RESUMO
Anti-angiogenesis targeting vascular endothelial growth factor receptor 2 (VEGFR2) has emerged as a vital tool for cancer treatment. In this study, a new series of biphenylurea/thiourea derivatives tagged with heteroarylsulfonamide motifs (3a-l) was designed and synthesized as novel VEGFR2 inhibitors. The biochemical profiles of the target compounds were investigated using viability of human umbilical vascular endothelial cells (HUVECs), migration assay and Western blot using sorafenib as reference antiangiogenic drug. Most of the tested compounds exhibited significant antiproliferative activity against HUVECs, where compounds 3a, 3e, 3g, 3h and 3l exhibited better antiproliferative activity than sorafenib. All compounds significantly inhibited VEGF stimulated migration of HUVECs at 10 µM dose with (3a, 3e, 3g, 3h and 3l) showing better or comparable inhibitory activities to that of sorafenib. Moreover, Western blotting analysis confirmed antiangiogenic effect of those compounds with significant reduction in the level of VEGFR-2 compared to sorafenib. Finally, cytotoxicity screening of these derivatives against four cancer cells and RPE1 as normal cell line was performed. The mechanistic effectiveness in cell cycle progression and apoptotic induction were evaluated for the promising compound 3e due to its remarkable cytotoxic activity against tested cancer cell lines and significant VEGFR-2 inhibition. Flow cytometric analysis showed that compound 3e induced cell growth arrest at G2/M phase and stimulated the apoptotic death of HepG2 cells.
Assuntos
Inibidores da Angiogênese/síntese química , Desenho de Fármacos , Inibidores de Proteínas Quinases/síntese química , Sulfonamidas/química , Tioureia/análogos & derivados , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/metabolismo , Inibidores da Angiogênese/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Sorafenibe/farmacologia , Relação Estrutura-Atividade , Tioureia/metabolismo , Tioureia/farmacologia , Fator A de Crescimento do Endotélio Vascular/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Sets of 3-alkenyl-2-oxindoles (6,10,13) were synthesized in a facile synthetic pathway through acid dehydration (EtOH/HCl) of the corresponding 3-hydroxy-2-oxoindolines (5,9,12). Single crystal (10a,c) and powder (12a,26f) X-ray studies supported the structures. Compounds 6c and 10b are the most effective agents synthesized (about 3.4, 3.3 folds, respectively) against PaCa2 (pancreatic) cancer cell line relative to the standard reference used (Sunitinib). Additionally, compound 10b reveals antiproliferative properties against MCF7 (breast) cancer cell with IC50 close to that of Sunitinib. CAM testing reveals that compounds 6 and 10 demonstrated qualitative and quantitative decreases in blood vessel count and diameter with efficacy comparable to that of Sunitinib, supporting their anti-angiogenic properties. Kinase inhibitory properties support their multi-targeted inhibitory activities against VEGFR-2 and c-kit in similar behavior to that of Sunitinib. Cell cycle analysis studies utilizing MCF7 exhibit that compound 6b arrests the cell cycle at G1/S phase while, 10b reveals accumulation of the tested cell at S phase. Compounds 6a and 10b reveal potent antiviral properties against SARS-CoV-2 with high selectivity index relative to the standards (hydroxychloroquine, chloroquine). Safe profile of the potent synthesized agents, against normal cells (VERO-E6, RPE1), support the possible development of better hits based on the attained observations.
Assuntos
Antineoplásicos/farmacologia , Antivirais/síntese química , Oxindóis/síntese química , SARS-CoV-2/efeitos dos fármacos , Animais , Antivirais/farmacologia , Ciclo Celular , Linhagem Celular Tumoral , Embrião de Galinha , Chlorocebus aethiops , Humanos , Oxindóis/farmacologia , Células Vero , Tratamento Farmacológico da COVID-19RESUMO
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.
