RESUMEN

Breast cancer has the highest incidence and mortality in females, while prostate cancer has the second-highest incidence in males. Studies have shown that compounds from Brazilian green propolis have antitumor activities and can selectively inhibit the AKR1C3 enzyme, overexpressed in hormone-dependent prostate and breast tumors. Thus, in an attempt to develop new cytotoxic inhibitors against these cancers, three prenylated compounds, artepillin C, drupanin and baccharin, were isolated from green propolis to synthesize new derivatives via coupling reactions with different amino acids. All obtained derivatives were submitted to antiproliferative assays against four cancer cells (MCF-7, MDA MB-231, PC-3, and DU145) and two normal cell lines (MCF-10A and PNT-2) to evaluate their cytotoxicity. In general, the best activity was observed for compound6e, derived from drupanin, which exhibited half-maximal inhibitory concentration (IC50) of 9.6 ± 3 µM and selectivity index (SI) of 5.5 against MCF-7 cells.In silicostudies demonstrated that these derivatives present coherent docking interactions and binding modes against AKR1C3, which might represent a possible mechanism of inhibition in MCF-7 cells.

Asunto(s)

Aminoácidos/farmacología , Antineoplásicos Fitogénicos/farmacología , Cinamatos/farmacología , Fenilpropionatos/farmacología , Própolis/química , Tricotecenos/farmacología , Aminoácidos/análisis , Aminoácidos/síntesis química , Antineoplásicos Fitogénicos/análisis , Antineoplásicos Fitogénicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cinamatos/análisis , Cinamatos/síntesis química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Fenilpropionatos/análisis , Fenilpropionatos/síntesis química , Própolis/análisis , Própolis/síntesis química , Própolis/farmacología , Relación Estructura-Actividad , Tricotecenos/análisis , Tricotecenos/síntesis química

RESUMEN

Chronic myeloid leukemia (CML) is a neoplasm characterized by BCR-ABL1, an oncoprotein with vital role in leukemogenesis. Its inhibition by tyrosine kinase inhibitors represents the main choice of treatment. However, therapeutic failure is worrying given the lack of pharmacological options. Pentacyclic triterpenes are phytochemicals with outstanding antitumoral properties and have also been explored as a basis for the design of potential leads. In this review, we have gathered and discuss data regarding both natural and semisynthetic pentacyclic triterpenes applied to CML cell treatment. We found consistent evidence that the class of pentacyclic triterpenes in general exerts promising pro-apoptotic and antiproliferative activities in sensitive and resistant CML cells, and thus represents a rich source for drug development. We also analyze the predicted drug-like properties of the molecules, discuss the structural changes with biological implications and show the great opportunities this class represents, as well as the perspectives they provide on drug discovery for CML treatment.

Asunto(s)

Antineoplásicos Fitogénicos/farmacología , Productos Biológicos/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Triterpenos Pentacíclicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Productos Biológicos/síntesis química , Productos Biológicos/química , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Estructura Molecular , Triterpenos Pentacíclicos/síntesis química , Triterpenos Pentacíclicos/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química

RESUMEN

Paclitaxel (PTX) has a great clinical significance as an antitumor drug, although several side effects are strongly dose-limiting. In this way, we prepared a PTX-loaded 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000] polymeric micelles (PM/PTX) in an attempt to improve safety and effectiveness of conventional PTX formulation (CrEL/EtOH/PTX). In this study, we evaluated from both formulations: stability after dilution, hemocompatibility, cellular uptake, acute toxicity in healthy mice, antitumor activity, and toxicity after multiple-dose treatment. PM/PTX appeared to be more stable than CrEL/EtOH/PTX after dilution. PM/PTX did not exhibit hemolytic activity (values <1%), even at high concentrations. In vitro cellular uptake study indicated that polymeric micelles were able to deliver more PTX (5.8 %) than CrEL/EtOH (2.7 %) to 4T1 cells. In the acute toxicity evaluation in healthy mice, CrEL/EtOH/PTX (single dose of 20 mg/kg) induced peripheral neuropathy, which was not observed in PM/PTX group. Similar results were observed after tumor-bearing mice received a multiple-dose regimen (seven doses of 10 mg/kg). Worth mentioning, we also evaluated vehicles, and CrEL/EtOH alone was not capable of inducing neuropathic pain. Besides, PM/PTX exhibited a higher antitumor activity with an inhibition ratio approximately 1.5-fold higher than CrEL/EtOH/PTX group. This study suggested that PM/PTX is safer than CrEL/EtOH/PTX, and was able to improve the antitumor effectiveness in a 4T1 breast cancer model.

