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1.
J Steroid Biochem Mol Biol ; 213: 105975, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34418527

RESUMEN

It is established that steroid based agents are an example of compounds obtained from natural patterns and are of great importance due to their application in the prevention and treatment of diseases. Selenosteroids are hybrids formed by attaching Se-moiety to a steroid molecule. In these types of hybrids, selenium can be present as selenide or as a part of selenosemicarbazones, isoselenocyanates, selenourea, etc. Attaching a Se-moiety to a biologically active steroid might enhance the biological properties of both fragments. Available literature indicates that these kinds of hybrids demonstrate significant anticancer activity, which renders them interesting in terms of medical use. In this review, we present various methods of synthesis and demonstrate that seleno-steroid compounds are promising molecules for further pharmaceutical application.


Asunto(s)
Antineoplásicos Hormonales/síntesis química , Técnicas de Química Sintética/métodos , Cianatos/síntesis química , Compuestos de Organoselenio/síntesis química , Compuestos de Selenio/síntesis química , Esteroides/síntesis química , Urea/análogos & derivados , Antineoplásicos Hormonales/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cianatos/farmacología , Humanos , Concentración 50 Inhibidora , Compuestos de Organoselenio/farmacología , Compuestos de Selenio/farmacología , Semicarbazonas/química , Esteroides/farmacología , Relación Estructura-Actividad , Urea/síntesis química , Urea/farmacología
2.
Drug Dev Res ; 81(4): 444-455, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-31916635

RESUMEN

Tamoxifen (TAM) is currently the endocrine treatment of choice for all stages of breast cancer; it has proven success in ER positive and ER negative patients. TAM is activated by endogenous CYP450 enzymes to the more biologically active metabolites 4-hydroxytamoxifen and endoxifen mainly via CYP2D6 and CYP3A4/5. CYP2D6 has been investigated for polymorphism; there is a large interindividual variation in the enzyme activity, this drastically effects clinical outcomes of tamoxifen treatment. Here in we report the design and synthesis of 10 novel compounds bearing a modified tamoxifen skeleton, ring C is substituted with different ester groups to bypass the CYP2D6 enzyme metabolism and employ esterase enzymes for activation. All compounds endorse flexibility on ring A. Compounds (II-X) showed MCF-7% growth inhibition >50% at a screening dose of 10 µM. These results were validated by yeast estrogen screen (YES) and E-Screen assay combined with XTT assay. Compound II (E/Z 4-[1-4-(3-Dimethylamino-propoxy)-phenyl)-3-(4-methoxy-phenyl)-2-methyl-propenyl]-phenol) showed nanomolar antiestrogenic activity (IC50 = 510 nM in YES assay) and was five times more potent in inhibiting the growth of MCF-7 BUS (IC50 = 96 nM) compared to TAM (IC50 = 503 nM). Esterified analogues VI, VII were three times more active than TAM on MCF-7 BUS (IC50 = 167 nM). Novel analogues are prodrugs that can ensure equal clinical outcomes to all breast cancer patients.


Asunto(s)
Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Citocromo P-450 CYP2D6/genética , Tamoxifeno/farmacología , Antineoplásicos Hormonales/síntesis química , Antineoplásicos Hormonales/química , Femenino , Humanos , Concentración 50 Inhibidora , Células MCF-7 , Polimorfismo Genético , Relación Estructura-Actividad , Tamoxifeno/análogos & derivados , Tamoxifeno/síntesis química
3.
Org Biomol Chem ; 17(19): 4892-4905, 2019 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-31041982

RESUMEN

A series of 2,3,4-triaryl-substituted 1,2,4-oxadiazole-5-ones have been prepared as fixed-ring analogues of tamoxifen (TAM), a drug inhibitor of Estradiol Receptor (ER) used in breast cancer therapy, by an efficient synthetic protocol based on a 1,3-dipolar cycloaddition of nitrones to isocyanates. Some of the newly synthesized compounds (14d-f, 14h and 14k) show a significant cytotoxic effect in a human breast cancer cell line (MCF-7) possessing IC50 values between 15.63 and 31.82 µM. In addition, compounds 14d-f, 14h and 14k are able to increase the p53 expression levels, activating also the apoptotic pathway. Molecular modeling studies of novel compounds performed on the crystal structure of ER reveal the presence of strong hydrophobic interactions with the aromatic rings of the ligands similar to TAM. These data suggest that 1,2,4-oxadiazole-5-ones can be considered analogues of TAM, and that their anticancer activity might be partially due to ER inhibition.