Assuntos
Antineoplásicos/química , Antivirais/química , Aspirina/química , Curcumina/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antivirais/metabolismo , Antivirais/farmacologia , COVID-19/patologia , COVID-19/virologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Desenho de Fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Ligação Proteica , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/isolamento & purificação , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
New functionalized acrylamide derivatives bearing sulfisoxazole moiety were designed to target bacterial dihydropteroate synthase (DHPS). The in vitro antimicrobial activities of these compounds were assessed. The E-configuration of compound 5b was proved by single crystal X-ray analysis. Compounds 5g and 5h displayed double the activity of ampicillin against B. subtilis. Also, 5h was two times more active than gentamycin against E. coli. Interestingly, compounds 5f-g, 7c, 8a, 8c exhibited two folds the potency of amphotericin B against S. racemosum while 5h displayed three folds the activity of amphotericin B against S. racemosum. Most of the synthesized compounds showed superior activities to the parent sulfisoxazole and were non-toxic to normal cells. DHPS is confirmed to be a putative target for our compounds via antagonizing their antibacterial activity by the folate precursor (p-aminobenzoic acid) and product (methionine) on E. coli ATCC 25922. Docking experiments against DHPS rationalized the observed antibacterial activity. Additionally, compound 5g was evaluated as a selective targeting vector for 99mTc that showed a remarkable uptake and targeting ability towards the infection site that was induced in mice.
Assuntos
Acrilamida/farmacologia , Antibacterianos/farmacologia , Di-Hidropteroato Sintase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Sulfisoxazol/farmacologia , Acrilamida/química , Antibacterianos/síntese química , Antibacterianos/química , Células Cultivadas , Di-Hidropteroato Sintase/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/crescimento & desenvolvimento , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Sulfisoxazol/químicaRESUMO
A series of N-substituted (Z)-2-imino-(5Z)-ylidene thiazolidines/thiazolidin-4-ones were synthesized and their antiproliferative activities against colon (HCT-116) and breast (MCF7) cancer cell lines were evaluated utilizing an MTT growth assay. A 2D-QSAR investigation was conducted to probe and validate the obtained antiproliferative properties for the thiazolidine derivatives. The majority of the thiazolidines exhibit higher potency against a colon cancer cell line relative to the standard reference. The p-halophenylimino p-anisylidene derivatives exhibited the highest anti-proliferative activity against HCT116 relative to control (IC50â¯=â¯8.9-10.0⯵M compared to 20.4⯵M observed for 5-fluorouracil as positive control). An X-ray study confirmed the Z, Z'-configurations for two examples of the synthesized compounds.
Assuntos
Antineoplásicos/farmacologia , Relação Quantitativa Estrutura-Atividade , Tiazolidinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Tiazolidinas/síntese química , Tiazolidinas/químicaRESUMO
Marine organisms have been considered as the richest sources of novel bioactive metabolites, which can be used for pharmaceutical purposes. In the last years, the interest for marine microorganisms has grown for their enormous biodiversity and for the evidence that many novel compounds isolated from marine invertebrates are really synthesized by their associated bacteria. Nevertheless, the discovery of a chemical communication Quorum sensing (QS) between bacterial cells and between bacteria and host has gained the researchers to expand the aim of their study toward the role of bacteria associated with marine invertebrates, such as marine sponge. In the present paper, we report the evaluation of biological activities of different extracts of bacteria Vibrio sp. and Bacillus sp. associated with marine sponges Dysidea avara and Ircinia variabilis, respectively. Moreover, we evaluated the biological activities of some diketopiperazines (DKPs), previously isolated, and able to activate QS mechanism. The results showed that all extracts, fractions, and DKPs showed low scavenging activity against DPPH and superoxide anion, low cytotoxic and anti-tyrosinase activities, but no antimicrobial and acetylcholinesterase inhibitory activities. One DKP [cyclo-(trans-4-hydroxy-L-prolyl-L-leucine)] has the highest α-glucosidase inhibitory activity even than the standard acarbose.