Asunto(s)

Antineoplásicos Fitogénicos/administración & dosificación , Portadores de Fármacos/administración & dosificación , Micelas , Nanopartículas/administración & dosificación , Paclitaxel/administración & dosificación , Enfermedades del Sistema Nervioso Periférico/prevención & control , Animales , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/toxicidad , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Portadores de Fármacos/síntesis química , Portadores de Fármacos/toxicidad , Femenino , Ratones , Ratones Endogámicos BALB C , Nanopartículas/química , Nanopartículas/toxicidad , Paclitaxel/síntesis química , Paclitaxel/toxicidad , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Polímeros/administración & dosificación , Polímeros/síntesis química , Carga Tumoral/efectos de los fármacos , Carga Tumoral/fisiología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos

RESUMEN

Dehydrodieugenol B and five related natural neolignans were isolated from the Brazilian plant species Nectandra leucantha. Three of these compounds were shown to be active against murine (B16F10) and human (A2058) melanoma cells but non-toxic to human fibroblasts (T75). These results stimulated the preparation of a series of 23 semi-synthetic derivatives in order to explore structure-activity relationships and study the biological potential of these derivatives against B16F10 and A2058 cell lines. These structurally-related neolignan derivatives were analyzed by multivariate statistics and machine learning, which indicated that the most important characteristics were related to their three-dimensional structure and, mainly, to the substituents on the neolignan skeleton. The results suggested that the presence of hydroxyl or alkoxyl groups at positions 3, 4 and 5 (with appropriate sidechains) promoted an increase in electropological and charge density, which seem to be important for biological activity against murine (B16F10) and human (A2058) melanoma cells.

Asunto(s)

Antineoplásicos Fitogénicos/farmacología , Diseño de Fármacos , Lignanos/farmacología , Animales , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Lignanos/síntesis química , Lignanos/química , Aprendizaje Automático , Ratones , Estructura Molecular , Análisis Multivariante , Relación Estructura-Actividad

RESUMEN

BACKGROUND: Cancer is a multifactorial disease, representing one of the leading causes of death worldwide. On a global estimate, breast cancer is the most frequently occurring cancer in women and cervical cancer, the fourth most common. Both types of cancer remain the major cause of cancer-related mortality in developing countries. A strategy for rational drug design is hybridization, which aims to bring together in one molecule, two or more pharmacophores in order to reach several biological targets. OBJECTIVE: The objective of this work was to develop new hybrids based on natural pharmacophores: Betulinic acid (1) and brosimine b (2), active in female cancer cell lines. METHODS: The coupling reactions were carried out by Steglich esterification. Different compounds were designed for the complete and simplified structural hybridization of molecules. The anticancer activities of the compounds were evaluated in human cervical adenocarcinoma (HeLa), human cervical metastatic epidermoid carcinoma (ME-180), and human breast adenocarcinoma (MCF-7) cell lines. RESULTS: Hybrid 3 presented higher potency (IC50 = 9.2 ± 0.5µM) and SI (43.5) selectively in MCF-7 cells (in relation to Vero cells) with its cytotoxic effect occurring via apoptosis. In addition, compound 6 showed activity in MCF-7 and HeLa cells with intermediate potency, but with high efficacy, acting via apoptosis as well. CONCLUSION: In this context, we showed that the combination of two complex structures generated the development of hybrids with differing inhibitory profiles and apoptotic modes of action, thus representing potential alternatives in female cancer treatment.

Asunto(s)

Antineoplásicos Fitogénicos/farmacología , Flavonoides/farmacología , Triterpenos Pentacíclicos/farmacología , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Flavonoides/síntesis química , Flavonoides/química , Células HeLa , Humanos , Conformación Molecular , Moraceae/química , Triterpenos Pentacíclicos/síntesis química , Triterpenos Pentacíclicos/química , Plantas Medicinales/química , Relación Estructura-Actividad , Células Tumorales Cultivadas , Ácido Betulínico

