Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 28
Filter
1.
Molecules ; 27(4)2022 Feb 09.
Article in English | MEDLINE | ID: covidwho-1715565

ABSTRACT

For most researchers, discovering new anticancer drugs to avoid the adverse effects of current ones, to improve therapeutic benefits and to reduce resistance is essential. Because the COX-2 enzyme plays an important role in various types of cancer leading to malignancy enhancement, inhibition of apoptosis, and tumor-cell metastasis, an indispensable objective is to design new scaffolds or drugs that possess combined action or dual effect, such as kinase and COX-2 inhibition. The start compounds A1 to A6 were prepared through the diazo coupling of 3-aminoacetophenone with a corresponding phenol and then condensed with two new chalcone series, C7-18. The newly synthesized compounds were assessed against both COX-2 and epidermal growth factor receptor (EGFR) for their inhibitory effect. All novel compounds were screened for cytotoxicity against five cancer cell lines. Compounds C9 and G10 exhibited potent EGFR inhibition with IC50 values of 0.8 and 1.1 µM, respectively. Additionally, they also displayed great COX-2 inhibition with IC50 values of 1.27 and 1.88 µM, respectively. Furthermore, the target compounds were assessed for their cytotoxicity against pancreatic ductal cancer (Panc-1), lung cancer (H-460), human colon cancer (HT-29), human malignant melanoma (A375) and pancreatic cancer (PaCa-2) cell lines. Interestingly, compounds C10 and G12 exhibited the strongest cytotoxic effect against PaCa-2 with average IC50 values of 0.9 and 0.8 µM, respectively. To understand the possible binding modes of the compounds under investigation with the receptor cites of EGFR and COX-2, a virtual docking study was conducted.


Subject(s)
Antineoplastic Agents , Chalcones , Cyclooxygenase 2 Inhibitors , Neoplasm Proteins , Neoplasms , Protein Kinase Inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Chalcones/chemical synthesis , Chalcones/chemistry , Chalcones/pharmacology , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2 Inhibitors/pharmacology , Drug Screening Assays, Antitumor , ErbB Receptors/antagonists & inhibitors , Humans , Molecular Structure , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Neoplasms/drug therapy , Neoplasms/enzymology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology
2.
Int J Mol Sci ; 23(4)2022 Feb 17.
Article in English | MEDLINE | ID: covidwho-1701976

ABSTRACT

Selenium has been extensively evaluated clinically as a chemopreventive agent with variable results depending on the type and dose of selenium used. Selenium species are now being therapeutically evaluated as modulators of drug responses rather than as directly cytotoxic agents. In addition, recent data suggest an association between selenium base-line levels in blood and survival of patients with COVID-19. The major focus of this mini review was to summarize: the pathways of selenium metabolism; the results of selenium-based chemopreventive clinical trials; the potential for using selenium metabolites as therapeutic modulators of drug responses in cancer (clear-cell renal-cell carcinoma (ccRCC) in particular); and selenium usage alone or in combination with vaccines in the treatment of patients with COVID-19. Critical therapeutic targets and the potential role of different selenium species, doses, and schedules are discussed.


Subject(s)
COVID-19/drug therapy , Neoplasms/drug therapy , Selenium/therapeutic use , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , COVID-19/virology , DNA Repair/drug effects , Drug Resistance, Neoplasm/drug effects , Humans , NF-E2-Related Factor 2/chemistry , NF-E2-Related Factor 2/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification , Selenium/chemistry , Selenium/metabolism , Selenium/pharmacology
3.
Molecules ; 27(3)2022 Jan 28.
Article in English | MEDLINE | ID: covidwho-1686898

ABSTRACT

Cancer is the second most fatal disease worldwide, with colon cancer being the third most prevalent and fatal form of cancer in several Western countries. The risk of acquisition of resistance to chemotherapy remains a significant hurdle in the management of various types of cancer, especially colon cancer. Therefore, it is essential to develop alternative treatment modalities. Naturally occurring alkaloids have been shown to regulate various mechanistic pathways linked to cell proliferation, cell cycle, and metastasis. This review aims to shed light on the potential of alkaloids as anti-colon-cancer chemotherapy agents that can modulate or arrest the cell cycle. Preclinical investigated alkaloids have shown anti-colon cancer activities and inhibition of cancer cell proliferation via cell cycle arrest at different stages, suggesting that alkaloids may have the potential to act as anticancer molecules.