Asunto(s)
Antineoplásicos Hormonales/síntesis química , Antineoplásicos Hormonales/farmacología , Oxadiazoles/síntesis química , Oxadiazoles/farmacología , Tamoxifeno/análogos & derivados , Antineoplásicos Hormonales/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Células MCF-7 , Estructura Molecular , Oxadiazoles/química , Teoría Cuántica , Relación Estructura-Actividad , Tamoxifeno/química , Células Tumorales Cultivadas
4.
Org Biomol Chem ; 17(9): 2315-2320, 2019 02 27.
Artículo en Inglés | MEDLINE | ID: mdl-30724943

RESUMEN

The direct carbolithiation of diphenylacetylenes and their cross-coupling procedure taking advantage of the intermediate alkenyllithium reagents are presented. By employing our recently discovered highly active palladium nanoparticle based catalyst, we were able to couple an alkenyllithium reagent with a high (Z/E) selectivity (10 : 1) and good yield to give the breast cancer drug tamoxifen in just 2 steps from commercially available starting materials and with excellent atom economy and reaction mass efficiency.


Asunto(s)
Antineoplásicos Hormonales/síntesis química , Antagonistas de Estrógenos/síntesis química , Tamoxifeno/síntesis química , Acetileno/análogos & derivados , Acetileno/síntesis química , Acetileno/química , Catálisis , Indicadores y Reactivos , Litio/química , Nanopartículas del Metal/química , Paladio/química
5.
Molecules ; 24(3)2019 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-30678347

RESUMEN

A series of estrone derivatives 3⁻8 was designed and synthesized using estrone arylmethylenes 2a,b as starting materials and their structures were confirmed by different spectral data and elemental analyses. All the newly synthesized compounds exhibited potent in vitro and in vivo cytotoxic activities against breast cancer cell lines. In addition, all compounds were subjected to in vitro and in vivo inhibition assays for EGFR and VEGFR-2 kinases as well as p53 ubiquitination activity to obtain more details about their mechanism of action. Based on the promising results, a molecular docking study was investigated for the most representative compound 5a against the two targets, EGFR and VEGFR-2 kinases, to assess its binding affinity, hoping to rationalize and obtain potent anticancer agents in the future.


Asunto(s)
Antineoplásicos Hormonales/química , Antineoplásicos Hormonales/farmacología , Diseño de Fármacos , Estrógenos/química , Estrógenos/farmacología , Modelos Moleculares , Animales , Antineoplásicos Hormonales/síntesis química , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Técnicas de Química Sintética , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Estrógenos/análogos & derivados , Estrógenos/síntesis química , Femenino , Humanos , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-Actividad Cuantitativa , Proteína p53 Supresora de Tumor/metabolismo , Ubiquitinación/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Arch Pharm (Weinheim) ; 352(3): e1800295, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30600539

RESUMEN

Nomegestrol acetate (NOMAc) is a synthetic progesterone analog and classified as a fourth-generation progestin. It has been approved in many countries for oral contraception, hormonal replacement therapy (HRT), and treatment of various gynecological disorders. There are several synthetic routes reported for the synthesis of NOMAc and they all share the very similar last three to five steps toward the conversion of 6-methylene to 6-methyl-6,7-unsaturated structure. Therefore the final product from different processing routes may have similar impurity profiles. In the analysis of NOMAc, we identified two impurities, impurity A (listed in EP 8.0) and impurity B (not specified in EP 8.0). Both impurities were further confirmed by synthesis. In addition, both impurities and NOMAc were evaluated for their in vitro cytotoxicities against L02 liver cells, mesenchymal stem cells, MCF-7 breast cancer cells, and C33A cervical cancer cells. These three analogs are not cytotoxic to the four cell lines at low concentrations (<20 µM). NOMAc and impurity A showed cytotoxicity to L02, MCF-7, and C33A cells at high concentrations, while impurity B did not show significant cytotoxicity to any of the cell lines tested.


