RESUMO
It was found that Argentatins A and B triterpenoids make up approximately 20-30 % of the waste resin produced from the industrial processes to isolate rubber from P. argentatum. We have developed an efficient protocol for synthesizing cycloartane-16ß-ol derivatives by opening the oxepane ring of argentatin B acetate (2) with BF3-OEt2. Although three new cycloartenol derivatives showed high cytotoxicity against PC-3 and HCT-15 cancer cell lines, nevertheless, the best results were obtained for (16ß,24R) -(16,24-epoxy-cycloartan-2(1H)-ylidene) acetate (14), compound with intact oxepane ring. These results indicate that the substituents in the argentatin nucleus and a side chain account for the cytotoxic activity. However, according to the selectivity index (SI), 14 did not show selectivity activity to cancer cell lines over the HaCat noncancerous cell line. The compound 3ß,16ß-Dihydroxy-cycloartan-24-one (5), synthesized by oxepane opening, demonstrated high cytotoxic activity to cancer cell lines and showed a remarkable selectivity to cancer cell lines over the noncancerous ones. These results suggest that 5 could lead to the development of new anticancer compounds.
Assuntos
Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Triterpenos/farmacologia , Triterpenos/química , Triterpenos/síntese química , Tetrazóis/farmacologia , Tetrazóis/síntese química , Tetrazóis/química , Estrutura Molecular , Relação Dose-Resposta a Droga , Sobrevivência Celular/efeitos dos fármacosRESUMO
From the aerial parts of Salvia carranzae Zamudio and Bedolla, three new icetexane-type diterpenoids were isolated. Their structures were established through spectroscopic methods and named the following: salvicarranzanolide (1), 19-deoxo-salvicarranzanolide (2) and 19-deoxo-20-deoxy-salvicarranzanolide (3). In addition, the known icetexane-type diterpenoids, 6,7,11,14-tetrahydro-7-oxo-icetexone (4), iso-icetexone (5), 19-deoxo-iso-icetexone (6), icetexone (7), 19-deoxo-icetexone (8) and 7α-acetoxy-6,7-dihydroicetexone (9), were also isolated, along with the abietanes sessein (10) and ferruginol (11). α-Tocopherol was also identified. Compounds 5, 6 and 8 were tested for their antiproliferative activity using the sulforhodamine B assay on six cancer and one normal human cell lines. Diterpenoids 5 and 6 showed noteworthy antiproliferative activity, exhibiting an IC50 (µM) = 0.43 ± 0.01 and 1.34 ± 0.04, respectively, for U251 (glioblastoma), an IC50 (µM) = 0.45 ± 0.01 and 1.29 ± 0.06 for K5621 (myelogenous leukemia), 0.84 ± 0.07 and 1.03 ± 0.10 for HCT-15 (colon cancer), and 0.73 ± 0.06 and 0.95 ± 0.09 for SKLU-1 (lung adenocarcinoma) cell lines. On the other hand, the phytotoxicity of compounds 5-7 and 9-10 was evaluated on seed germination and root growth in some weeds such as Medicago sativa, Panicum miliaceum, Amaranthus hypochondriacus and Trifolium pratense as models. While compounds 5 and 10 exhibited a moderate inhibitory effect on the root growth of A. hypochondriacus and T. pratense at 100 ppm, the diterpenoids 6, 7 and 9 were ineffective in all the plant models. Taxonomic positions based on the chemical profiles found are also discussed.