Assuntos
Bactérias/química , Dicetopiperazinas/farmacologia , Poríferos/microbiologia , Animais , Antioxidantes/química , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Biodiversidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dicetopiperazinas/análise , Dicetopiperazinas/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Glucosidases/análise , Glucosidases/antagonistas & inibidores , HumanosRESUMO
Cancer is a leading cause of death in several countries. In the search for new anticancer drugs, marine organisms have played an important role in the discovery of lead compounds and the development of new pharmaceuticals for their wide diversity of chemical structures and biological activities. In the present study, the cytotoxicity on colorectal cancer cells HCT116 exerted by marine fungus Aspergillus sp. 2C1-EGY extracts associated with the soft coral Sinularia sp. was investigated; the sub-fractions Fr 2c and Fr 2d had significantly high cytotoxic activity (88 and 85%, respectively). Moreover, the major hexadecanoic, octadecanoic, and octadecenoic acids as well as their methyl esters were isolated. GC/MS analysis revealed the identification of 46 major and minor compounds, from which 19 saturated and unsaturated fatty acids and eight fatty acid esters were identified.
Assuntos
Antozoários/microbiologia , Antineoplásicos/farmacologia , Aspergillus/química , Produtos Biológicos/farmacologia , Animais , Antineoplásicos/química , Aspergillus/classificação , Aspergillus/genética , Produtos Biológicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Espectroscopia de Ressonância Magnética , Filogenia , RNA Ribossômico 18S/genéticaRESUMO
Cancer remains a formidable global health challenge, with current treatment modalities such as chemotherapy, radiotherapy, surgery, and targeted therapy often hindered by low efficacy and adverse side effects. The indole scaffold, a prominent heterocyclic structure, has emerged as a promising candidate in the fight against cancer. This review consolidates recent advancements in developing natural and synthetic indolyl analogs, highlighting their antiproliferative activities against various cancer types over the past five years. These analogs are categorized based on their efficacy against common cancer types, supported by biochemical assays demonstrating their antiproliferative properties. In this review, emphasis is placed on elucidating the mechanisms of action of these compounds. Given the limitations of conventional cancer therapies, developing targeted therapeutics with enhanced selectivity and reduced side effects remains a critical focus in oncological research.
RESUMO
CONTEXT: This study is a continuation of our previous work in which a bioassay screening of 346 methanol extracts from 281 Egyptian plant species was carried out for in vitro schistosomicidal activity. OBJECTIVE: Another 309 methanol extracts from 278 plant species were subjected to the bioassay screening using the same technique on viable Schistosoma mansoni Sambon (Schistosomatidae) mature worms in specialized culture medium (Roswell Park Memorial Institute medium 1640) in a trial to discover a source for a schistosomiasis drug from Egyptian flora. MATERIAL AND METHODS: The methanol plant extracts were tested in vitro against viable S. mansoni mature worms in culture medium. Viability of worms was examined after exposure to 100 µg/ml of the extract in the medium for 24 h. Negative (dimethyl sulfoxide) and positive (praziquantel) controls were simultaneously used. Extracts showing schistosomicidal activity were further subjected to determination of their (Lethal concentration) LC50 and LC90 values. RESULTS: Confirmed in vitro antischistosomal activity was found in 42 extracts. Of these, 14 plant species possessed considerably high antischistosomal activity (LC50 ≤ 15 µg/ml), viz. Callistemon viminalis (Soland. Ex Gaertn) Cheel, C. rigidus R.Br., C. speciosus (Sims.) DC, C. citrinus Stapf, Eucalyptus citriodora Hook, E. rostrata Dehnh., Eugenia edulis Vell, E. javanica Lam syn. Syzygium samarangense (Blume) Merril, Melaleuca leucadendron (L.) L., M. stypheloides Sm. (all belong to Myrtaceae), Cryptostegia grandiflora R.Br. (Asclepiadaceae), Zilla spinosa (L.) Prantl (Cruciferae), Ficus trijuja L. (Moraceae) and Fagonia mollis Delile (Zygophylacae). DISCUSSION AND CONCLUSION: These species may represent additional natural sources of bioactive material that deserve further investigation for drug discovery against schistosomiasis.
