RESUMEN

This is the first report on a unique hybrid molecule made of estradiol and testosterone (TS). This distinctive hybrid molecule (1) was designed to interact with both the estrogen receptor (ER) and the androgen receptor (AR) found in hormone-dependent female and male cancer cells, and was synthesized using ethynylestradiol (17EE) as the estrogenic component and 7α-(4-azido-but-2-enyl)-4-androsten-17ß-ol-3-one as the androgenic counterpart in a seven-step reaction with âˆ¼ 26 % overall yield. We reasoned that the dual receptor binding ability could allow 1 to act as an antihormone. This was tested on hormone-dependent and hormone-independent breast cancer (BCa) and prostate cancer (PCa) cells. The antiproliferative activity was also assessed on colon and skin cancer cells. We found that 1 was active against MCF7 (ER + ) BCa cells (IC50 of 4.9 µM), had lower inhibitory potency on LNCaP (AR + ) PCa cells (IC50 > 5 µM) and no effect on PC3 and DU145 (AR-) PCa cells. This suggests that the estrogenic component of 1 can interact with the ER on MCF7 cells more effectively than the androgenic component with the AR on LNCaP PCa cells, possibly due to a suboptimal spacer or linkage site(s). Nonetheless, the hybrid 1 was active against colon (HT-29) and melanoma (M21) cancer cells (IC50 of 3.5 µM and 2.3 µM, respectively), and had low cross-reactivity with the drug- and androgen-metabolizing cytochrome P450 3A4 (CYP3A4, IC50 ≫ 5 µM). These findings demonstrate the anticancer potential of 1 and warrant further explorations on this new type of hybrids.

Asunto(s)

Antineoplásicos , Proliferación Celular , Estradiol , Testosterona , Humanos , Testosterona/farmacología , Testosterona/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Estradiol/farmacología , Estradiol/química , Estradiol/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Línea Celular Tumoral , Relación Estructura-Actividad , Receptores de Estrógenos/metabolismo , Receptores Androgénicos/metabolismo , Estructura Molecular , Masculino

RESUMEN

The synthesis of a 17α-linked C2-symmetric testosterone dimer and its dihydrotestosterone analog is reported. The dimers were synthesized using a short five-step reaction sequence with 28% and 38% overall yield for the testosterone and dihydrotestosterone dimer, respectively. The dimerization reaction was achieved by an olefin metathesis reaction with 2nd generation Hoveyda-Grubbs catalyst. The dimers and their corresponding 17α-allyl precursors were tested for the antiproliferative activity on androgen-dependent (LNCaP) and androgen-independent (PC3) prostate cancer cell lines. The effects on cells were compared with that of the antiandrogen cyproterone acetate (CPA). The results showed that the dimers were active on both cell lines, with an increased activity towards androgen-dependent LNCaP cells. However, the testosterone dimer (11) was fivefold more active than the dihydrotestosterone dimer (15), with an IC50 of 11.7 µM vs. 60.9 µM against LNCaP cells, respectively, and more than threefold more active than the reference drug CPA (IC50 of 40.7 µM). Likewise, studies on the interaction of new compounds with drug-metabolizing cytochrome P450 3A4 (CYP3A4) showed that 11 was a fourfold stronger inhibitor than 15 (IC50 of 3 µM and 12 µM, respectively). This suggests that changes in the chemical structure of sterol moieties and the manner of their linkage could largely affect both the antiproliferative activity of androgen dimers and their crossreactivity with CYP3A4.

Asunto(s)

Neoplasias de la Próstata , Testosterona , Masculino , Humanos , Testosterona/química , Dihidrotestosterona/farmacología , Dihidrotestosterona/metabolismo , Andrógenos/metabolismo , Andrógenos/farmacología , Citocromo P-450 CYP3A , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Línea Celular , Línea Celular Tumoral

RESUMEN

The conjugation of chitosan 15 and 100 KD with anticancer drugs cis- and trans-Pt (NH3)2Cl2 (abbreviated cis-Pt and trans-Pt) were studied at pH 5-6. Using multiple spectroscopic methods and thermodynamic analysis to characterize the nature of drug-chitosan interactions and the potential application of chitosan nanoparticles in drug delivery. Analysis showed that both hydrophobic and hydrophilic contacts are involved in drug-polymer interactions, while chitosan size and charge play a major role in the stability of drug-polymer complexes. The overall binding constants are Kch-15-cis-Pt = 1.44 (±0.6) × 105 M-1, Kch-100-cis-Pt = 1.89 (±0.9) × 105 M-1 and Kch-15-trans-Pt = 9.84 (±0.5) × 104 M-1, and Kch-100-trans-Pt = 1.15 (±0.6) × 105 M-1. More stable complexes were formed with cis-Pt than with trans-Pt-chitosan adducts, while stronger binding was observed for chitosan 100 in comparison to chitosan 15 KD. This study indicates that polymer chitosan 100 is a stronger drug carrier than chitosan 15 KD in vitro.