Asunto(s)
Antineoplásicos Hormonales/síntesis química , Descubrimiento de Drogas/métodos , Megestrol/síntesis química , Norpregnadienos/síntesis química , Congéneres de la Progesterona/síntesis química , Antineoplásicos Hormonales/química , Antineoplásicos Hormonales/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Contaminación de Medicamentos , Humanos , Megestrol/química , Megestrol/farmacología , Estructura Molecular , Norpregnadienos/química , Norpregnadienos/farmacología , Congéneres de la Progesterona/química , Congéneres de la Progesterona/farmacología
7.
Bioorg Med Chem Lett ; 28(8): 1352-1356, 2018 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-29548575

RESUMEN

Z-Endoxifen is widely regarded as the most active metabolite of tamoxifen, and has recently demonstrated a 26.3% clinical benefit in a phase I clinical trial to treat metastatic breast cancer after the failure of standard endocrine therapy. Future pharmacological and pre-clinical studies of Z-endoxifen would benefit from reliable and efficient synthetic access to the drug. Here, we describe a short and efficient, stereoselective synthesis of Z-endoxifen capable of delivering multi-gram (37 g) quantities of the drug in >97% purity with a Z/E ratio >99% after trituration.


Asunto(s)
Antineoplásicos Hormonales/síntesis química , Tamoxifeno/análogos & derivados , Antineoplásicos Hormonales/química , Estereoisomerismo , Tamoxifeno/síntesis química , Tamoxifeno/química
8.
J Med Chem ; 60(15): 6693-6703, 2017 08 10.
Artículo en Inglés | MEDLINE | ID: mdl-28699738

RESUMEN

The combination of photodynamic therapy and other cancer treatment modalities is a promising strategy to enhance therapeutic efficacy and reduce side effects. In this study, a tamoxifen-zinc(II) phthalocyanine conjugate linked by a triethylene glycol chain has been synthesized and characterized. Having tamoxifen as the targeting moiety, the conjugate shows high specific affinity to MCF-7 breast cancer cells overexpressed estrogen receptors (ERs) and tumor tissues, therefore leading to a cytotoxic effect in the dark due to the cytostatic tamoxifen moiety, and a high photocytotoxicity due to the photosensitizing phthalocyanine unit against the MCF-7 cancer cells. The high photodynamic activity of the conjugate can be attributed to its high cellular uptake and efficiency in generating intracellular reactive oxygen species. Upon addition of exogenous 17ß-estradiol as an ER inhibitor, the cellular uptake and photocytotoxicity of the conjugate are reduced significantly. As shown by confocal microscopy, the conjugate is preferentially localized in the lysosomes of the MCF-7 cells.


Asunto(s)
Antineoplásicos Hormonales/farmacología , Indoles/farmacología , Compuestos Organometálicos/farmacología , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacología , Aldehídos/farmacología , Animales , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/síntesis química , Línea Celular Tumoral , Estradiol/farmacología , Fluoresceínas/farmacología , Colorantes Fluorescentes , Humanos , Indoles/administración & dosificación , Indoles/síntesis química , Isoindoles , Lisosomas/metabolismo , Ratones Endogámicos BALB C , Compuestos Organometálicos/administración & dosificación , Compuestos Organometálicos/síntesis química , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/síntesis química , Especies Reactivas de Oxígeno/metabolismo , Receptores de Estrógenos/antagonistas & inhibidores , Moduladores Selectivos de los Receptores de Estrógeno/administración & dosificación , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Tamoxifeno/administración & dosificación , Tamoxifeno/síntesis química , Compuestos de Zinc
9.
Future Med Chem ; 8(3): 249-56, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26898104

RESUMEN

BACKGROUND: Tamoxifen (TAM) is metabolized to the more active 4-hydroxytamoxifen by CYP2D6 enzyme. Due to the genetic polymorphisms in CYP2D6, clinical outcomes of TAM treatment vary. Novel flexible TAM analogs with altered activation pathway were synthesized and were tested for their antiproliferative action on MCF-7 cell lines and their binding affinity for ERα and ERß. RESULTS: All compounds showed better antiproliferative activity than TAM. Compound 3 showed 80-times more ERα binding than TAM, 900-times more selectivity toward ERα. Compound 3 was tested on the entire National Cancer Institute cancerous cell lines; results indicated a broad spectrum anticancer activity. CONCLUSION: The novel analogs were more potent than TAM with higher selectivity toward ERα and with potential metabolic stability toward CYP2D6.