Assuntos
Descoberta de Drogas , Extratos Vegetais/farmacologia , Plantas/química , Schistosoma mansoni/efeitos dos fármacos , Esquistossomicidas/farmacologia , Animais , Egito , Feminino , Concentração Inibidora 50 , Masculino , Metanol/química , Myrtaceae/química , Componentes Aéreos da Planta/química , Extratos Vegetais/isolamento & purificação , Schistosoma mansoni/crescimento & desenvolvimento , Esquistossomicidas/isolamento & purificação , Solventes/químicaRESUMO
The goal of this work was to design nude bilosomes (Bil) and D-alpha-tocopheryl polyethylene glycol succinate (TPGS) surface coated bilosomes as an oral delivery platform for improving the antitumor activity and poor oral permeability of Curcumin (CUR). Twelve different formulae were acquired from 31.22 factorial analysis considering different independent variables: bile salt type; Sodium taurocholate (STC) or Sodium cholate (SC) and weight percent; 1% or 5 % W/W, both at 2 levels respectively, while Span 60:Cholesterol ratio at 3 levels (1:1, 5:1, 9:1). Following optimization, the selected optimum formula was picked up based on the favorable minimum particle size (187.2 ± 2.2 nm), maximum zeta potential value (-41.3 ± 2.2 mV) and maximum entrapment efficiency (93.4 ± 5.1%) which was further coated with TPGS. The mean fluorescence intensity (MFI) of CUR permeated from the optimum TPGS-F7 and CUR-Bil (F7) formulae exhibited 6.6 and 3.4 folds increase respectively adopting ex-vivo duodenal permeation assay relative to that of CUR suspension. Moreover, the cellular uptake efficiency via the established Caco-2 cells revealed that the uptake of CUR was 61.9 ± 5.3% and 34.76 ± 0.61% from TPGS-F7 and CUR-Bil (F7) relative to the uptake efficiency of CUR suspension (7.4 ± 2.12%). Coherently, TPGS-CUR-Bil showed excellent response expressed in dominant reduction in IC50 value (2.8 ± 0.07 µg/ml) against multidrug resistant (MDR) tumors following 48 h incubation of Doxorubicin Resistant Breast Cancer (MCF-7/ADR) cell lines.
Assuntos
Antineoplásicos , Neoplasias da Mama , Curcumina , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Células CACO-2 , Curcumina/farmacologia , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Feminino , Humanos , Células MCF-7 , Tamanho da Partícula , Polietilenoglicóis/uso terapêutico , Vitamina E , alfa-TocoferolRESUMO
A series of 1â³-(alkylsulfonyl)-dispiro[indoline-3,2'-pyrrolidine-3',3â³-piperidine]-2,4â³-diones 6aâo has been synthesized through regioselective multi-component azomethine dipolar cycloaddition reaction of 1-(alkylsulfonyl)-3,5-bis(ylidene)-piperidin-4-ones 3aâh. X-ray diffraction studies (6bâd,h) confirmed the structures. The majority of the synthesized analogs reveal promising antiproliferation properties against a variety of human cancer cell lines (MCF7, HCT116, A431 and PaCa2) with good selectivity index towards normal cell (RPE1). Some of the synthesized agents exhibit potent inhibitory properties against the tested cell lines with higher efficacies than the standard references (sunitinib and 5-fluorouracil). Compound 6m is the most potent. Multi-targeted inhibitory properties against EGFR and VEGFR-2 have been observed for the synthesized agents. Flow cytometry supports the antiproliferation properties and shows the tested agents as apoptosis and necrosis forming. Vero cell viral infection model demonstrates the anti-SARS-CoV-2 properties of the synthesized agents. Compound 6f is the most promising (about 3.3 and 4.8 times the potency of the standard references, chloroquine and hydroxychloroquine). QSAR models explain and support the observed biological properties.