Subject(s)
Alkaloids/chemistry , Alkaloids/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Cycle Checkpoints/drug effects , Colonic Neoplasms/drug therapy , Alkaloids/therapeutic use , Animals , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Cell Proliferation/drug effects , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Drug Discovery , Humans
4.
J Mater Chem B ; 9(47): 9642-9657, 2021 12 08.
Article in English | MEDLINE | ID: covidwho-1684136

ABSTRACT

Cancer is a growing threat to human beings. Traditional treatments for malignant tumors usually involve invasive means to healthy human tissues, such as surgical treatment and chemotherapy. In recent years the use of specific stimulus-responsive materials in combination with some non-contact, non-invasive stimuli can lead to better efficacy and has become an important area of research. It promises to develop personalized treatment systems for four types of physical stimuli: light, ultrasound, magnetic field, and temperature. Nanomaterials that are responsive to these stimuli can be used to enhance drug delivery, cancer treatment, and tissue engineering. This paper reviews the principles of the stimuli mentioned above, their effects on materials, and how they work with nanomaterials. For this aim, we focus on specific applications in controlled drug release, cancer therapy, tissue engineering, and virus detection, with particular reference to recent photothermal, photodynamic, sonodynamic, magnetothermal, radiation, and other types of therapies. It is instructive for the future development of stimulus-responsive nanomaterials for these aspects.


Subject(s)
Antineoplastic Agents/therapeutic use , Delayed-Action Preparations/therapeutic use , Metal Nanoparticles/therapeutic use , Neoplasms/drug therapy , Radiation-Sensitizing Agents/therapeutic use , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/radiation effects , Delayed-Action Preparations/chemistry , Delayed-Action Preparations/radiation effects , Humans , Infrared Rays , Magnetic Phenomena , Metal Nanoparticles/chemistry , Metal Nanoparticles/radiation effects , Radiation-Sensitizing Agents/chemistry , Radiation-Sensitizing Agents/radiation effects , SARS-CoV-2/isolation & purification , Temperature , Tissue Engineering/methods , Ultrasonic Waves , Viral Load/methods
5.
Int J Mol Sci ; 22(23)2021 Nov 30.
Article in English | MEDLINE | ID: covidwho-1542586

ABSTRACT

Compounds of natural origin, an infinite treasure of bioactive chemical entities, persist as an inexhaustible resource for discovering new medicines. In this review, we summarize the naturally occurring ellagitannins, sanguiins, which are bioactive constituents of various traditional medicinal plants, especially from the Rosaceae family. In-depth studies of sanguiin H-6 as an antimicrobial, antiviral, anticancer, anti-inflammatory, and osteoclastogenesis inhibitory agent have led to potent drug candidates. In addition, recently, virtual screening studies have suggested that sanguiin H-6 might increase resistance toward SARS-CoV-2 in the early stages of infection. Further experimental investigations on ADMET (absorption, distribution, metabolism, excretion, and toxicity) supplemented with molecular docking and molecular dynamics simulation are still needed to fully understand sanguiins' mechanism of action. In sum, sanguiins appear to be promising compounds for additional studies, especially for their application in therapies for a multitude of common and debilitating ailments.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Hydrolyzable Tannins/chemistry , Hydrolyzable Tannins/pharmacology , Animals , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , COVID-19/drug therapy , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Pharmacokinetics , Rosaceae/chemistry , SARS-CoV-2/drug effects
6.
Theranostics ; 11(14): 7005-7017, 2021.
Article in English | MEDLINE | ID: covidwho-1524524

ABSTRACT

The tumor suppressor protein p53 remains in a wild type but inactive form in ~50% of all human cancers. Thus, activating it becomes an attractive approach for targeted cancer therapies. In this regard, our lab has previously discovered a small molecule, Inauhzin (INZ), as a potent p53 activator with no genotoxicity. Method: To improve its efficacy and bioavailability, here we employed nanoparticle encapsulation, making INZ-C, an analog of INZ, to nanoparticle-encapsulated INZ-C (n-INZ-C). Results: This approach significantly improved p53 activation and inhibition of lung and colorectal cancer cell growth by n-INZ-C in vitro and in vivo while it displayed a minimal effect on normal human Wi38 and mouse MEF cells. The improved activity was further corroborated with the enhanced cellular uptake observed in cancer cells and minimal cellular uptake observed in normal cells. In vivo pharmacokinetic evaluation of these nanoparticles showed that the nanoparticle encapsulation prolongates the half-life of INZ-C from 2.5 h to 5 h in mice. Conclusions: These results demonstrate that we have established a nanoparticle system that could enhance the bioavailability and efficacy of INZ-C as a potential anti-cancer therapeutic.