Asunto(s)

Antineoplásicos , Quitosano , Nanopartículas , Quitosano/química , Cisplatino/metabolismo , Portadores de Fármacos , Nanopartículas/química , Polímeros

RESUMEN

Amaryllidaceae alkaloids (AAs) are a structurally diverse family of alkaloids recognized for their many therapeutic properties, such as antiviral, anti-cholinesterase, and anticancer properties. Norbelladine and its derivatives, whose biological properties are poorly studied, are key intermediates required for the biosynthesis of all ~650 reported AAs. To gain insight into their therapeutic potential, we synthesized a series of O-methylated norbelladine-type alkaloids and evaluated their cytotoxic effects on two types of cancer cell lines, their antiviral effects against the dengue virus (DENV) and the human immunodeficiency virus 1 (HIV-1), and their anti-Alzheimer's disease (anti-cholinesterase and -prolyl oligopeptidase) properties. In monocytic leukemia cells, norcraugsodine was highly cytotoxic (CC50 = 27.0 µM), while norbelladine was the most cytotoxic to hepatocarcinoma cells (CC50 = 72.6 µM). HIV-1 infection was impaired only at cytotoxic concentrations of the compounds. The 3,4-dihydroxybenzaldehyde (selectivity index (SI) = 7.2), 3',4'-O-dimethylnorbelladine (SI = 4.8), 4'-O-methylnorbelladine (SI > 4.9), 3'-O-methylnorbelladine (SI > 4.5), and norcraugsodine (SI = 3.2) reduced the number of DENV-infected cells with EC50 values ranging from 24.1 to 44.9 µM. The O-methylation of norcraugsodine abolished its anti-DENV potential. Norbelladine and its O-methylated forms also displayed butyrylcholinesterase-inhibition properties (IC50 values ranging from 26.1 to 91.6 µM). Altogether, the results provided hints of the structure−activity relationship of norbelladine-type alkaloids, which is important knowledge for the development of new inhibitors of DENV and butyrylcholinesterase.

Asunto(s)

Alcaloides , Alcaloides de Amaryllidaceae , Amaryllidaceae , Alcaloides/química , Alcaloides/farmacología , Amaryllidaceae/metabolismo , Alcaloides de Amaryllidaceae/química , Antivirales/farmacología , Butirilcolinesterasa , Inhibidores de la Colinesterasa , Humanos , Tiramina/análogos & derivados

RESUMEN

The binding of tRNA to aminobenzoic acid derivatives DAB-0 (N'-[4-(2,5-dioxo-pyrrolidin-1-yl)-benzoyl]-hydrazine carboxylic acid tert-butyl ester) and DAB-1 (N'-[4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-benzoyl]-hydrazine carboxylic acid tert-butyl ester) was investigated in aqueous solution at physiological pH. Thermodynamic parameters ΔH0 -4.8 to -4.30 (kJ mol-1), ΔS0 24.20 to 22 (J mol-1K-1) and ΔG0 -12 to -11.40 (kJ mol-1) showed that DAB-0 and DAB-1 readily bind tRNA via ionic interactions with DAB-1 forming stronger tRNA adducts. Similar binding sites to A-T and G-C bases were located with DAB-0 and DAB-1. The binding efficacy ranged from 40% to 50%. No alteration of tRNA conformation was detected upon drug complexation. Communicated by Ramaswamy H. Sarma.