Assuntos
Alcaloides , Diterpenos , Neoplasias Pulmonares , Salvia , Humanos , Abietanos/farmacologia , Abietanos/química , Salvia/química , Diterpenos/farmacologia , Diterpenos/química , Linhagem Celular Tumoral , Estrutura MolecularRESUMO
A high-yielding total synthesis of the indole alkaloid prenostodione was completed in 4 steps and 44% overall yield from 1H-indole-3-carboxylic acid. The expedient syntheses of prenostodiones containing distinct substituents at the para position of the phenyl frame underscored the scope of this methodology. The cytotoxic activities of the tert-butyl esters of prenostodione analogues were tested using six tumor cell lines. Preliminary structure-activity studies revealed the importance of the identity of the aromatic substituent at the C-4 position for cytotoxic activity. The IC50 values of these compounds were found to compare satisfactorily with those of the commercially available drugs etoposide and cisplatin. Furthermore, the compounds with, respectively, -OMe (14d) and -NO2 (14f) groups at C-4 were more selective than these control compounds in PC-3, K-562, and MCF-7 cells. Also, computational studies were carried out to determine the ADMET profiles and passive membrane permeabilities of the compounds. The results suggested the promise of 14d and 14f as hit compounds for the development of new anticancer agents.
Assuntos
IndóisRESUMO
The first example of conjugation of open-resorcinarenes with chlorambucil, ibuprofen, naproxen and indomethacin are presented. The cytotoxic properties of the obtained conjugates were tested against the cancer cell lines U-251, PC-3, K-562, HCT-15, MCF-7 and SKLU-1. It was found that the conjugate with chlorambucil, naproxen or indomethacin (having 8 moieties) was toxic towards cancer cell lines U-251 and K-562, with no activity against non-cancerous COS-7 cells. The conjugates with naproxen and indomethacin showed high selectivity towards U-251 tumor cells.
Assuntos
Antineoplásicos/farmacologia , Calixarenos/farmacologia , Fenilalanina/análogos & derivados , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Células COS , Calixarenos/síntese química , Calixarenos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Fenilalanina/síntese química , Fenilalanina/química , Fenilalanina/farmacologia , Relação Estrutura-AtividadeRESUMO
In this paper, we designed and extended modification basing on the flutamide structure. A series of flutamide-conjugates were obtained with methyl bromoacetate and ethylenediamine. Through the synthesis of two conjugates with 3,5-bis(dodecyloxy)benzoate derivatives, these flutamide conjugates were tested for anticancer activity. Among the compounds tested, the flutamide-conjugates showed good inhibition activity against cancer cell lines U-251, PC-3 and K-562. The conjugates showed a better inhibitory effect than free flutamide and did not show activity against normal COS-7 monkey kidney fibroblast cells. It was also observed that the flutamide conjugates had an inhibitory effect against human colorectal adenocarcinoma HCT-15.
Assuntos
Antineoplásicos/farmacologia , Flutamida/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Flutamida/síntese química , Flutamida/química , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A collection of fourteen diphenylamine macrocyclic derivatives containing a peptide chain with different substituents was synthesized using a protocol of two Ugi four component reactions (Ugi-4CR) and a Buchwald-Hartwig macrocyclization. Their anti-inflammatory effects were assayed with an ear edema model using 12-O-tetradecanoylphorbol-13-acetate, while the activity of myeloperoxidase was determined to evaluate the index of leukocyte infiltration. Compound 5e had an ID50 of 0.18 µM per ear with a potency higher than that of the reference drugs indomethacin and celecoxib (0.24 and 0.91 µM per ear, respectively). Moreover, the cytotoxicity of the macrocycles was determined in two healthy cell lines, showing a low percentage of toxicity.
Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Difenilamina/química , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Técnicas de Química Sintética , Ciclização , Relação Dose-Resposta a Droga , Edema/tratamento farmacológico , Concentração Inibidora 50 , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Compostos Macrocíclicos/química , Compostos Macrocíclicos/uso terapêutico , Camundongos , Modelos Moleculares , Conformação Molecular , Células RAW 264.7RESUMO
Sensitizing activities exerted by 3,4-dihydro-7-hydroxycadalene (1), rac-3,7-dihydroxy-3(4H)-isocadalen-4-one (4) and (1R,4R)-4H-1,2,3,4-tetrahydro-1-hydroxycadalen-15-oic acid (9), the major cadinanes isolated from Heterotheca inuloides, towards multidrug-resistant MES-SA/MX2 and parental MES-SA epithelial human uterine sarcoma cell lines were evaluated. We also evaluated the in silico interactions (expressed as ΔGbinding in kcal/mol) of cadinanes 1, 4 and 9 in an in vitro assay, and also tested several structurally related natural compounds with the multidrug resistance protein (MDR1, P-glycoprotein), human multidrug resistance protein 1 (MRP1), and breast cancer resistance protein (BCRP) structures as pharmacological targets using AutoDock and AutoDock Vina. Compound 1 potentiated the cytotoxicity of doxorubicin and mitoxantrone drugs in resistant MES-SA/MX2 cells, compared to cells treated with each drug alone. Compound 1 could reverse the resistance to doxorubicin 12.44 fold at a concentration of 5⯵M. It also re-sensitized cells to mitoxantrone 3.94 fold. Hence, compound 1 may be considered as a potential chemosensitizing agent to overcome multidrug resistance in cancer. The docking analysis suggested that there are interactions between cadinanes from H. inuloides and MDR1, MRP1, and BCRP proteins mainly through π-π interactions and hydrogen bonds.
Assuntos
Transportadores de Cassetes de Ligação de ATP/química , Antineoplásicos Fitogênicos/farmacologia , Asteraceae/química , Produtos Biológicos/farmacologia , Sesquiterpenos Policíclicos/farmacologia , Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Sesquiterpenos Policíclicos/química , Sesquiterpenos Policíclicos/isolamento & purificação , Relação Estrutura-AtividadeRESUMO
A possible way of improving the activity and selectivity profile of antitumor agents is to design drug carrier systems employing soluble macromolecules. Thus, four resorcinarene-PAMAM-dendrimer conjugates of chlorambucil with different groups in the lower part of the macrocycle and different length dendritic arms showed a good stability of the chemical link between drug and spacer. Evaluation of the cytotoxicity of the resorcinarene-PAMAM-dendrimer-chlorambucil conjugate employing a sulforhodamine B (SRB) assay in K-562 (human chronic myelogenous leukemia cells) demonstrated that the conjugate was more potent as an antiproliferative agent than chlorambucil.
Assuntos
Antineoplásicos/administração & dosagem , Calixarenos/química , Clorambucila/administração & dosagem , Portadores de Fármacos/química , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Fenilalanina/análogos & derivados , Dendrímeros/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Fenilalanina/químicaRESUMO
A series of organotin(IV) complexes was herein prepared and characterized. A one-pot synthetic strategy afforded reasonable to high yields, depending on the nature of the ligand. All new complexes were fully characterized by spectroscopic techniques, consisting of IR, MS and NMR (1H, 13C and 119Sn). The in vitro cytotoxicity tests demonstrated that the organotin complexes produced a greater inhibition, versus cisplatin (the positive control), of the growth of six human cancer cell lines: U-251 (glioblastoma), K-562 (chronic myelogenous leukemia), HCT-15 (colorectal), MCF-7 (breast), MDA-MB-231 (breast) and SKLU-1 (non-small cell lung). The potency of this cytotoxic activity depended on the nature of the substituent bonded to the aromatic ring. All complexes exhibited excellent IC50 values. The test compounds were also screened in vitro for their antifungal effect against Candida glabrata and Candida albicans, showing minimum inhibitory concentration (MIC) values lower than those obtained for fluconazole. A brine shrimp bioassay was performed to examine the toxic properties. Molecular docking studies demonstrated that the organotin(IV) complexes bind at the active site of topoisomerase I in a similar manner to topotecan, sharing affinity for certain amino acid side chains (Ile535, Arg364 and Asp533), as well as for similar DNA regions (DA113, DC112 and DT10).