Assuntos
Antineoplásicos , Tratamento Farmacológico da COVID-19 , Compostos de Espiro , Antineoplásicos/química , Linhagem Celular Tumoral , Humanos , Indóis , Estrutura Molecular , SARS-CoV-2 , Compostos de Espiro/química , Compostos de Espiro/farmacologiaRESUMO
Three sets of isatin-based Schiff bases were synthesized utilizing the molecular hybridization approach. Some of the synthesized Schiff bases show significant to moderate antiproliferative properties against MCF7 (breast), HCT116 (colon), and PaCa2 (pancreatic) cancer cell lines with potency compared to reference drugs 5-fluorouracil (5-FU) and Sunitinib. Among all, compound 17 f (3-((1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)imino)-1-((1-(2-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-methylindolin-2-one) exhibits promising antiproliferative properties against the MCF7 cancer cell line with 2.1-fold more potency than Sunitinib. However, among all the synthesized compounds, three (5-methylisatin derivatives) were the most effective against HCT116 in comparison to 5-FU. Compound 17 f exhibited the highest anti-angiogenic effect on the vasculature as it significantly reduced BV from 43â mm to 2â mm in comparison to 5.7â mm for Sunitinib and flow cytometry supports the arrest of the cell cycle at G1/S phases. In addition, compound 17 f also showed high VEGFR-2 inhibition properties against breast cancer cell lines. Robust 2D-QSAR studies supported the biological data.
Assuntos
Antineoplásicos , Isatina , Fluoruracila/farmacologia , Humanos , Relação Quantitativa Estrutura-Atividade , Bases de Schiff/farmacologia , Sunitinibe , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
A high-throughput screen of the cytotoxic activity of 2000 molecules from a commercial library in three human colon cancer cell lines and two normal cell types identified the acridine acriflavin to be a colorectal cancer (CRC) active drug. Acriflavine was active in cell spheroids, indicating good drug penetration and activity against hypoxic cells. In a validation step based on primary cultures of patient tumor cells, acriflavine was found to be more active against CRC than ovarian cancer and chronic lymphocytic leukemia. This contrasted to the activity pattern of the CRC active standard drugs 5-fluorouracil, irinotecan and oxaliplatin. Mechanistic studies indicated acriflavine to be a dual topoisomerase I and II inhibitor. In conclusion, the strategy used seems promising for identification of new diagnosis-specific cancer drugs.
Assuntos
Acriflavina/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase II/farmacologia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Fluoruracila/farmacologia , Ensaios de Triagem em Larga Escala , Humanos , Irinotecano , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Masculino , Compostos Organoplatínicos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , OxaliplatinaRESUMO
BACKGROUND: Bacterial infections are considered as one of the major global health threats, so it is very essential to design and develop new antibacterial agents to overcome the drawbacks of existing antibacterial agents. METHODS: The aim of this work is to synthesize a series of new fluoroquinolone-3-carboxamide amino acid conjugates by molecular hybridization. We utilized benzotriazole chemistry to synthesize the desired hybrid conjugates. RESULTS: All the conjugates were synthesized in good yields, characterized, evaluated for their antibacterial activity. The compounds were screened for their antibacterial activity using methods adapted from the Clinical and Laboratory Standards Institute. Synthesized conjugates were tested for activity against medically relevant pathogens; Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27856) Staphylococcus aureus (ATCC 25923) and Enterococcus faecalis (ATCC 19433). CONCLUSION: The observed antibacterial experimental data indicates the selectivity of our synthesized conjugates against E.Coli. The protecting group on amino acids decreases the antibacterial activity. The synthesized conjugates are non-toxic to the normal cell lines. The experimental data were supported by computational studies.