RESUMEN

The essential oils (EOs) obtained from the leaves of Iryanthera polyneura Ducke trees was chemically Assessed and tested for the ability of inhibiting the growth of Candida albicans, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus mutans and S. sanguinis. The oil was also tested against breast (MCF-7) and prostate (PC-3) cancer cell lines. Minimum bactericidal concentrations (MBCs) and 50 % inhibition concentrations (IC50 ) values were obtained. EOs were active against Gram-positive bacteria. Spathulenol, α-cadinol and τ-muurolol were major components of EOs. The oils showed a higher cytotoxicity against PC-3 than MCF-7 cells, although the oils were active against both cell types. Oils obtained from leaves collected in the dry season were more active against E. faecalis, S. aureus and PC-3, while the oils obtained from leaves collected in the rainy season were more active against S. mutans, S. sanguinis and MCF-7. The antibacterial and cytotoxic activities of the essential oils from the leaves of I. polyneura are related to the seasonal climate variation and are influenced by compounds that are minor components of the oils.

Asunto(s)

Antibacterianos/farmacología , Antineoplásicos Fitogénicos/farmacología , Myristicaceae/química , Aceites Volátiles/farmacología , Hojas de la Planta/química , Estaciones del Año , Antibacterianos/síntesis química , Antibacterianos/química , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Brasil , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células MCF-7 , Pruebas de Sensibilidad Microbiana , Aceites Volátiles/síntesis química , Aceites Volátiles/química , Células PC-3 , Bosque Lluvioso

RESUMEN

In this work, several normal, oil-in-water (o/w) microemulsions (MEs) were prepared using peppermint essential oil, jojoba oil, trans-anethole, and vitamin E as oil phases to test their capacity to load paclitaxel (PTX). Initially, pseudo-ternary partial phase diagrams were constructed in order to find the normal microemulsion region using d-α-tocopherol polyethylene glycol 1000 succinate (TPGS-1000) as surfactant and isobutanol (iso-BuOH) as co-surfactant. Selected ME formulations were loaded with PTX reaching concentrations of 0.6 mg mL-1 for the peppermint oil and trans-anethole MEs, while for the vitamin E and jojoba oil MEs, the maximum concentration was 0.3 mg mL-1. The PTX-loaded MEs were stable according to the results of heating-cooling cycles and mechanical force (centrifugation) test. Particularly, drug release profile for the PTX-loaded peppermint oil ME (MEPP) showed that ∼ 90% of drug was released in the first 48 h. Also, MEPP formulation showed 70% and 90% viability reduction on human cervical cancer (HeLa) cells after 24 and 48 h of exposure, respectively. In addition, HeLa cell apoptosis was confirmed by measuring caspase activity and DNA fragmentation. Results showed that the MEPP sample presented a major pro-apoptotic capability by comparing with the unloaded PTX ME sample.

Asunto(s)

Antineoplásicos Fitogénicos/síntesis química , Apoptosis/efectos de los fármacos , Citotoxinas/síntesis química , Nanosferas/química , Paclitaxel/síntesis química , Aceites de Plantas/síntesis química , Antineoplásicos Fitogénicos/farmacocinética , Apoptosis/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Citotoxinas/farmacocinética , Relación Dosis-Respuesta a Droga , Liberación de Fármacos , Células HeLa , Humanos , Mentha piperita , Paclitaxel/farmacocinética , Aceites de Plantas/farmacocinética , Polietilenglicoles/síntesis química , Polietilenglicoles/farmacocinética , Tensoactivos/síntesis química , Tensoactivos/farmacocinética , Vitamina E/síntesis química , Vitamina E/farmacocinética

Asunto(s)

Antibacterianos/farmacología , Antifúngicos/farmacología , Antineoplásicos Fitogénicos/farmacología , Productos Biológicos/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Triazoles/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antifúngicos/síntesis química , Antifúngicos/química , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Productos Biológicos/síntesis química , Productos Biológicos/química , Humanos , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/química , Triazoles/síntesis química , Triazoles/química

RESUMEN

BACKGROUND: A series of symmetrical 1,4-disubstituted bis-1,2,3-triazoles was prepared by double copper catalyzed Azide-alkyne Cycloaddition (CuAAC) from aliphatic bis-azides and a tetraethylene glycol bis-azide derivative. The eighteen novel compounds were evaluated in vitro for their cytotoxic activity against two human tumor cell lines: Human breast adenocarcinoma (MDA-MB 231) and ovarian adenocarcinoma (TOV-21G). RESULTS AND CONCLUSION: The results of colorimetric MTT assays showed that compounds 4j and 4q exhibited a better selectivity index and cell viability comparable with the standard drug doxorubicin. These compounds induced apoptosis in both tested cell lines, as assessed by BrdU assay. The results suggest that these structurally simple compounds may be promising prototypes for antitumoral agents.