Assuntos
Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Artemia/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Candida glabrata/efeitos dos fármacos , Compostos Orgânicos de Estanho/farmacologia , Animais , Antifúngicos/síntese química , Antifúngicos/química , 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 , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos Orgânicos de Estanho/síntese química , Compostos Orgânicos de Estanho/química , Relação Estrutura-AtividadeRESUMO
p-[bis(chloro-2-ethyl)amino]-L-phenylalanine (melphalan) is an approved anti-cancer agent with a broad spectrum of antitumor activity. However, it has some disadvantages, such as poor water-solubility followed by rapid elimination, which reduce the target specificity. To solve these problems, porphyrin- poly(amidoamine) or PAMAM-conjugates of melphalan were synthesized and characterized. The dendrimeric conjugates showed satisfactory water solubility. It was found that the size of the dendrimer played a crucial role in controlling the drug content and diameter of the melphalan-conjugates. The in vitro studies of cell cytotoxicity revealed that by employing the dendrimeric conjugation strategy and using the PAMAM dendritic arms as spacers, the conjugates had good anti-cancer activity and lower toxicity than free melphalan.
Assuntos
Antineoplásicos/farmacologia , Dendrímeros/química , Portadores de Fármacos/química , Melfalan/farmacologia , Porfirinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Solubilidade , Água/químicaRESUMO
The effects of ten natural cadinane sesquiterpenoids isolated from Heterotheca inuloides on the pathways of the NF-κB, Nrf2 and STAT3 transcription factors were studied for the first time. The main constituent in this species, 7-hydroxy-3,4-dihydrocadalene (1), showed anti-NF-κB activity and activated the antioxidant Nrf2 pathway, which may explain the properties reported for the traditional use of the plant. In addition to the main metabolite, a structurally similar compound, 7-hydroxy-cadalene (2), also displayed anti-NF-κB activity. Thus, both natural compounds were used as templates for the preparation of a novel semi-synthetic derivative set, including esters and carbamates, which were evaluated for their potential in vitro antiproliferative activities against six human cancer cell lines. Carbamate derivatives 32 and 33 were found to exhibit potent activity against human colorectal adenocarcinoma and showed important selectivity in cancer cells. Among ester derivatives, compound 13 was determined to be a more potent NF-κB inhibitor and Nrf2 activator than its parent, 7-hydroxy-3,4-dihydrocadalene (1). Furthermore, this compound decreases levels of phospho-IκBα, a protein complex involved in the NF-κB activation pathway. Molecular simulations suggest that all active compounds interact with the activation loop of the IKKß subunit in the IKK complex, which is the responsible of IκBα phosphorylation. Thus, we identified two natural, and one semi-synthetic, NF-κB and Nrf2 modulators and two new promising cytotoxic compounds.
Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Asteraceae/química , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Simulação de Acoplamento Molecular , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Sesquiterpenos Policíclicos , Fator de Transcrição STAT3/imunologia , Transdução de Sinais/efeitos dos fármacosRESUMO
The aim of this study was to synthesize several 16-dehydropregnenolone derivatives containing an imidazole ring at C-21 and a different ester moiety at C-3 as inhibitors of 5α-reductase 1 and 2 isoenzymes. Their binding capacity to the androgen receptor (AR) was also studied. Additionally, we evaluated their pharmacological effect in a castrated hamster model and their cytotoxic activity on a panel of cancer cells (PC-3, MCF7, SK-LU-1). The results showed that only the derivatives with an alicyclic ester at C-3 showed 5α-R2 enzyme inhibition activity, the most potent of them being 21-(1H-imidazol-1-yl)-20-oxopregna-5,16-dien-3ß-yl-cyclohexanecarboxylate with an IC50 of 29nM. This is important because prostatic benign hyperplasia is directly associated with the presence of 5α-R2. However, all the derivatives failed to inhibit 5α-R1 or bind to the AR. These alicyclic ester derivatives decreased the weight and size of androgen-dependent glands in the hamster, indicating they are very active in vivo and are not toxic. In addition, the 21-(1H-imidazol-1-yl)-20-oxopregna-5,16-dien-3ß-yl-acetate derivative showed the highest cytotoxic activity on the three cancer cell lines studied. It is therefore important in the synthesis of steroidal compounds to consider the size of the ester moiety at C-3 of the steroid skeleton, which is key in obtaining biological activity, as observed in this experiment.
Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Colestenona 5 alfa-Redutase/efeitos dos fármacos , Pregnenolona/análogos & derivados , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Humanos , Espectrometria de Massas , Camundongos , Pregnenolona/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , RatosRESUMO
An efficient method for the synthesis of 1-(trifluoromethylsulfonamido)propan-2-yl benzoates is described, the products of the reaction were characterized by heteronuclear single quantum coherence spectroscopy (HSQC), heteronuclear multiple bond correlation (HMBC) and NMR experiments. The overall process began with the activation of the oxazoline ring by triflic anhydride, followed by the opening of the five-membered ring in the 5-methyl-2-phenyl-4,5-dihydrooxazole system. The cytotoxic activity of the new trifluoromethyl sulfonamides was evaluated with six cancer cell lines and human gingival fibroblasts, posteriorly analyzing the influence on cytotoxicity exerted by the withdrawing and donor substituents at the para-position of the phenyl ring. Compounds 3b-e showed cytotoxic activity, with IC50 values ranging from 17-17.44 µM for the cell lines tested, finding the highest effect for compound 3e.
Assuntos
Ésteres/síntese química , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Sulfonamidas/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ésteres/química , Ésteres/farmacologia , Ésteres/toxicidade , Fibroblastos/efeitos dos fármacos , Gengiva/citologia , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
From the aerial parts of Salvia ballotiflora, eleven diterpenoids were isolated; among them, four icetexanes and one abietane (1-5) are reported for the first time. Their structures were established by spectroscopic means, mainly ¹H- and 13C-NMR, including 1D and 2D homo- and hetero-nuclear experiments. Most of the isolated diterpenoids were tested for their antiproliferative, anti-inflammatory, and radical scavenging activities using the sulforhodamine B assay on six cancer cell lines, the TPA-induced ear edema test in mice, and the reduction of the DPPH assay, respectively. Some diterpenoids showed anti-proliferative activity, these being icetexanes 6 and 3, which were the most active with IC50 (µM) = 0.27 ± 0.08 and 1.40 ± 0.03, respectively, for U251 (human glioblastoma) and IC50 (µM) = 0.0.46 ± 0.05 and 0.82 ± 0.06 for SKLU-1 (human lung adenocarcinoma), when compared with adriamycin (IC50 (µM) = 0.08 ± 0.003 and 0.05 ± 0.003, as the positive control), respectively. Compounds 3 and 10 showed significant reduction of the induced ear edema of 37.4 ± 2.8 and 25.4 ± 3.0% (at 1.0 µmol/ear), respectively. Compound 4 was the sole active diterpenoid in the antioxidant assay (IC50 = 98. 4 ± 3.3), using α-tocopherol as the positive control (IC50 (µM) = 31.7 ± 1.04). The diterpenoid profile found is of chemotaxonomic relevance and reinforces the evolutionary link of S. ballotiflora with other members of the section Tomentellae.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Neoplasias/tratamento farmacológico , Abietanos/química , Abietanos/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Canfanos , Linhagem Celular Tumoral , Diterpenos/química , Diterpenos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Neoplasias/patologia , Panax notoginseng , Salvia/química , Salvia miltiorrhizaRESUMO
Curcumin (1) and ten derivatives (2-11) were synthesized and evaluated as cytotoxic and antioxidant agents. The results of primary screening by Sulforhodamine B assay against five human cancer cell lines (U-251 MG, glioblastoma; PC-3, human prostatic; HCT-15, human colorectal; K562, human chronic myelogenous leukemia; and SKLU-1, non-small cell lung cancer) allowed us to calculate the half maximal inhibitory concentration (IC50) values for the more active compounds against HCT-15 and K562 cell lines. Compounds 2 and 10 were the most active against both cell lines and were more active than curcumin itself. Thiobarbituric acid reactive substances (TBARS) assay showed that 7 has potent activity; even stronger than curcumin, α-tocopherol, and quercetin.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , Curcumina/síntese química , Curcumina/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Curcumina/análogos & derivados , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , RatosRESUMO
Testosterone (T) plays a crucial role in prostate growth. In androgen-dependent tissues T is reduced to dihydrotestosterone (DHT) because of the presence of the 5α-reductase enzyme. This androgen is more active than T, since it has a higher affinity for the androgen receptor (AR). When this mechanism is altered, androgen-dependent diseases, including prostate cancer, could result. The aim of this study was to synthesize several 16-dehydropregnenolone acetate derivatives containing a triazole ring at C-21 and a linear or alicyclic ester moiety at C-3 of the steroidal skeleton. These steroids were designed as potential inhibitors of the activity of both types (1 and 2) of 5α-reductase. The cytotoxic activity of these compounds was also evaluated on a panel of PC-3, MCF7, and SK-LU-1 human cancer cell lines. The results from this study showed that with the exception of steroids 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3ß-yl-propionate and 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3ß-yl-pentanoate, the compounds exhibit a lower inhibitory activity for both isoenzymes of 5α-reductase than finasteride. Furthermore the 3ß-hydroxy-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-20-one and 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3ß-yl-acetate derivatives display 80% cytotoxic activity on the SK-LU-1 cell line. These results also indicated that the triazole derivatives, which have a hydroxyl or acetoxy group at C-3, could have an anticancer effect, whereas the derivatives with a alicyclic ester group at C-3 do not show biological activity.