Assuntos
Aminoácidos/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Fluoroquinolonas/síntese química , Fluoroquinolonas/farmacologia , Modelos Moleculares , Antibacterianos/química , Linhagem Celular , Técnicas de Química Sintética , Fluoroquinolonas/química , Testes de Sensibilidade Microbiana , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
Most of the currently used cancer therapeutics are natural products. These agents were generally discovered based on their toxicity to tumour cells using various bioassays. Although the exact mechanisms of action of the most commonly used cancer therapeutics such as anthracyclins, podophyllotoxins and camptothecin are incompletely understood, it is becoming increasingly clear that these agents often show complex modes of action at the cellular level, interacting with numerous targets. Such complex modes of action may be the very reason for clinical efficacy. For discovering new cytotoxic anticancer drugs sophisticated screening methods were used. The principles of such screening projects conducted, using collections of purified natural products or extracts from plants have been described. By performing simple but robust prescreening tests such as the brine shrimp assay, bioactive extracts can be identified. Extracts (65) prepared from a collection of Egyptian plants were identified that showed cytotoxity on HepG2 cells. Interestingly, 22 (33%) of these raw extracts, induced > 2-fold induction of caspase-cleavage activity in a colon carcinoma cell line, consistent with induction of apoptosis. Only a fraction of the diversity of the biosphere has been tested for biological activity and novel cancer therapeutics remains to be discovered.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Extratos Vegetais/farmacologia , Antineoplásicos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Caspases/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Ativação Enzimática/efeitos dos fármacos , Células HCT116 , Células Hep G2 , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Extratos Vegetais/química , Especificidade da EspécieRESUMO
Photodynamic therapy (PDT) is a non-invasive treatment strategy that includes the combination of three components-a photosensitizer, a light source, and tissue oxygen. PDT can be used for the treatment of skin diseases such as squamous cell carcinoma. The photosensitizer used in this study is the naturally derived chlorophyll derivative chlorin e6 (Ce6), which was encapsulated in ultradeformable ethosomes. Singlet oxygen production by Ce6 upon laser light irradiation was not significantly affected by encapsulation into ethosomes. PDT of squamous cell carcinoma cells treated with Ce6 ethosomes triggered increased mitochondrial superoxide levels and increased caspase 3/7 activity, resulting in concentration- and light-dose-dependent cytotoxicity. Ce6 ethosomes showed good penetration into 3D squamous cell carcinoma spheroids, which upon laser light irradiation exhibited reduced size, proliferation, and viability. The PDT effect of Ce6 ethosomes was specific and showed higher cytotoxicity against squamous cell carcinoma spheroids compared to normal skin fibroblast spheroids. In addition, PDT treatment of squamous cell carcinoma xenografts grown on chorioallantoic membranes of chick eggs (CAM) exhibited reduced expression of Ki-67 proliferation marker and increased terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining, indicating reduced proliferation and activation of apoptosis, respectively. The results demonstrate that Ce6-loaded ethosomes represent a convenient formulation for photodynamic treatment of squamous cell carcinoma.
RESUMO
A set of dispiro[indoline-3,2'-pyrrolidine-3',3''-pyrrolidines] 8a-l was regioselectively synthesized utilizing multi-component azomethine cycloaddition reaction of 3-(arylmethylidene)pyrrolidine-2,5-diones 5a-e, isatins 6a-c and sarcosine 7. Single crystal X-ray studies of 8c add conclusive support for the structure. Compounds 8e and 8g reveal cholinesterase inhibitory properties with promising efficacy against both AChE and BChE and were found to be more selective towards AChE than BChE as indicted by the selectivity index like Donepezil (a clinically used cholinesterase inhibitory drug). Molecular modeling studies assist in understanding the bio-observations and identifying the responsible parameters behind biological properties.
