRD characterization, the representative peak of 5-FU was recorded at 2θ = 28.80°. The shifting of this specific peak and development of many new ones in the spectra of cocrystals proved the development of new structural entities. Finally, the anticancer activity of all cocrystals was evaluated in comparison to that of API. All cocrystals manifest significantly greater growth inhibition potential than the main active pharmaceutical ingredient. 5-FU−Cinnamic acid (3C) was the one that proved to be the most potent anticancer agent at all four concentrations: 4.82% (12 μg/mL), 34.21% (25 μg/mL), 55.08% (50 μg/mL), and 67.29% (100 μg/mL). In short, this study proved to be a true example to enhance the anticancer potential of 5-FU following fairly easy fabrication requirements of the cocrystallization phenomenon. After the successful synthesis of these supramolecular synthons and subsequent enhancement of growth inhibition potential of 5-FU, these cocrystals can further be evaluated for in vivo trials and membrane crossing potentials in the future.
Saudi Pharmaceutical Journal, 2019
This study reports the formation of 5-FU co-crystals with four different pharmacologically safe co-formers; Urea, Thiourea, Acetanilide and Aspirin using methanol as a solvent. Two fabrication schemes were followed i.e., solid-state grinding protocol, in which API and co-formers were mixed through vigorous grinding while in the other method separate solutions of both the components were made and mixed together. The adopted approaches offer easy fabrication protocols, no temperature maintenance requirements , no need of expensive solvents, hardly available apparatus, isolation and purification of the desired products. In addition, there is no byproducts formation, In fact, a phenomenon embracing the requirements of green synthesis. Through FTIR analysis; for API the NAH absorption frequency was recorded at 3409.02 cm À1 and that of AC@O was observed at 1647.77 cm À1. These characteristics peaks of 5-FU were significantly shifted and recorded at 3499.40 cm À1 and 1649.62 cm À1 for 5-FU-Ac (3B) and 3496.39 cm À1 and 1659.30 cm À1 for 5-FU-As (4B) co-crystals for NAH and AC@O groups respectively. The structural differences between API and co-crystals were further confirmed through PXRD analysis. The characteristic peak of 5-FU at 2h = 28.79918 o was significantly shifted in the graphs of co-crystals not only in position but also with respect to intensity and FWHM values. In addition, new peaks were also recorded in all the spectra of co-formers confirming the structural differences between API and co-formers. In addition, percent growth inhibition was also observed by all the co-crystals through MTT assay against HCT 116 colorectal cell lines in vitro. At four different concentrations; 25, 50, 100 and 200 mg/mL, slightly different trends of the effectiveness of API and co-crystals were observed. However; among all the co-crystal forms, 5-FU-thiourea co-crystals obtained through solution method (2B) proved to be the most effective growth inhibitor at all the four above mentioned concentrations.
Synthesis and Preliminary Kinetic Study of 5-fluorouracil Derivatives for Targeting Colon Tumor
JOURNAL OF ADVANCES IN CHEMISTRY, 2011
5-Fluorouracil (5-FU) is used widely as an anticancer drug to treat solid cancers, such as colon, breast, rectal, and pancreatic cancers; although it’s clinical application is greatly limited by its short plasma half-life, poor tumor affinity, myelosuppression, and gastrointestinal toxicity. To tackle these problems, numerous modifications of the 5- Fu structure have been performed.Thus, 5-Fu as possible colon specific prodrugs were synthesized in which 5-Fu is attached to amino acids (alanine & phenylalanine) using succinate group as a spacer via amide or ester bond. An approach to improve the properties of 5-fluorouracil is the chemical transformation into bioreversible derivatives (prodrugs) which are converted to the parent drug by enzymatic and / or chemical hydrolysis. The synthesis of the target compounds were accomplished following multistep reaction procedures, the chemical reaction followed up and the purity of the products were checked by TLC. The structures of the fina...
RSC advances, 2024
New amide conjugates 1-6 of hydroxycinnamic acids (HCA) and 5 0-deoxy-5-fluorocytidine (5-dFCR), the prodrug of 5-fluorouracil (5-FU), were synthesized and tested in vitro against pancreatic cancer lines (PDAC). The compounds showed slightly higher efficacy against primary BxPC-3 cells (IC 50 values of 14-45 mM) than against metastatic AsPC-1 (IC 50 values of 37-133 mM), and similar to that of 5-FU for both PDAC lines. Compound 1, which has a para-(acetyloxy)coumaroyl substituent, was found to be the most potent (IC 50 = 14 mM) with a selectivity index of approximately 7 to normal dermal fibroblasts (IC 50 = 96 mM). The potential pharmacological profiles were discussed on the basis of the ADME data. Docking to the carboxylesterase CES2 showed that the synthesized compounds have the ability to bind via hydrogen bonding between a specific acetate group of the sugar moiety and Ser228, which belongs to the catalytic triad that causes hydrolysis. Docking to albumin, a major transport protein in the circulatory system, revealed a strong interaction of the conjugates at the binding site which is native to warfarin and responsible for its transport in the body.