Asunto(s)
Antineoplásicos Hormonales/síntesis química , Antineoplásicos Hormonales/farmacología , Diseño de Fármacos , Ésteres/farmacología , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacología , Antineoplásicos Hormonales/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Ésteres/síntesis química , Ésteres/química , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Humanos , Células MCF-7 , Estructura Molecular , Relación Estructura-Actividad , Tamoxifeno/síntesis química , Tamoxifeno/química
10.
Int J Oncol ; 47(1): 280-6, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25964080

RESUMEN

Estrogens act through interactions with estrogen receptors (ERs) to play diverse roles in various pathophysiological conditions. A number of synthetic selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, have been developed and used to treat ER-related diseases, including breast cancer and osteoporosis. Here, we identified a novel compound, bis(4-hydroxyphenyl)methanone-O-isopentyl oxime, designated NJK14013, as an ER agonist. NJK14013 activated ER-dependent transcription in a concentration-dependent manner, while suppressing androgen receptor-dependent transcriptional activity. It induced the activation-related phosphorylation of ER and enhanced the transcription of growth regulation by estrogen in breast cancer 1 (GREB1), further supporting its ER-stimulating activity. NJK14013 exerted anti-proliferative effects on various cancer cell lines, including an ER-negative breast cancer cell line, suggesting that it is capable of suppressing the growth of cancer cells independent of its ER-modulating activity. In addition, NJK14013 treatment resulted in significant apoptotic death of MCF7 and Ishikawa cancer cells, but did not induce apoptosis in non-cancer human umbilical vein endothelial cells. Collectively, our findings demonstrate that NJK14013 is a novel SERM that can activate ER-mediated transcription in MCF7 cells and suppress the proliferation of various cancer cells, including breast cancer cells and endometrial cancer cells. These results suggest that NJK14013 has potential as a novel SERM for anticancer or hormone-replacement therapy with reduced risk of carcinogenesis.


Asunto(s)
Antineoplásicos Hormonales/farmacología , Receptor alfa de Estrógeno/agonistas , Neoplasias/genética , Oximas/síntesis química , Oximas/farmacología , Receptores de Estrógenos/genética , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Antineoplásicos Hormonales/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7 , Masculino , Proteínas de Neoplasias/genética , Neoplasias/tratamiento farmacológico
11.
Eur J Pharm Sci ; 76: 231-7, 2015 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-26002041

RESUMEN

Ligands of 18-kDa translocator protein (TSPO) are known for their ability to potently and dose-dependently stimulate steroid biosynthesis in steroidogenic cells. In this study, we investigated a number of 2-phenyl-imidazo[1,2-a]pyridine acetamide derivatives, analogs of alpidem, for their ability to bind TSPO and to affect steroidogenesis in a mouse Leydig tumor cell line. We observed that not only some compounds behaved as agonists, stimulating steroidogenesis (e.g., 3 and 4) with EC50 values (15.9 and 6.99µM) close to that determined for FGIN-1-27 used as positive control (7.24µM), but two compounds, namely 5 and 6, which on the other hand are the most lipophilic ones in the investigated series, behaved as antagonists, by significantly inhibiting steroid production at concentrations at least twenty times lower than the cytotoxic ones. To our surprise, the newly synthesized compound 3, which is a strict analog of alpidem bearing at the para position of the 2-phenyl group a methoxy group instead of chlorine, achieved a ten-fold stimulation of the steroid production (for comparison FGIN-1-27 achieved 1.6-fold stimulation). Within the limits of the examined property space, some unprecedented SARs were unveiled, which can help in understanding the key molecular factors underlying the transition from agonism to antagonism in the steroidogenesis process. Besides the substitution pattern and the physicochemical features (mainly hydrogen bonding potential) of the substituents at the positions C(6) and C(8) of the imidazo[1,2-a]pyridine nucleus, and at the para position of the 2-phenyl group, the structure-activity relationship analysis suggested lipophilicity, whose increase seems to be generally related to steroidogenesis inhibition, and steric hindrance, which appeared as a stimulation-limiting factor, as two main properties to control in the design or optimization of novel imidazo[1,2-a]pyridine-based TSPO ligands endowed with potential in modulating the steroidogenesis process.