RESUMO
A series of new fluoroquinolone conjugates 8a-g and 9a-f were synthesized via benzotriazole-mediated synthetic approach with good yield and purity. Some of the synthesized analogs exhibited significant antibacterial properties against Escherichia coli and Staphylococcus aureus with potency higher than that of the parent drugs through in vitro standard bioassay procedure (conjugates 8c and 8d reveal antimicrobial properties with potency 1.9, 61.9, 20.7 and 2.4, 37.1, 8.3 folds relative to the parent antibiotic 6 against E. coli, S. aureus, and Enterococcus faecalis, respectively). The observed experimental data were supported by enzymatic DNA gyrase inhibitory property. Developed BMLR-QSAR model validates the observed experimental data and recognizes the parameters responsible for the enhanced antibacterial properties.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Ácido Dicloroacético/farmacologia , Fluoroquinolonas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Antibacterianos/síntese química , Ácido Dicloroacético/química , Escherichia coli/efeitos dos fármacos , Fluoroquinolonas/química , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/químicaRESUMO
Cisplatin is a clinically important chemotherapeutical agent used to treat epithelial malignancies. High concentrations (20-100 microM) of cisplatin have been used in numerous studies to induce apoptosis of carcinoma cells grown in monolayer culture over 24-48 hr. These conditions may not be relevant to 3-D tumor tissue in vivo and the importance of apoptosis for tumor response is controversial. We here studied the effects of cisplatin on a 3-D colon carcinoma in vitro model (multicellular spheroids). Cisplatin at a dose of 40 microM induced active caspase-3 preferentially in the peripheral 30 microm cell layer of spheroids, mainly during late stages (72-96 hr). The p53 response to cisplatin was also largely confined to peripheral cell layers. Despite the use of a high cisplatin concentration, a significant fraction of the cells in the spheroids survived treatment. A high proportion of surviving cells stained positive for beta-galactosidase, a marker of premature senescence. Cells growth-arrested by cisplatin treatment showed a higher spontaneous cell death rate than untreated proliferating cells. We propose that acute apoptosis is of minor significance for the overall response of carcinoma cells to cisplatin treatment.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Técnicas de Cultura de Células , Cisplatino/farmacologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Animais , Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Humanos , Técnicas Imunoenzimáticas , Camundongos , Camundongos SCID , Esferoides Celulares , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Curcumin is a well-known example of plant origin exhibiting promising diverse biological properties such as, anti-inflammatory and antitumor as well as poor pharmacokinetic/pharmacodynamic properties. This is why effective agents based on its chemical scaffold were explored. METHODS: A set of 3,5-bis(ylidene)-1-(alkylsulfonyl)piperidin-4-ones were synthesized in excellent yield (80- 96%) through dehydrohalogenation reaction of 3,5-bis(ylidene)-4-piperidinones with the corresponding alkane sulfonyl chloride in the presence of triethylamine. Antiproliferative properties of the synthesized compounds (dienone/curcumin inspired analogues) were studied by the standard MTT technique. RESULTS: Most of the synthesized compounds revealed antiproliferative properties against HCT116 (colon) and A431 (skin/squamous) cancer cell lines with IC50 values at sub-micromolar level. Compound 36 also exhibited potency against MCF7 (breast) and A549 (lung) cancer cell lines (IC50 = 2.23, 4.27µM, respectively) higher than that of the reference standards (IC50 = 3.15, 5.93µM for 5-fluorouracil and doxorubicin against MCF7 and A549 cell lines, respectively). Cytotoxic properties of the synthesized compounds against non-cancer RPE1 cell line supported the safety profile of the effective agents against normal cells. Molecular modeling (3Dpharmacophore and 2D-QSAR) studies validated the observed bio-properties and explained the parameters governing activity. Inhibitory properties of compounds 27 and 29 (representative examples of the promising antiproliferative agents synthesized) supported their mode of action against topoisomerase IIα. CONCLUSION: The synthesized scaffold is a promising antitumor agent (with special selectivity against colon and skin/squamous cancer cell lines) so, it can be considered for further investigation and development of highly effective hits/leads based on the computational models obtained.