Subject(s)
Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Indoles/pharmacology , Lung Neoplasms/drug therapy , Nanoparticles/chemistry , Phenothiazines/pharmacology , Tumor Suppressor Protein p53/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Biological Availability , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Humans , Indoles/chemistry , Indoles/pharmacokinetics , Indoles/therapeutic use , Mice , Mice, Inbred C57BL , Microscopy, Electron, Transmission , Nanoparticles/toxicity , Nanoparticles/ultrastructure , Phenothiazines/chemistry , Phenothiazines/pharmacokinetics , Phenothiazines/therapeutic use , Spectroscopy, Fourier Transform Infrared , Tumor Suppressor Protein p53/genetics , Xenograft Model Antitumor Assays
7.
Molecules ; 26(22)2021 Nov 20.
Article in English | MEDLINE | ID: covidwho-1524087

ABSTRACT

A series of methyl ß-D-galactopyranoside (MGP, 1) analogs were selectively acylated with cinnamoyl chloride in anhydrous N,N-dimethylformamide/triethylamine to yield 6-O-substitution products, which was subsequently converted into 2,3,4-tri-O-acyl analogs with different acyl halides. Analysis of the physicochemical, elemental, and spectroscopic data of these analogs revealed their chemical structures. In vitro antimicrobial testing against five bacteria and two fungi and the prediction of activity spectra for substances (PASS) showed promising antifungal functionality comparing to their antibacterial activities. Minimum inhibition concentration (MIC) and minimum bactericidal concentration (MBC) tests were conducted for four compounds (4, 5, 6, and 9) based on their activity. MTT assay showed low antiproliferative activity of compound 9 against Ehrlich's ascites carcinoma (EAC) cells with an IC50 value of 2961.06 µg/mL. Density functional theory (DFT) was used to calculate the thermodynamic and physicochemical properties whereas molecular docking identified potential inhibitors of the SARS-CoV-2 main protease (6Y84). A 150-ns molecular dynamics simulation study revealed the stable conformation and binding patterns in a stimulating environment. In-silico ADMET study suggested all the designed molecules to be non-carcinogenic, with low aquatic and non-aquatic toxicity. In summary, all these antimicrobial, anticancer and in silico studies revealed that newly synthesized MGP analogs possess promising antiviral activity, to serve as a therapeutic target for COVID-19.


Subject(s)
Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Galactose/analogs & derivatives , Animals , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacokinetics , Antifungal Agents/chemistry , Antifungal Agents/pharmacokinetics , Antifungal Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , COVID-19/drug therapy , Cell Line, Tumor , Coronavirus 3C Proteases/chemistry , Galactose/chemistry , Galactose/pharmacokinetics , Galactose/pharmacology , Gram-Positive Bacteria/drug effects , Mice , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Dynamics Simulation , SARS-CoV-2/enzymology , Static Electricity , Thermodynamics
8.
Molecules ; 26(21)2021 Oct 20.
Article in English | MEDLINE | ID: covidwho-1512506

ABSTRACT

Three silver(I) dipeptide complexes [Ag(GlyGly)]n(NO3)n (AgGlyGly), [Ag2(GlyAla)(NO3)2]n (AgGlyAla) and [Ag2(HGlyAsp)(NO3)]n (AgGlyAsp) were prepared, investigated and characterized by vibrational spectroscopy (mid-IR), elemental and thermogravimetric analysis and mass spectrometry. For AgGlyGly, X-ray crystallography was also performed. Their stability in biological testing media was verified by time-dependent NMR measurements. Their in vitro antimicrobial activity was evaluated against selected pathogenic microorganisms. Moreover, the influence of silver(I) dipeptide complexes on microbial film formation was described. Further, the cytotoxicity of the complexes against selected cancer cells (BLM, MDA-MB-231, HeLa, HCT116, MCF-7 and Jurkat) and fibroblasts (BJ-5ta) using a colorimetric MTS assay was tested, and the selectivity index (SI) was identified. The mechanism of action of Ag(I) dipeptide complexes was elucidated and discussed by the study in terms of their binding affinity toward the CT DNA, the ability to cleave the DNA and the ability to influence numbers of cells within each cell cycle phase. The new silver(I) dipeptide complexes are able to bind into DNA by noncovalent interaction, and the topoisomerase I inhibition study showed that the studied complexes inhibit its activity at a concentration of 15 µM.