Asunto(s)
Antineoplásicos Hormonales/farmacología , Antagonistas de Hormonas/farmacología , Imidazoles/farmacología , Tumor de Células de Leydig/tratamiento farmacológico , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Piridinas/farmacología , Receptores de GABA/efectos de los fármacos , Inhibidores de la Síntesis de Esteroides/farmacología , Neoplasias Testiculares/tratamiento farmacológico , Animales , Antineoplásicos Hormonales/síntesis química , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Antagonistas de Hormonas/síntesis química , Enlace de Hidrógeno , Imidazoles/síntesis química , Tumor de Células de Leydig/metabolismo , Tumor de Células de Leydig/patología , Ligandos , Masculino , Ratones , Estructura Molecular , Neoplasias Hormono-Dependientes/metabolismo , Neoplasias Hormono-Dependientes/patología , Piridinas/síntesis química , Receptores de GABA/metabolismo , Inhibidores de la Síntesis de Esteroides/síntesis química , Relación Estructura-Actividad , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patología
12.
J Pept Sci ; 21(5): 426-35, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25908176

RESUMEN

Hormone based drug targeting is a promising tool for selective tumor therapy. In this study, synthesis and systematic comparative biological evaluation of novel drug containing analogs of gonadotropin-releasing hormone GnRH-I and GnRH-II is reported demonstrating their suitability for tumor targeting. The cytotoxic conjugates were prepared by the attachment of the chemotherapeutical agent daunorubicin (Dau) to GnRH analogs directly or through an enzyme-labile spacer with oxime linkage. All conjugates were found to be proteolytically stable under circumstances applied in biological assays. Both GnRH-I and GnRH-II were able to bind similarly to high-affinity GnRH-I receptors on human pituitary and human prostate cancer cells. The in vitro long-term cytotoxic effect of the conjugates was comparable with that of the free drug in human breast and colon cancer cell lines. Furthermore, a concentration-dependent cellular uptake profile was observed. The in vitro apoptotic effect of the compounds was evaluated by flow cytometry analysis using annexin-V. Our results show that both the GnRH-I and the GnRH-II based analogs might be applied for targeted tumor therapy.


Asunto(s)
Antineoplásicos Hormonales/síntesis química , Antineoplásicos Hormonales/farmacología , Daunorrubicina/química , Hormona Liberadora de Gonadotropina/análogos & derivados , Antineoplásicos Hormonales/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Daunorrubicina/farmacología , Hormona Liberadora de Gonadotropina/química , Células HT29 , Humanos , Células MCF-7 , Masculino , Neoplasias Hipofisarias/tratamiento farmacológico , Neoplasias Hipofisarias/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Receptores LHRH/metabolismo
13.
J Enzyme Inhib Med Chem ; 30(1): 152-9, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24666307

RESUMEN

The role of progesterone in women's cancers as well as the knowledge of the progesterone receptor (PR) structure has prompted the design of different therapies. The aim of this review is to describe the basic structure of PR agonists and antagonists as well as the recent treatments for illness associated with the progesterone receptor. The rational design for potent and effective drugs for the treatment of female cancer must consider the structural changes of the androgen and progestogen skeleton which are an indicator of their activity as progestins or antiprogestins. The presence of a hydroxyl group at C-17 in the progesterone skeleton brings about a loss of progestational activity whereas acetylation induces a progestational effect. The incorporation of an ethynyl functional group to the testosterone framework results in a loss of androgenic activity with a concomitant enhancement of the progestational effect. On the other hand, an ester function at C-3 of dehydroepiandrosterone skeleton induces partial antagonism to the PR.