Asunto(s)

Alquinos/química , Antineoplásicos Fitogénicos/farmacología , Azidas/química , Cobre/química , Triazoles/farmacología , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Catálisis , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Reacción de Cicloadición , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/química , Células Tumorales Cultivadas

RESUMEN

Benzylidenespirostanols were prepared by two-step synthesis including BF3·Et2O-catalyzed aldol condensation of several acetylated steroid sapogenins with benzaldehyde followed by saponification. The obtained compounds showed moderate cytotoxicity against three cancer cell lines (T-lymphoblastic leukemia cell line CEM, breast carcinoma cell line MCF7 and cervical carcinoma cell line HeLa) and normal human fibroblasts (BJ). The most active of the five tested substances was 3c (lowest IC50 for MCF7 cells 19.9±0.1µM) without any selectivity towards human cancer and normal cells, respectively.

Asunto(s)

Antineoplásicos Fitogénicos/síntesis química , Sapogeninas/síntesis química , Espirostanos/síntesis química , Esteroides/síntesis química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células MCF-7 , Sapogeninas/química , Sapogeninas/farmacología , Espirostanos/química , Espirostanos/farmacología , Esteroides/química , Esteroides/farmacología

RESUMEN

Biflorin 1 is a biologically active quinone, isolated from Capraria biflora. Five new biflorin-based nitrogen derivatives were synthesized, of which two were mixtures of (E)- and (Z)- isomers: (Z)-2a, (Z)-2b, (Z)-3a, (Z)- and (E)-3b, (Z)- and (E)-3c. The antibacterial activity was investigated using the microdilution method for determining the minimum inhibitory concentration (MIC) against six bacterial strains. Tests have shown that these derivatives have potential against all bacterial strains. The cytotoxic activity was also evaluated against three strains of cancer cells, but none of the derivatives showed activity.

Asunto(s)

Antibacterianos/farmacología , Antineoplásicos Fitogénicos/farmacología , Hidrazonas/farmacología , Naftoquinonas/farmacología , Oximas/farmacología , Scrophulariaceae/química , Antibacterianos/síntesis química , Antibacterianos/química , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Bacterias/efectos de los fármacos , Infecciones Bacterianas/tratamiento farmacológico , Línea Celular Tumoral , Humanos , Hidrazonas/síntesis química , Hidrazonas/química , Pruebas de Sensibilidad Microbiana , Naftoquinonas/síntesis química , Naftoquinonas/química , Neoplasias/tratamiento farmacológico , Oximas/síntesis química , Oximas/química

RESUMEN

Five oleanane-type saponins, 3-O-ß-D-glucuronopyranosylzanhic acid 28-O-ß-D-xylopyranosyl-(1→3)-[α-L-rhamnopyranosyl-(1→2)]-(4-O-acetyl)-ß-D-fucopyranosyl ester (1), 3-O-ß-D-glucopyranosylzanhic acid 28-O-ß-D-xylopyranosyl-(1→3)-[α-L-rhamnopyranosyl-(1→2)]-(4-O-acetyl)-ß-D-fucopyranosyl ester (2), zanhic acid 28-O-ß-D-xylopyranosyl-(1→3)-[α-L-rhamnopyranosyl-(1→2)]-(4-O-acetyl)-ß-D-fucopyranosyl ester (3), zanhic acid 28-O-α-L-rhamnopyranosyl-(1→2)-4-O-[(3'-hydroxy-2'-methyl-butyroyloxy)-3-hydroxy-2-methyl-butyroyloxy]-ß-D-fucopyranosyl ester (4), medicagenic acid 28-O-α-L-rhamnopyranosyl-(1→2)-4-O-[(3'-hydroxy-2'-methyl-butyroyloxy)-3-hydroxy-2-methyl-butyroyloxy]-ß-D-fucopyranosyl ester (5), were isolated from the root barks of Ganophyllum giganteum. Compounds 4 and 5 possessed an unusual substitution of the C-4 position of the ß-D-fucopyranosyl moiety by a C10 ester group formed by two symmetrical C5 nilic acid. From a chemotaxonomic point of view, their structures are in accordance with the previous saponins isolated from the Doratoxyleae tribe of the Sapindaceae family. Their cytotoxicity and anti-inflammatory activity were also evaluated.