Assuntos
Inibidores de 5-alfa Redutase/química , Inibidores de 5-alfa Redutase/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Pregnenolona/análogos & derivados , Inibidores de 5-alfa Redutase/síntese química , Animais , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colestenona 5 alfa-Redutase/metabolismo , Humanos , Masculino , Mesocricetus , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Pregnenolona/síntese química , Pregnenolona/química , Pregnenolona/farmacologia , RatosRESUMO
It is well known that testosterone (T) under the influence of 5α-reductase enzyme is converted to dihydrotestosterone (DHT), which causes androgen-dependent diseases. The aim of this study was to synthesize new dehydroepiandrosterone derivatives (3a-e, 4a-i, 6 and 7) having potential inhibitory activity against the 5α-reductase enzyme. This paper also reports the in vivo pharmacological effect of these steroidal molecules. The results from this study showed that all compounds exhibited low inhibitory activity for 5α-reductase type 1 and 2 enzymes and they failed to bind to the androgen receptor. Furthermore, in the in vivo experiment, steroids 3b, 4f, and 4 g showed comparable antiandrogenic activity to that of finasteride; only derivatives 4d and 7 produced a considerable decrease in the weight of the prostate gland of gonadectomized hamsters treated with (T). On the other hand, compounds 4a, f and h showed 100% inhibition of the growth of prostate cancer cell line PC-3, with compound 4 g having a 98.2% antiproliferative effect at 50 µM. The overall data indicated that these steroidal molecules, having an aromatic ester moiety at C-3 (4f-h), could have anticancer properties.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Colestenona 5 alfa-Redutase/antagonistas & inibidores , Desidroepiandrosterona/análogos & derivados , Desidroepiandrosterona/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Células Cultivadas , Colestenona 5 alfa-Redutase/metabolismo , Cricetinae , Feminino , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Próstata/efeitos dos fármacos , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , RatosRESUMO
Drug release from hyperbranched Janus dendrimer-drug conjugates and their subsequent activity are influenced by the different drugs in each dendron and the linker. To understand these effects, we synthetized new Janus-type dendrimers of first and second generation. One dendron with 2,2-Bis(hydroxymethyl)propionic acid functionalized with ibuprofen and the second dendron was obtained with 3-aminopropanol-amidoamine and prednisone. The dendrimers were obtained by copper(I)-catalyzed Click azide-alkyne cycloaddition for the formation of a triazole as a dendrimeric nucleus of Janus dendrimer conjugates are reported. The influence of ibuprofen, prednisone, and spacer on cancer activity of Janus dendrimers conjugates is reported. The IC50 values of the anticancer activity on cancer cell lines the Janus dendrimer of second generation was higher in comparison to the first generation dendrimer. Similarly, the anticancer activity was higher compared to the dendron conjugates. Also, no cytotoxic effects of dendrons and dendrimers on non-cancerous kidney COS-7 cell line was observed. The interesting anticancer activity of the prepared prednisone-ibuprofen Janus dendrimer conjugates suggest that the dendrimers could be of potential use as new anticancer drug.