Subject(s)
Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Dipeptides/chemistry , Silver/chemistry , Anti-Infective Agents/chemical synthesis , Antineoplastic Agents/chemical synthesis , Cell Cycle/drug effects , Cell Line, Tumor , Chemical Phenomena , Chemistry Techniques, Synthetic , Coordination Complexes/chemical synthesis , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Stability , Humans , Molecular Conformation , Molecular Dynamics Simulation , Spectrum Analysis , Structure-Activity Relationship , Thermogravimetry
9.
Bioorg Chem ; 117: 105466, 2021 12.
Article in English | MEDLINE | ID: covidwho-1499653

ABSTRACT

Series of piperidone-salicylate conjugates were synthesized through the reaction of 3E,5E-bis(arylidene)-4-piperidones with the appropriate acid chloride of acetylsalicylate in the presence of triethylamine. All the synthesized conjugates reveal antiproliferative properties against A431 (squamous skin) cancer cell line with potency higher than that of 5-fluorouracil. Many of the synthesized agents also exhibit promising antiproliferative properties against HCT116 (colon) cancer cell line, of which 5o and 5c are the most effective with 12.9, 9.8 folds potency compared with Sunitinib. Promising activity is also shown against MCF7 (breast) cancer cell line with 1.19, 1.12 folds relative to 5-fluorouracil. PI-flow cytometry of compound 5c supports the arrest of cell cycle at G1-phase. However, compound 5o and Sunitinib arrest the cell cycle at S-phase. The synthesized conjugates can be considered as multi-targeted tyrosine kinase inhibitors due to the promising properties against VEGFR-2 and EGFR in MCF7 and HCT116. CDOCKER studies support the EGFR inhibitory properties. Compounds 5p and 5i possessing thienylidene heterocycle are anti-SARS-CoV-2 with high therapeutic indices. Many of the synthesized agents show enhanced COX-1/2 properties than aspirin with better selectivity index towards COX-2 relative to COX-1. The possible applicability of the potent candidates discovered as antitumor and anti-SARS-CoV-2 is supported by the safe profile against normal (non-cancer, RPE1 and VERO-E6) cells.


Subject(s)
Antineoplastic Agents/chemistry , Antiviral Agents/chemistry , Aspirin/chemistry , Curcumin/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , COVID-19/pathology , COVID-19/virology , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Cyclooxygenase 1/chemistry , Cyclooxygenase 1/metabolism , Cyclooxygenase 2/chemistry , Cyclooxygenase 2/metabolism , Drug Design , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Humans , Inhibitory Concentration 50 , Molecular Docking Simulation , Protein Binding , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/metabolism
10.
Mar Drugs ; 19(10)2021 Sep 22.
Article in English | MEDLINE | ID: covidwho-1480860

ABSTRACT

To discover the new medical entity from edible marine algae, our continuously natural product investigation focused on endophytes from marine macroalgae Grateloupia sp. Two new azaphilones, 8a-epi-hypocrellone A (1), 8a-epi-eupenicilazaphilone C (2), together with five known azaphilones, hypocrellone A (3), eupenicilazaphilone C (4), ((1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-2,4-dihydroxy-3-methylbenzaldehyde (5), sclerotiorin (6), and isochromophilone IV (7) were isolated from the alga-derived fungus Penicillium sclerotiorum. The structures of isolated azaphilones (1-7) were elucidated by spectrometric identification, especially HRESIMS, CD, and NMR data analyses. Concerning bioactivity, cytotoxic, anti-inflammatory, and anti-fibrosis activities of those isolates were evaluated. As a result, compound 1 showed selective toxicity toward neuroblastoma cell line SH-SY5Y among seven cancer and one fibroblast cell lines. 20 µM of compounds 1, 3, and 7 inhibited the TNF-α-induced NFκB phosphorylation but did not change the NFκB activity. Compounds 2 and 6 respectively promoted and inhibited SMAD-mediated transcriptional activities stimulated by TGF-ß.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents/pharmacology , Benzopyrans/pharmacology , Microalgae , Penicillium , Pigments, Biological/pharmacology , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Aquatic Organisms , Benzopyrans/chemistry , Benzopyrans/therapeutic use , Cell Line, Tumor/drug effects , Fibroblasts/drug effects , Functional Food , Neuroblastoma/drug therapy , Pigments, Biological/chemistry , Pigments, Biological/therapeutic use , Structure-Activity Relationship
11.
Int J Mol Sci ; 22(19)2021 Oct 02.
Article in English | MEDLINE | ID: covidwho-1463709