Asunto(s)
Antineoplásicos Hormonales/química , Neoplasias de la Mama/tratamiento farmacológico , Progestinas/química , Receptores de Progesterona/agonistas , Receptores de Progesterona/antagonistas & inhibidores , Acetilación , Antineoplásicos Hormonales/síntesis química , Antineoplásicos Hormonales/farmacología , Sitios de Unión , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Deshidroepiandrosterona/química , Diseño de Fármacos , Femenino , Humanos , Hidroxilación , Progesterona/química , Progestinas/síntesis química , Progestinas/farmacología , Unión Proteica , Receptores de Progesterona/metabolismo , Relación Estructura-Actividad , Testosterona/química
14.
Daru ; 22: 83, 2014 Dec 24.
Artículo en Inglés | MEDLINE | ID: mdl-25539909

RESUMEN

BACKGROUND: Breast cancer is the most common type of female cancer. One class of hormonal therapy for breast cancer drugs -non steroidal aromatase inhibitors- are triazole analogues. In this work, some derivatives of these drugs was designed and synthesized. All synthesized compounds were evaluated for their cytotoxic activities on breast cancer cell lines (MDA-MB-231, T47D and MCF-7). METHODS: Our synthetic route for designed compounds started from 4-bromotolunitrile which was reacted with 1H-1,2,4-triazole to afford 4-(4-cyanobenzyl)-1,2,4-triazole. The reaction of later compound with aromatic aldehydes led to formation of the designed compounds. Eleven novel derivatives 1a-k were tested for their cytotoxic activities on three human breast cancer cell lines. RESULTS: Among the synthesized compound, 4-[2-(3-chlorophenyl)-1-(1H-1,2,4-triazol-1-yl)ethenyl]benzonitrile (1c) showed the highest activity against MCF-7 and MDA-MB-231 cell lines and 4-[2-(4-methoxyphenyl)-1-(1H-1,2,4-triazol-1-yl)ethenyl]benzonitrile (1 h) exhibited highest activity against T47D cell line. According to cytotoxic activities results, compound 4-[2-(4-dimethylamino)-1-(1H-1,2,4-triazol-1-yl)ethenyl]benzonitrile (1 k) showed comparative activity against T47D and MDA-MB-231 cell lines with compound (1 h) and our reference drug Etoposide. CONCLUSION: In the process of anti-cancer drug discovery, to find new potential anti-breast cancer agents, we designed and synthesized a novel series of letrozole analogs. Cytotoxicity evaluation revealed that compounds (1c) and (1 k) were the most potent compounds with comparative activity with Etoposide. The results revealed that π-π interactions are responsible for the enzyme inhibitions of compounds (1 c) and (1 k).


Asunto(s)
Antineoplásicos Hormonales/síntesis química , Antineoplásicos Hormonales/farmacología , Inhibidores de la Aromatasa/síntesis química , Inhibidores de la Aromatasa/farmacología , Neoplasias de la Mama/patología , Diseño Asistido por Computadora , Diseño de Fármacos , Simulación del Acoplamiento Molecular , Nitrilos/síntesis química , Nitrilos/farmacología , Triazoles/síntesis química , Triazoles/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Concentración 50 Inhibidora , Letrozol , Células MCF-7 , Estructura Molecular , Relación Estructura-Actividad
15.
Eur J Med Chem ; 82: 233-41, 2014 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-24908652

RESUMEN

The antiestrogenic activity of three natural salpichrolides A, G and B (1, 3 and 4) and of five synthetic analogs containing an aromatic D ring and a simplified side chain (5-9), was evaluated on MCF-7 cells. The 2,3-ene-1-keto steroids 8 and 9 were obtained from 3ß-acetoxy-17(13→18)-abeo-5αH-pregna-13,15,17-trien-20-one, the key step for these syntheses being a Wharton carbonyl rearrangement of a 1,2-epoxy-3-keto steroid to the allylic alcohol using hydrazine hydrate. The antiestrogenic activity was evaluated by performing dose-response experiments in ER(+) MCF-7 breast cancer cells. Dose-dependent proliferation was quantified via [(3)H]-thymidine incorporation after 3 days treatment. Salpichrolides A, G and B and analogs 5, 8 and 9 were active as antiestrogens with compound 9 being the most active of the synthetic analogs. Compounds 5 and 9 were also evaluated against the ER(-) cell line MDA-MB-231 and shown to be inactive.