Asunto(s)

Antiinflamatorios no Esteroideos/síntesis química , Antineoplásicos Fitogénicos/síntesis química , Productos Biológicos/síntesis química , Ácido Oleanólico/análogos & derivados , Sapindaceae/química , Saponinas/síntesis química , Acilación , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Productos Biológicos/química , Productos Biológicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Hidrólisis , Inflamación/tratamiento farmacológico , Ratones , Conformación Molecular , Ácido Oleanólico/química , Raíces de Plantas/química , Saponinas/química , Saponinas/farmacología , Relación Estructura-Actividad

RESUMEN

Using several reactions that include homologations and asymmetric epoxidations as well as Ugi and Huisgen couplings, we generated a small focused library of new derivatives from the labdane-type diterpene grindelic acid. These compounds were evaluated as cytotoxic agents against a panel of five human solid tumor cell lines (HBL-100, HeLa, SW1573, T-47D, and WiDr). The presence of the diamide functionalizations enhanced the cytotoxic effect. N-Benzyl-N-(1-(benzylamino)-2-methyl-1-oxopropan-2-yl)grindelicamide, proved to be the most active product in all cell lines tested, with values of 0.95 (±0.38) µM against HBL-100 cells.

Asunto(s)

Antineoplásicos Fitogénicos/farmacología , Productos Biológicos/farmacología , Diterpenos/química , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Productos Biológicos/síntesis química , Productos Biológicos/química , Proliferación Celular/efectos de los fármacos , Diterpenos/síntesis química , Diterpenos/farmacología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales Cultivadas

RESUMEN

In this study, we synthesized a series of phenylpropanoic acid derivatives based on modifications at four selected points of the molecular scaffold. The in vitro antiproliferative activities of the compounds were examined in representative human solid tumor cell lines. A SAR was established pointing out the relevance of the substituents. The best activity profiles were obtained for the derivatives bearing more lipophilic esters (GI50 3.1-21 microM).

Asunto(s)

Antineoplásicos Fitogénicos/farmacología , Fenilpropionatos/farmacología , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cromatografía en Capa Delgada , Ensayos de Selección de Medicamentos Antitumorales , Cromatografía de Gases y Espectrometría de Masas , Humanos , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Fenilpropionatos/síntesis química , Fenilpropionatos/química , Espectrofotometría Infrarroja , Relación Estructura-Actividad

RESUMEN

We report a facile protocol to obtain 22-substituted furostans and pseudosapogenins in high yields from (25R)- and (25S)-sapogenins. This method involves the treatment of the sapogenin with acetic-trifluoroacetic mixed anhydride and BF(3)·OEt(2) at room temperature, followed by the addition of a nucleophile (H(2)O, MeOH or KSeCN). In the case of 22-hydroxyfurostans, they can be transformed to pseudosapogenins by treatment with p-toluensulfonic acid.

Asunto(s)

Antineoplásicos Fitogénicos/síntesis química , Química Farmacéutica , Sapogeninas/síntesis química , Espirostanos/química , Anhídridos Acéticos , Antineoplásicos Fitogénicos/análisis , Bencenosulfonatos/química , Boranos/química , Cianuros/química , Fluoroacetatos , Espectroscopía de Resonancia Magnética , Metanol/química , Estructura Molecular , Sapogeninas/análisis , Espirostanos/análisis , Estereoisomerismo , Temperatura , Ácido Trifluoroacético/química , Agua/química

RESUMEN

Podophyllotoxin (1) has been known to possess anti-tumor activity and is still considered an important lead for research and development of antineoplastic agents. Derivatives of podophyllotoxin, namely etoposide (2), etopophos (3) and teniposide (4) have been developed and are currently used in clinic for the treatment of a variety of malignancies. These agents are also used in combination therapies with other drugs. Due to the drug resistance developed by cancer cells as well as side effects associated with the use of these agents in clinic, the search for new effective anticancer analogues of podophyllotoxin remains an intense area of research. The structural complexity of podophyllotoxin, arising from the presence of four stereogenic carbons in ring C has restricted most of the structural activity relationship (SAR) studied by derivatization of the parent natural product rather than by de novo multi-step chemical synthesis. These issues provide strong impetus to a search for analogues of 1 with simplified structures, which can be accessible via short synthetic sequences from simple starting materials. Even if such initial compounds might have diminished cytotoxic potencies compared with the parent cyclolignan, the ease of preparation of carefully designed libraries of analogues would lead to more informative SAR studies and expeditious structure optimization. In this regard, during the last two decades considerable efforts have been made to synthesize aza- analogs of podophyllotoxin, i. e. aza-podophyllotoxins, with hetero atoms at different positions of the podophyllotoxin skeleton, while keeping the basic podophyllotoxin structure. Recently, there have been significant efforts towards the convenient synthesis of aza-analogs of 1. The use of multicomponent reactions (MCRs) and the synergies of ultrasound and microwave irradiations have increased the synthetic speed and variety of azapodophyllotoxins which are and will be available to be tested against a diverse population of carcinomas and other diseases. It has been reported that several aza-podophyllotoxins retain a great fraction of the cytotoxicity associated with the parent lignan. This review focuses on the strategies towards synthesis of various aza-podophyllotoxin analogues and their biological activities.