ABSTRACT

Cancer persists as a global challenge due to the extent to which conventional anticancer therapies pose high risks counterbalanced with their therapeutic benefit. Naturally occurring substances stand as an important safer alternative source for anticancer drug development. In the current study, a series of modified lupane and ursane derivatives was subjected to in vitro screening on the NCI-60 cancer cell line panel. Compounds 6 and 7 have been identified as highly active with GI50 values ranging from 0.03 µM to 5.9 µM (compound 6) and 0.18-1.53 µM (compound 7). Thus, these two compounds were further assessed in detail in order to identify a possible antiproliferative mechanism of action. DAPI (4',6-diamidino-2-phenylindole) staining revealed that both compounds induced nuclei condensation and overall cell morphological changes consistent with apoptotic cell death. rtPCR analysis showed that both compounds induced upregulation of proapoptotic Bak and Bad genes while downregulating Bcl-XL and Bcl-2 antiapoptotic genes. Molecular docking analysis revealed that both compounds exhibited high scores for Bcl-XL inhibition, while compound 7 showed higher in silico Bcl-XL inhibition potential as compared to the native inhibitor ATB-737, suggesting that compounds may induce apoptotic cell death through targeted antiapoptotic protein inhibition, as well.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Biological Products/pharmacology , Triterpenes/pharmacology , Angiogenesis Inhibitors , Antineoplastic Agents/chemistry , Binding Sites , Biological Products/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Models, Molecular , Molecular Conformation , Molecular Structure , Protein Binding , Structure-Activity Relationship , Triterpenes/chemistry
12.
Mar Drugs ; 18(10)2020 Sep 26.
Article in English | MEDLINE | ID: covidwho-1389432

ABSTRACT

For a long time, algal chemistry from terrestrial to marine or freshwater bodies, especially chlorophytes, has fascinated numerous investigators to develop new drugs in the nutraceutical and pharmaceutical industries. As such, chlorophytes comprise a diverse structural class of secondary metabolites, having functional groups that are specific to a particular source. All bioactive compounds of chlorophyte are of great interest due to their supplemental/nutritional/pharmacological activities. In this review, a detailed description of the chemical diversity of compounds encompassing alkaloids, terpenes, steroids, fatty acids and glycerides, their subclasses and their structures are discussed. These promising natural products have efficiency in developing new drugs necessary in the treatment of various deadly pathologies (cancer, HIV, SARS-CoV-2, several inflammations, etc.). Marine chlorophyte, therefore, is portrayed as a pivotal treasure in the case of drugs having marine provenience. It is a domain of research expected to probe novel pharmaceutically or nutraceutically important secondary metabolites resulting from marine Chlorophyta. In this regard, our review aims to compile the isolated secondary metabolites having diverse chemical structures from chlorophytes (like Caulerpa ssp., Ulva ssp., Tydemania ssp., Penicillus ssp., Codium ssp., Capsosiphon ssp., Avrainvillea ssp.), their biological properties, applications and possible mode of action.


Subject(s)
Biological Products/pharmacology , Chlorophyta/chemistry , Chlorophyta/metabolism , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Biological Products/chemistry , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Humans , Neoplasms/drug therapy , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , SARS-CoV-2
13.
Biol Aujourdhui ; 215(1-2): 25-43, 2021.
Article in French | MEDLINE | ID: covidwho-1358361

ABSTRACT

Targeted protein degradation (TPD), discovered twenty years ago through the PROTAC technology, is rapidly developing thanks to the implication of many scientists from industry and academia. PROTAC chimeras are heterobifunctional molecules able to link simultaneously a protein to be degraded and an E3 ubiquitin ligase. This allows the protein ubiquitination and its degradation by 26S proteasome. PROTACs have evolved from small peptide molecules to small non-peptide and orally available molecules. It was shown that PROTACs are capable to degrade proteins considered as "undruggable" i.e. devoid of well-defined pockets and deep grooves possibly occupied by small molecules. Among these "hard to drug" proteins, several can be degraded by PROTACs: scaffold proteins, BAF complex, transcription factors, Ras family proteins. Two PROTACs are clinically tested for breast (ARV471) and prostate (ARV110) cancers. The protein degradation by proteasome is also induced by other types of molecules: molecular glues, hydrophobic tagging (HyT), HaloPROTACs and homo-PROTACs. Other cellular constituents are eligible to induced degradation: RNA-PROTACs for RNA binding proteins and RIBOTACs for degradation of RNA itself (SARS-CoV-2 RNA). TPD has recently moved beyond the proteasome with LYTACs (lysosome targeting chimeras) and MADTACs (macroautophagy degradation targeting chimeras). Several techniques such as screening platforms together with mathematical modeling and computational design are now used to improve the discovery of new efficient PROTACs.