Asunto(s)
Antineoplásicos Hormonales/farmacología , Ergosterol/análogos & derivados , Antagonistas de Estrógenos/farmacología , Antineoplásicos Hormonales/síntesis química , Antineoplásicos Hormonales/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Ergosterol/síntesis química , Ergosterol/química , Ergosterol/farmacología , Antagonistas de Estrógenos/síntesis química , Antagonistas de Estrógenos/química , Humanos , Células MCF-7 , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales Cultivadas
16.
Bioorg Med Chem Lett ; 23(16): 4617-21, 2013 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-23830503

RESUMEN

We first report the application of 3-acyl-5-hydroxybenzofurans as a scaffold to develop potential drugs for breast cancer. Seven novel derivative compounds were synthesized by using a microwave-assisted synthesis method. Those compounds exhibited different antiproliferation against human breast cancer MCF-7 cells, with the best activity of IC50=43.08µM for compound 1. A Quantum Mechanics Polarized Ligand Docking (QPLD) study was carried out to investigate the binding interactions between these compounds and estrogen receptor alpha (ERα). The simulation results showed that the trend of receptor-ligand binding interactions was same as that of their antiproliferative activities. A detailed analysis indicated that compound 1 possesses the highest Van der Waals and hydrogen bond interactions compared to the other six compounds and better inhibitors are achievable by enhancing the hydrogen bond interactions. Based on these results, we addressed that 3-acyl-5-hydroxybenzofuran is an attractive scaffold for designing drugs against breast cancer.


Asunto(s)
Antineoplásicos Hormonales/síntesis química , Benzofuranos/síntesis química , Neoplasias de la Mama/tratamiento farmacológico , Teoría Cuántica , Antineoplásicos Hormonales/química , Antineoplásicos Hormonales/farmacología , Benzofuranos/química , Benzofuranos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Hidroxilación , Células MCF-7 , Estructura Molecular
17.
Bioorg Med Chem Lett ; 23(6): 1712-5, 2013 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-23403084

RESUMEN

The design and synthesis of 11 fluorinated derivatives of tamoxifen are described. Growth inhibition values (GI50) on human HT-29, M21, MCF7, and MDA-MB-231 tumor cells are also reported. In general, the GI50 values are similar or slightly higher than tamoxifen with the most active compound on MCF7 cell line having a GI50=3.6µM. Surprisingly, as opposed to tamoxifen, both geometrical isomers behave similarly. We hypothesize that this behavior is due to in vitro isomerization of the compounds.


Asunto(s)
Antineoplásicos Hormonales/síntesis química , Tamoxifeno/análogos & derivados , Alquenos/química , Antineoplásicos Hormonales/química , Antineoplásicos Hormonales/toxicidad , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HT29 , Halogenación , Humanos , Células MCF-7 , Estereoisomerismo , Tamoxifeno/síntesis química , Tamoxifeno/toxicidad
18.
Molecules ; 18(1): 914-33, 2013 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-23344201

RESUMEN

We synthesized two series of androstane derivatives as inhibitors of type 3 and type 5 17ß-hydroxysteroid dehydrogenases (17ß-HSDs). In the first series, four monospiro derivatives at position C17 were prepared from androsterone (ADT) or epi-ADT. After the protection of the alcohol at C3, the C17-ketone was alkylated with the lithium acetylide of tetrahydro-2-(but-3-ynyl)-2-H-pyran, the triple bond was hydrogenated, the protecting groups hydrolysed and the alcohols oxidized to give the corresponding 3-keto-17-spiro-lactone derivative. The other three compounds were generated from this keto-lactone by reducing the ketone at C3, or by introducing one or two methyl groups. In the second series, two dispiro derivatives at C3 and C17 were prepared from epi-ADT. After introducing a spiro-δ-lactone at C17 and an oxirane at C3, an aminolysis of the oxirane with L-isoleucine methyl ester provided an amino alcohol, which was treated with triphosgene or sodium methylate to afford a carbamate- or a morpholinone-androstane derivative, respectively. These steroid derivatives inhibited 17ß-HSD3 (14-88% at 1 µM; 46-94% at 10 µM) and 17ß-HSD5 (54-73% at 0.3 µM; 91-92% at 3 µM). They did not produce any androgenic activity and did not bind steroid (androgen, estrogen, glucocorticoid and progestin) receptors, suggesting a good profile for prostate cancer therapy.


Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , Androstanos/síntesis química , Antineoplásicos Hormonales/síntesis química , 17-Hidroxiesteroide Deshidrogenasas/biosíntesis , Androstanos/farmacología , Antineoplásicos Hormonales/farmacología , Carbamatos/síntesis química , Carbamatos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células HEK293 , Humanos , Lactonas/síntesis química , Lactonas/farmacología , Morfolinas/síntesis química , Morfolinas/farmacología , Relación Estructura-Actividad
19.
Curr Med Chem ; 19(34): 5854-62, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22934807

RESUMEN

Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with a poor prognosis. Treatment options for advanced ACC are limited. Indeed, radical tumor resection can lead to local or metastatic recurrence, and mitotane (Lysodren(®)), the only recognized adrenolytic drug, offers modest response rates, notably due to some of its physico-chemical and pharmacological properties (i.e. hydrophobicity, low bioavailability). Meantime, high cumulative doses of Lysodren(®) usually cause systemic toxicities. To reduce adverse health effects, the search of safe and efficient mitotane nano-formulations as well as the full characterization and testing of its enantiomers can represent valuable therapeutic options. Interestingly, recent investigations showed that solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) could considerably improve the efficacy of mitotane (i.e. enhanced solubility and bioavailability, progressive release of the loaded drug into blood and targeted tissues) as well as its safety (i.e. lower toxicity, higher biocompatibility). These two nano-carriers for mitotane delivery and targeting are of particular interest over other polymeric particles (i.e. low-cost, efficient and simple scaling to an industrial production level following green methods). Besides, emerging studies suggested that the S-(-)- mitotane is more potent than the R-(+)-mitotane for ACC treatment. Therefore, the production of pure and active S-(-)-mitotane might offer synergic or additive benefits for ACC patients when combined to solid lipid-based nanocarriers. In this review, we first provide an updated overview of the ACC disease before emphasizing on the promising mitotane drug nano-systems, as well as on the separation, purification and production of single mitotane enantiomer using state-of-art chromatographic-based methods.


Asunto(s)
Carcinoma Corticosuprarrenal/tratamiento farmacológico , Antineoplásicos Hormonales/uso terapéutico , Portadores de Fármacos/química , Lípidos/química , Mitotano/uso terapéutico , Neoplasia Endocrina Múltiple/tratamiento farmacológico , Nanoestructuras/química , Carcinoma Corticosuprarrenal/diagnóstico , Antineoplásicos Hormonales/síntesis química , Antineoplásicos Hormonales/química , Humanos , Mitotano/síntesis química , Mitotano/química , Neoplasia Endocrina Múltiple/diagnóstico , Estereoisomerismo
20.
ACS Chem Neurosci ; 3(2): 105-13, 2012 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-22860180

RESUMEN

We recently found that tamoxifen suppresses l-glutamate transport activity of cultured astrocytes. Here, in an attempt to separate the l-glutamate transporter-inhibitory activity from the estrogen receptor-mediated genomic effects, we synthesized several compounds structurally related to tamoxifen. Among them, we identified two compounds, 1 (YAK01) and 3 (YAK037), which potently inhibited l-glutamate transporter activity. The inhibitory effect of 1 was found to be mediated through estrogen receptors and the mitogen-activated protein kinase (MAPK)/phosphatidylinositol 3-kinase (PI3K) pathway, though 1 showed greatly reduced transactivation activity compared with that of 17ß-estradiol. On the other hand, compound 3 exerted its inhibitory effect through an estrogen receptor-independent and MAPK-independent, but PI3K-dependent pathway, and showed no transactivation activity. Compound 3 may represent a new platform for developing novel l-glutamate transporter inhibitors with higher brain transfer rates and reduced adverse effects.


Asunto(s)
Antineoplásicos Hormonales/farmacología , Ácido Glutámico/metabolismo , Neuroglía/metabolismo , Receptores de Estrógenos/efectos de los fármacos , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacología , Animales , Antineoplásicos Hormonales/síntesis química , Transporte Biológico Activo/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Células Cultivadas , Descubrimiento de Drogas , Transportador 1 de Aminoácidos Excitadores/antagonistas & inhibidores , Transportador 2 de Aminoácidos Excitadores , Espacio Extracelular/metabolismo , Proteínas de Transporte de Glutamato en la Membrana Plasmática/antagonistas & inhibidores , Células HEK293 , Humanos , Espectroscopía de Resonancia Magnética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Neuroglía/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Ratas , Ratas Wistar , Receptores de Estrógenos/agonistas , Tamoxifeno/síntesis química
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