Synthesis of New 5-Fluorouracil Derivatives as Possible Prodrug for Targeting Cancer Cells
On the other hand, compound VI had lower rate of hydrolysis at pH 6 and enough rate of hydrolysis at pH 7.4 (t½=104.4 min and t½81.6 min respectively). According to the results mentioned above, compounds II and V can be good candidates as 5fluorouracil prodrugs that can selectively deliver the parent drug into the cancer cells by the effect of pH. Key word:5-Fluorouracil,Prodrug, Cancer targeting.
Design and Synthesis of azo Derivatives of 5-Fluorouacil for Targeting Colon Cancer
JOURNAL OF ADVANCES IN CHEMISTRY, 2014
5-Fluorouracil (5-FU) is a drug that belong to the antimetabolite class of antineoplastic agents, with a broad spectrum of activity against solid tumors, the use of oral 5-FU was abandoned decades ago because of its irregular absorption and rapid degradation. A potential strategy to improve the selective properties of 5-FU is the chemical transformation into reversible derivatives (prodrugs) which are converted to the parent drug by virtue of enzymatic or chemical means. In the present study, three derivatives of 5-fluorouracil have been designed to be synthesized as an azo derivatives of 5-fluorouracil in order to selectively deliver 5-fluorouracil into the cancer cells of the colon. The synthesis of the target compounds were accomplished following multistep reaction procedures. The chemical reactions were followed up and purity of the products was checked by TLC. The structure of the final compounds and their intermediates were characterized and identified by their melting poin...
BMC Chemistry, 2021
Background 1,2,4-oxadiazole derivatives exhibited significant anti-cancer activity when they were evaluated, against human cancer cell lines. They also showed anti-inflammatory, analgesic, diabetic, immunosuppressive, α,β3-receptor antagonist, antimicrobial, anti-helminthic, histamine-H3 and antiparasitic properties. A pyrimidine analog, 5 fluoro-uracil is a chemotherapeutic drug used for treating multiple solid malignant tumors. But its application is limited, as it has side effects like low bioavailability and high toxicity. Molecular docking is an exemplary tool, helps in identifying target and designing a drug containing high bio-availability and minimum toxicity. Results A set of 1,2,4-oxadiazole linked 5-fluoruracil derivatives (7a–j) were synthesized and their structures were confirmed by 1HNMR, 13CNMR and Mass spectral analysis. Further, these compounds were investigated for their anticancer activity towards a panel of four human cancer cell lines such as (MCF-7, MDA MB-231)...
Assiut University Journal of Multidisciplinary Scientific Research, 2019
In the present study samarium-5-fluorouracil (5-FU) complex was prepared to enhance the effectiveness of the 5-FU drug. This complex was characterized by UV/VIS spectrometry high performance liquid chromatography and differential scanning calorimetry. Furthermore, the antitumor effect of the prepared complex was explored on the human colon cancer cell Caco2 via evaluation of the cytotoxic activity of this complex through trypan blue cell viability. Apoptosis was also assessed through morphological changes, by Annexin V=PI flow cytometric analysis. The results revealed that the trivalent Sm enhance the 5-FU effect against the chemo-resistant colorectal carcinoma cell line.
Attenuation of the antitumor activity of 5-fluorouracil by (R)-5-fluoro-5,6-dihydrouracil
Cancer research, 1995
5-Ethynyluracil (5-EU; 776C85) is a potent mechanism-based inactivator of dihydropyrimidine dehydrogenase that improves the antitumor activity of 5-fluorouracil (5-FU) to a greater extent than can be accounted for by the improved 5-FU pharmacokinetics that result from preventing the catabolism of 5-FU. We therefore tested the effects of (R)-5-fluoro-5,6-dihydrouracil (5-FUH2), the 5-FU catabolite extensively formed in the absence of 5-EU, on the antitumor activity and toxicity of 5-FU in 5-EU-treated rats bearing large s.c. tumors. Rats were dosed once weekly for 3 weeks with the following regimens: 100 mg/kg 5-FU (maximum tolerated dose), 10 mg/kg 5-FU 1 h after 1 mg/kg 5-EU, or 10 mg/kg 5-FU plus 90 mg/kg 5-FUH2 1 h after 1 mg/kg 5-EU. The latter regimen was designed to approximate the exposure produced from 5-FU in the absence of 5-EU, where > 80% of the dose is catabolized. 5-FU produced complete and sustained tumor regressions in 94% of the animals pretreated with 5-EU. In c...
Medicinal Chemistry Research, 2011
The present work reports the synthesis of 20 novel fluorine-containing quinoline and pyrimido[4,5-b]quinoline derivatives bearing a sulfonamide moiety. The new synthesized compounds were designed in compliance with the general pharmacophoric requirements for carbonic anhydrase (CA) inhibiting anticancer drugs, as this may play a role in their anticancer activity. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against human breast cancer cell line (MCF7). Compounds 11 and 12 exhibited better activities than the reference drug doxorubicin (IC50 = 71.8 μM) with IC50 values of 52.6 μM and 67.3 μM, respectively. On the other hand, compounds 6, 10, and 13 showed IC50 values (71.8 μM, 69.8 μM, and 70.8 μM, respectively) comparable to that of the reference drug doxorubicin. In addition, docking of the synthesized compounds into human carbonic anhydrase isozyme II (hCA II) active site was performed in order to predict the affinity and the orientation of these compounds at the isozyme active site. Also, the most active compounds, 11 and 12, were selected and evaluated for their ability to enhance the cell killing effect of γ-radiation.