TITLE: Dégradation induite des protéines par des molécules PROTAC et stratégies apparentées : développements à visée thérapeutique. ABSTRACT: Alors que, pour la plupart, les médicaments actuels sont de petites molécules inhibant l'action d'une protéine en bloquant un site d'interaction, la dégradation ciblée des protéines, découverte il y a une vingtaine d'années via les petites molécules PROTAC, connaît aujourd'hui un très grand développement, aussi bien au niveau universitaire qu'industriel. Cette dégradation ciblée permet de contrôler la concentration intracellulaire d'une protéine spécifique comme peuvent le faire les techniques basées sur les acides nucléiques (oligonucléotides antisens, ARNsi, CRISPR-Cas9). Les molécules PROTAC sont des chimères hétéro-bifonctionnelles capables de lier simultanément une protéine spécifique devant être dégradée et une E3 ubiquitine ligase. Les PROTAC sont donc capables de provoquer l'ubiquitinylation de la protéine ciblée et sa dégradation par le protéasome 26S. De nature peptidique, puis non peptidique, les PROTAC sont maintenant administrables par voie orale. Ce détournement du système ubiquitine protéasome permet aux molécules PROTAC d'élargir considérablement le champ des applications thérapeutiques puisque l'élimination de protéines dépourvues de poches ou de crevasses bien définies, dites difficiles à cibler, devient possible. Cette technologie versatile a conduit à la dégradation d'une grande variété de protéines comme des facteurs de transcription, des sérine/thréonine/tyrosine kinases, des protéines de structure, des protéines cytosoliques, des lecteurs épigénétiques. Certaines ligases telles que VHL, MDM2, cereblon et IAP sont couramment utilisées pour être recrutées par les PROTAC. Actuellement, le nombre de ligases pouvant être utilisées ainsi que la nature des protéines dégradées sont en constante augmentation. Deux PROTAC sont en étude clinique pour les cancers du sein (ARV471) et de la prostate (ARV110). La dégradation spécifique d'une protéine par le protéasome peut aussi être induite par d'autres types de molécules synthétiques : colles moléculaires, marqueurs hydrophobes, HaloPROTAC, homo-PROTAC. D'autres constituants cellulaires sont aussi éligibles à une dégradation induite : ARN-PROTAC pour les protéines se liant à l'ARN et RIBOTAC pour la dégradation de l'ARN lui-même comme celui du SARS-CoV-2. Des dégradations induites en dehors du protéasome sont aussi connues : LYTAC, pour des chimères détournant la dégradation de protéines extracellulaires vers les lysosomes, et MADTAC, pour des chimères détournant la dégradation par macroautophagie. Plusieurs techniques, en particulier des plates-formes de criblage, la modélisation mathématique et la conception computationnelle sont utilisées pour le développement de nouveaux PROTAC efficaces.


Subject(s)
COVID-19/drug therapy , Drug Design , Molecular Targeted Therapy/methods , Proteolysis , Recombinant Fusion Proteins/pharmacology , SARS-CoV-2/drug effects , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Autophagy , Catalysis , Humans , Lysosomes/metabolism , Neoplasm Proteins/antagonists & inhibitors , Neoplasms/drug therapy , Proteasome Endopeptidase Complex/metabolism , Protein Conformation , Protein Processing, Post-Translational/drug effects , Protein Stability , Proteolysis/drug effects , RNA/drug effects , RNA-Binding Proteins/antagonists & inhibitors , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/pharmacokinetics , Structure-Activity Relationship , Ubiquitin-Protein Ligases/metabolism , Ubiquitination
14.
Biomolecules ; 11(7)2021 07 16.
Article in English | MEDLINE | ID: covidwho-1323103

ABSTRACT

Cyclooxygenase-2 (COX-2) is an important enzyme involved in prostaglandins biosynthesis from arachidonic acid. COX-2 is frequently overexpressed in human cancers and plays a major tumor promoting function. Accordingly, many efforts have been devoted to efficiently target the catalytic site of this enzyme in cancer cells, by using COX-2 specific inhibitors such as celecoxib. However, despite their potent anti-tumor properties, the myriad of detrimental effects associated to the chronic inhibition of COX-2 in healthy tissues, has considerably limited their use in clinic. In addition, increasing evidence indicate that these anti-cancerous properties are not strictly dependent on the inhibition of the catalytic site. These findings have led to the development of non-active COX-2 inhibitors analogues aiming at preserving the antitumor effects of COX-2 inhibitors without their side effects. Among them, two celecoxib derivatives, 2,5-Dimethyl-Celecoxib and OSU-03012, have been developed and suggested for the treatment of viral (e.g., recently SARS-CoV-2), inflammatory, metabolic diseases and cancers. These molecules display stronger anti-tumor properties than celecoxib and thus may represent promising anti-cancer molecules. In this review, we discuss the impact of these two analogues on cancerous processes but also their potential for cancer treatment alone or in combination with existing approaches.