Asunto(s)

Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/farmacología , Técnicas de Química Sintética/métodos , Podofilotoxina/síntesis química , Podofilotoxina/farmacología , Podophyllum/química , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Podofilotoxina/química , Podofilotoxina/uso terapéutico

RESUMEN

In an effort to identify natural product-based molecular-targeted antitumor agents, mammea-type coumarins from the tropical/subtropical plant Mammea americana were found to inhibit the activation of HIF-1 (hypoxia-inducible factor-1) in human breast and prostate tumor cells. In addition to the recently reported mammea E/BB (15), bioassay-guided fractionation of the active extract yielded 14 mammea-type coumarins including three new compounds, mammea F/BB (1), mammea F/BA (2), and mammea C/AA (3). The absolute configuration of C-1' in 1 was determined by the modified Mosher's method on a methylated derivative. These coumarins were evaluated for their effects on mitochondrial respiration, HIF-1 signaling, and tumor cell proliferation/viability. Acetylation of 1 afforded a triacetoxylated product (A-2) that inhibited HIF-1 activation with increased potency in both T47D (IC(50) 0.83 µM for hypoxia-induced) and PC-3 cells (IC(50) 0.94 µM for hypoxia-induced). Coumarins possessing a 6-prenyl-8-(3-methyloxobutyl) substituent pattern exhibited enhanced HIF-1 inhibitory effects. The O-methylated derivatives were less active at inhibiting HIF-1 and suppressing cell proliferation/viability. Mechanistic studies indicate that these compounds act as anionic protonophores that potently uncouple mitochondrial electron transport and disrupt hypoxic signaling.

Asunto(s)

Antineoplásicos Fitogénicos , Respiración de la Célula/efectos de los fármacos , Cumarinas , Factor 1 Inducible por Hipoxia/efectos de los fármacos , Mammea/química , Algoritmos , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Cumarinas/síntesis química , Cumarinas/química , Cumarinas/aislamiento & purificación , Cumarinas/farmacología , Dominica , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Estructura Molecular , Corteza de la Planta/química , Prenilación , Relación Estructura-Actividad

RESUMEN

Semisynthetic aromatic amides from ARAUCARIA ARAUCANA diterpene acids have been shown to display a relevant gastroprotective effect with low cytotoxicity. The aim of this work was to assess the gastroprotective effect of amino acid amides from imbricatolic acid and its 8(9)-en isomer in the ethanol/HCl-induced gastric lesions model in mice as well as to determine the cytotoxicity of the obtained compounds on the following human cell lines: normal lung fibroblasts (MRC-5), gastric adenocarcinoma (AGS), and liver hepatocellular carcinoma (Hep G2). The diterpenes 15-acetoxyimbricatolic acid, its 8(9)-en isomer, 15-hydroxyimbricatolic acid, and the 8(9)-en derivative, bearing a COOH function at C-19, were used as starting compounds. New amides with C-protected amino acids were prepared. The study reports the effect of a single oral administration of either compound 50 min before the induction of gastric lesions by ethanol/HCl. Some 20 amino acid monoamides were obtained. Dose-response experiments on the glycyl derivatives showed that at a single oral dose of 100 mg/kg, the compounds presented an effect comparable to the reference drug lansoprazole at 20 mg/kg and at 50 mg/kg reduced gastric lesions by about 50%. All derivatives obtained in amounts > 30 mg were compared at a single oral dose of 50 mg/kg. The best gastroprotective effect was observed for the exomethylene derivatives bearing a valine residue at C-19 either with an acetoxy or free hydroxy group at C-15. The tryptophanyl derivative from the acetate belonging to the 8,9-en series presented selective cytotoxicity against hepatocytes. The glycyl amide of 15-acetoxyimbricatolic acid was the most cytotoxic and less selective compound with IC50 values between 47 and 103 µM for the studied cell lines. This is the first report on the obtention of semisynthetic amino acid amides from labdane diterpenes.