Assuntos
Antracenos , Antineoplásicos , Dendrímeros , Antineoplásicos/farmacologia , Dendrímeros/farmacologia , Ibuprofeno , Prednisona , Cobre/químicaRESUMO
BACKGROUND: The synthesis of conjugates with nonsteroidal anti-inflammatory drugs could improve their activity with less toxicity and these compounds could be used for the treatment of cancer. OBJECTIVE: The aim of the present investigation was the synthesis of 3,5-bis(dodecyloxy)benzoate - PAMAM conjugates with indomethacin and mefenamic acid to examine their anticancer activity. METHODS: The anticancer activity was studied of the conjugates against six human cancer cells U- 251, PC-3, K-562, HCT-15, MCF-7, SKLU-1, and the COS-7 (as a control) cell lines. The conjugates with indomethacin and mefenamic acid were characterized by 1H, 13C NMR one- and twodimension spectroscopy. RESULTS: All the conjugates synthetized with indomethacin or mefenamic acid showed anticancer activity against all the human cancer cell lines. The first generation of indomethacin conjugates showed better activity against the PC-3 (human prostatic adenocarcinoma) cell line than the second generation. But the second generation with indomethacin showed better activity against PC-3 than the first generation. The second-generation conjugate with mefenamic acid had strong selectivity to PC-3 cells with an IC50 value of 10.23 ± 1.2 µM in vitro. CONCLUSION: In the paper, we report the synthesis and spectroscopic analyses of new indomethacin or mefenamic acid conjugates. The overall results showed that the conjugate of the second generation with mefenamic acid could be a potential nanocarrier for human prostatic adenocarcinoma cancer treatment, our research will be continued.
Assuntos
Adenocarcinoma , Antineoplásicos , Humanos , Indometacina/farmacologia , Ácido Mefenâmico/farmacologia , Benzoatos , Linhagem Celular Tumoral , Antineoplásicos/químicaRESUMO
BACKGROUND: Janus Dendrimer represents a novel class of synthetic nanocarriers. Since it is possible to introduce multiple drugs and target moieties, this helps the designing of new biocompatible forms with pharmacological activities comprised of different drugs with tailor-made functionalities, such as anticancer and nonsteroidal anti-inflammatory, which could improve the anticancer activity with less toxicity. AIMS: This study aimed to determine the anticancer activity of the Janus dendrimers formed by two dendrons. One dendron conjugates with chlorambucil, and the other dendron conjugates with Ibuprofen. METHODS: The cytotoxicity of the drug carriers was determined by the sulforhodamine B (SRB) assay for three cell lines. PC-3 (human prostatic adenocarcinoma), HCT-15 (human colorectal adenocarcinoma), MFC-7 (human breast cancer) and the COS-7 African green monkey kidney (used as a control) cell lines were seeded into 96-well plates at a density of 5x103 cells/well and cultured for 24 h before use. All the obtained compounds were characterized by 1H and 13C NMR one and two dimensions, UV-vis, FTIR, MALDI-TOF, Electrospray mass, and FAB+. Microscopic images were taken in an Inverted microscope Nikon, Diaphot 300, 10x4 in culture medium. RESULTS: Janus dendrimers (G1 and G2) were synthesized via an azide-alkyne click-chemistry reaction attaching on one face dendrons with ibuprofen molecules and, on the other face, attached a chlorambucil-derivative. The IC50 behavior of the conjugates of the first and second generations showed anticancer activity against PC-3, HCT-15, and MFC-7 cell lines. The second generation was more active against PC-3, HCT-15 and MFC-7 with IC50 of 3.8±0.5, 3.0±0.2 and 3.7±1.1 ïM, respectively Conclusion: The new Janus dendrimers with anticancer chlorambucil and nonsteroidal anti-inflammatory Ibuprofen can improve the anticancer activity of chlorambucil with less toxicity.