Subject(s)
Antineoplastic Agents/therapeutic use , Celecoxib/therapeutic use , Cyclooxygenase 2 Inhibitors/therapeutic use , Neoplasms/drug therapy , Pyrazoles/therapeutic use , Sulfonamides/therapeutic use , Animals , Antineoplastic Agents/adverse effects , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Celecoxib/adverse effects , Celecoxib/analogs & derivatives , Celecoxib/pharmacology , Cell Cycle/drug effects , Cyclooxygenase 2 Inhibitors/adverse effects , Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2 Inhibitors/pharmacology , Humans , Pyrazoles/adverse effects , Pyrazoles/chemistry , Pyrazoles/pharmacology , Sulfonamides/adverse effects , Sulfonamides/chemistry , Sulfonamides/pharmacology
15.
Molecules ; 26(13)2021 Jun 23.
Article in English | MEDLINE | ID: covidwho-1295887

ABSTRACT

A possible inhibitor of proteases, which contains an indole core and an aromatic polar acetylene, was designed and synthesized. This indole derivative has a molecular architecture kindred to biologically relevant species and was obtained through five synthetic steps with an overall yield of 37% from the 2,2'-(phenylazanediyl)di(ethan-1-ol). The indole derivative was evaluated through docking assays using the main protease (SARS-CoV-2-Mpro) as a molecular target, which plays a key role in the replication process of this virus. Additionally, the indole derivative was evaluated as an inhibitor of the enzyme kallikrein 5 (KLK5), which is a serine protease that can be considered as an anticancer drug target.


Subject(s)
Acetylene/chemistry , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Indoles/chemistry , Protease Inhibitors/chemistry , Protease Inhibitors/chemical synthesis , SARS-CoV-2/enzymology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Drug Discovery , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Kallikreins/antagonists & inhibitors , Models, Molecular , Molecular Docking Simulation , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects
16.
Int J Mol Sci ; 22(12)2021 Jun 18.
Article in English | MEDLINE | ID: covidwho-1282514

ABSTRACT

Nanotechnology is an important application in modern cancer therapy. In comparison with conventional drug formulations, nanoparticles ensure better penetration into the tumor mass by exploiting the enhanced permeability and retention effect, longer blood circulation times by a reduced renal excretion and a decrease in side effects and drug accumulation in healthy tissues. The most significant classes of nanoparticles (i.e., liposomes, inorganic and organic nanoparticles) are here discussed with a particular focus on their use as delivery systems for small molecule tyrosine kinase inhibitors (TKIs). A number of these new compounds (e.g., Imatinib, Dasatinib, Ponatinib) have been approved as first-line therapy in different cancer types but their clinical use is limited by poor solubility and oral bioavailability. Consequently, new nanoparticle systems are necessary to ameliorate formulations and reduce toxicity. In this review, some of the most important TKIs are reported, focusing on ongoing clinical studies, and the recent drug delivery systems for these molecules are investigated.


Subject(s)
Antineoplastic Agents/pharmacology , Nanotechnology , Protein Kinase Inhibitors/pharmacology , Theranostic Nanomedicine , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Clinical Trials as Topic , Drug Compounding , Drug Evaluation, Preclinical , Humans , Nanoparticles/chemistry , Neoplasms/diagnosis , Neoplasms/drug therapy , Neoplasms/etiology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Structure-Activity Relationship , Treatment Outcome
17.
Mol Biol Rep ; 48(5): 4757-4765, 2021 May.
Article in English | MEDLINE | ID: covidwho-1240047

ABSTRACT

Recently, special attention has been paid to marine origin compounds such as carbohydrates, peptides, lipids, and carotenoids, which are extracted from microalgae and have anticancer, anti-inflammatory, antimicrobial (e.g., anti-COVID-19 activity), and antioxidant properties in biomedicine and pharmaceutical biotechnology. In addition, these photosynthetic marine microorganisms have several applications in biotechnology and are suitable hosts for the production of recombinant proteins/peptides, such as monoclonal antibodies and vaccines. Silica-based nanoparticles obtained from diatoms (a microalgae group) are used as drug delivery carriers owing to their biodegradability, easy functionalization, low cost, and simple features compared to synthetics, which make these agents proper alternatives for synthetic silica nanoparticles. Therefore, diatom-based nanoparticles are a viable option for the delivery of anti-cancer drugs and reducing the side-effects of cancer chemotherapy.