Asunto(s)

Antiulcerosos/farmacología , Antineoplásicos Fitogénicos/farmacología , Cycadopsida/química , Diterpenos/farmacología , Extractos Vegetales/farmacología , Estómago/efectos de los fármacos , 2-Piridinilmetilsulfinilbencimidazoles/farmacología , Adenocarcinoma/tratamiento farmacológico , Amidas/síntesis química , Amidas/farmacología , Amidas/uso terapéutico , Aminoácidos/síntesis química , Aminoácidos/farmacología , Aminoácidos/uso terapéutico , Animales , Antiulcerosos/síntesis química , Antiulcerosos/uso terapéutico , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/uso terapéutico , Línea Celular , Línea Celular Tumoral , Modelos Animales de Enfermedad , Diterpenos/aislamiento & purificación , Diterpenos/uso terapéutico , Etanol , Fibroblastos/efectos de los fármacos , Humanos , Ácido Clorhídrico , Isomerismo , Lansoprazol , Neoplasias Hepáticas/tratamiento farmacológico , Masculino , Ratones , Fitoterapia , Extractos Vegetales/síntesis química , Extractos Vegetales/uso terapéutico , Estómago/patología , Neoplasias Gástricas/tratamiento farmacológico

RESUMEN

INTRODUCTION: The antiproliferative effect of eleven neolignans, two lignans and one diterpene isolated from three Lauraceae plants, four benzofurans and two bicyclooctanes synthetic derivatives was evaluated in vitro on a set of five human cancer cells from solid tumors with a high incidence in Colombia. OBJECTIVE: To evaluate the cytotoxic effect of twenty compounds on the tumor cell lines HeLa, A-549, Hep-2, PC-3, and MCF-7. MATERIALS AND METHODS. Fourteen natural compounds were isolated by chromatographic techniques from three native Colombian plants (Pleurothyrium cinereum, Ocotea macrophylla and Nectandra amazonum), whose structures were established by spectroscopic methods; six synthetic derivatives were prepared by oxyarylation and diazomethane methylation. Antiproliferative effect and cell recovery were performed by means of in vitro treatment of tumor cell lines with test compounds, evaluating cell viability by resazurin staining. RESULTS: Among test compounds, only neolignans ocophyllal A, cinerin D, kaurenoic acid, two benzofuran-derivatives, and synthetic (-)-cinerin A were found to have antiproliferative effect at different levels. Bicyclooctanoids as well as kaurenoic acid exhibited activity against all human cancer cells while benzofuranoids showed selective activity against HeLa. Furthermore, compounds (-)-cinerin A and kaurenoic acid exhibited total lethal effect against all-five cell lines and PC-3, Hep-2, and A549 cell lines, respectively. CONCLUSION: Test compounds exhibiting antiproliferative activity showed interesting results, which would promote their use as lead compounds on further studies for anticancer agents development.

Asunto(s)

Antineoplásicos Fitogénicos/aislamiento & purificación , Citotoxinas/aislamiento & purificación , Lauraceae/química , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/farmacología , Benzofuranos/síntesis química , Benzofuranos/farmacología , Compuestos Bicíclicos con Puentes/aislamiento & purificación , Compuestos Bicíclicos con Puentes/farmacología , Línea Celular Tumoral/efectos de los fármacos , Colombia , Citotoxinas/síntesis química , Citotoxinas/farmacología , Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Lignanos/aislamiento & purificación , Lignanos/farmacología , Estructura Molecular , Ocotea/química , Extractos Vegetales/química , Relación Estructura-Actividad

RESUMEN

Two new boldine derivatives: the 3-thiocarbamateboldine (3) and the 2,9-O,O-diacetyl-3-thiocarbamateboldine (4) have been synthesized and their cytotoxicity evaluated.

Asunto(s)

Antineoplásicos Fitogénicos/síntesis química , Aporfinas/química , Aporfinas/síntesis química , Peumus/química , Tiocarbamatos/química , Tiocarbamatos/síntesis química , Aporfinas/aislamiento & purificación , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Humanos , Tiocarbamatos/aislamiento & purificación