Subject(s)
Biological Factors/pharmacology , Microalgae/chemistry , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Biological Factors/chemistry , Drug Carriers , Nanoparticles , Photosynthesis
18.
Molecules ; 25(22)2020 Nov 11.
Article in English | MEDLINE | ID: covidwho-917015

ABSTRACT

Flavonoids are phytochemical compounds present in many plants, fruits, vegetables, and leaves, with potential applications in medicinal chemistry. Flavonoids possess a number of medicinal benefits, including anticancer, antioxidant, anti-inflammatory, and antiviral properties. They also have neuroprotective and cardio-protective effects. These biological activities depend upon the type of flavonoid, its (possible) mode of action, and its bioavailability. These cost-effective medicinal components have significant biological activities, and their effectiveness has been proved for a variety of diseases. The most recent work is focused on their isolation, synthesis of their analogs, and their effects on human health using a variety of techniques and animal models. Thousands of flavonoids have been successfully isolated, and this number increases steadily. We have therefore made an effort to summarize the isolated flavonoids with useful activities in order to gain a better understanding of their effects on human health.


Subject(s)
Flavonoids/chemistry , Flavonoids/pharmacology , Alzheimer Disease/drug therapy , Alzheimer Disease/prevention & control , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Antimalarials/chemistry , Antimalarials/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antioxidants/chemistry , Antioxidants/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cardiovascular System/drug effects , Flavonoids/economics , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Mice , Nervous System/drug effects , Neurons/drug effects , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Plant Extracts/pharmacology , Plant Leaves/chemistry , Plants/chemistry , Polyphenols/chemistry , Polyphenols/pharmacology , Quercetin/chemistry , Quercetin/pharmacology , Rats , Rats, Sprague-Dawley , Rats, Wistar , Stroke/drug therapy , Stroke/prevention & control
19.
Bioorg Med Chem ; 32: 115973, 2021 02 15.
Article in English | MEDLINE | ID: covidwho-1064894

ABSTRACT

Amongst heterocyclic compounds, quinoline is an advantaged scaffold that appears as a significant assembly motif for the development of new drug entities. Quinoline and its derivatives tested with diverse biological activity constitute an important class of compounds for new drug development. Therefore, many scientific communities have developed these compounds as intent structure and evaluated their biological activities. The present, review provides brief natural sources of quinoline and including a new extent of quinoline-based marketed drugs. This review also confers information about the biological activities of quinoline derivatives such as antibacterial, antifungal, antimycobacterial, antiviral, anti-protozoal, antimalarial, anticancer, cardiovascular, CNS effects, antioxidant, anticonvulsant, analgesic, anti-inflammatory, anthelmintic and miscellaneous activities.


Subject(s)
Analgesics/pharmacology , Anti-Infective Agents/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antineoplastic Agents/pharmacology , Antioxidants/pharmacology , Antiprotozoal Agents/pharmacology , Analgesics/chemistry , Anti-Infective Agents/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Antineoplastic Agents/chemistry , Antioxidants/chemistry , Antiprotozoal Agents/chemistry , Humans , Molecular Structure , Quinolines/chemistry , Quinolines/pharmacology
20.
Biomed Pharmacother ; 134: 111017, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1064876

ABSTRACT

Myricetin(MYR) is a flavonoid compound widely found in many natural plants including bayberry. So far, MYR has been proven to have multiple biological functions and it is a natural compound with promising research and development prospects. This review comprehensively retrieved and collected the latest pharmacological abstracts on MYR, and discussed the potential molecular mechanisms of its effects. The results of our review indicated that MYR has a therapeutic effect on many diseases, including tumors of different types, inflammatory diseases, atherosclerosis, thrombosis, cerebral ischemia, diabetes, Alzheimer's disease and pathogenic microbial infections. Furthermore, it regulates the expression of Hippo, MAPK, GSK-3ß, PI3K/AKT/mTOR, STAT3, TLR, IκB/NF-κB, Nrf2/HO-1, ACE, eNOS / NO, AChE and BrdU/NeuN. MYR also enhances the immunomodulatory functions, suppresses cytokine storms, improves cardiac dysfunction, possesses an antiviral potential, can be used as an adjuvant treatment against cancer, cardiovascular injury and nervous system diseases, and it may be a potential drug against COVID-19 and other viral infections. Generally, this article provides a theoretical basis for the clinical application of MYR and a reference for its further use.


Subject(s)
Biomedical Research/trends , Flavonoids/pharmacology , Inflammation Mediators/antagonists & inhibitors , Inflammation Mediators/metabolism , Animals , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Biomedical Research/methods , Cell Proliferation/drug effects , Cell Proliferation/physiology , Flavonoids/chemistry , Humans
SELECTION OF CITATIONS
SEARCH DETAIL