Asunto(s)

Preparaciones Farmacéuticas , ARN , Sitios de Unión , ARN de Transferencia , Termodinámica

RESUMEN

The synthesis of two isomeric testosterone dimers and an androstenedione dimer is reported. The design takes advantage of an efficient transformation of testosterone leading to the synthesis of the key diene, 7α-(buta-1,3-dienyl)-4-androsten-17ß-ol-3-one, through an elimination reaction. It was found that in some instances the same reaction led to partial epimerization of the 17ß-hydroxyl group into the 17α-hydroxyl group. The specific orientation of the hydroxyl function was confirmed by NMR spectroscopy. Capitalizing on this unforeseen side reaction, several dimers were assembled using an olefin metathesis reaction with Hoveyda-Grubbs catalyst. This led to the formation of two isomeric testosterone dimers with 17α-OH or 17ß-OH (14α and 14ß) as well as an androstenedione dimer (14). The new dimers and their respective precursors were tested on androgen-dependent (LNCaP) and androgen independent (PC3 and DU145) prostate cancer cells. It was discovered that the most active dimer was made of the natural hormone testosterone (14ß) with an average IC50 of 13.3 µM. In LNCaP cells, 14ß was ∼5 times more active than the antiandrogen drug cyproterone acetate (IC50 of 12.0 µM vs. 59.6 µM, respectively). At low concentrations (0.25-0.5 µM), 14α and 14ß were able to completely inhibit LNCaP cell growth induced by testosterone or dihydrotestosterone. Furthermore, cross-reactivity of androgen-based dimers with sterol-metabolizing cytochrome P450 3A4 was explored and the results are disclosed herein.

Asunto(s)

Androstenodiona/farmacología , Antineoplásicos/farmacología , Citocromo P-450 CYP3A/metabolismo , Diseño de Fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Testosterona/farmacología , Androstenodiona/síntesis química , Androstenodiona/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Dimerización , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Estructura Molecular , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Proteínas Recombinantes , Relación Estructura-Actividad , Testosterona/síntesis química , Testosterona/química , Células Tumorales Cultivadas

RESUMEN

The design of C2-symmetric biologically active molecules is a subject of interest to the scientific community. It provides the possibility of discovering medicine with higher biological potential than the parent drugs. Such molecules are generally produced by classic chemistry, considering the shortness of reaction sequence and the efficacy for each step. This review describes and analyzes recent advances in the field and emphasizes selected C2-symmetric molecules (or axial symmetric molecules) made during the last 10 years. However, the description of the dimers is contextualized by prior work allowing its development, and they are categorized by their structure and/or by their properties. Hence, this review presents dimers composed of steroids, sugars, and nucleosides; known and synthetic anticancer agents; polyphenol compounds; terpenes, known and synthetic antibacterial agents; and natural products. A special focus on the anticancer potential of the dimers transpires throughout the review, notwithstanding their structure and/or primary biological properties.

Asunto(s)

Antibacterianos/química , Antineoplásicos/química , Productos Biológicos/química , Terpenos/química , Antibacterianos/uso terapéutico , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Productos Biológicos/uso terapéutico , Dimerización , Humanos , Nucleósidos/química , Esteroides/química , Relación Estructura-Actividad

RESUMEN

Muscle-invasive bladder cancer (MIBC) is an aggressive form of urothelial bladder carcinoma (UBC) with poorer outcomes compared to the non-muscle invasive form (NMIBC). Higher recurrent rates and rapid progression after relapse in UBC is known to be linked with chronic inflammation. Here, the preclinical murine models of NMIBC (MB49) and MIBC (MB49-I) were used to assess the antitumor effects of DAB-1, an anti-inflammatory aminobenzoic acid derivative we have developed in order to target cancer-related inflammation. A subchronic toxicity study on cancer-free mice shown that DAB-1 treatment did not affect normal mouse development or normal function of vital organs. In mice bearing MB49-I tumors, whole body accumulation of the radioconjugate [131I]DAB-1 was higher than in control mice, the main sites of [131I]DAB-1 accumulation being the liver (34%), the intestines (21%), and the tumors (18%). In vivo molecular therapy of ectopic and orthotopic tumors indicated that treatment with DAB-1 efficiently inhibited tumor growth, metastasis formation, and mortality rate. The antitumor efficacy of DAB-1 was associated with strong decreased tumor cell proliferation and iNOS expression in tumor tissues and deactivation of macrophages from tumor-bearing mice. Mechanistic investigations revealed that DAB-1 efficiently inhibited i) TNFα/NFΚB and IL6/STAT3 signaling pathways activation; ii) TNFα-induced NO production by decreasing NFΚB transcriptional activation and functional iNOS expression; and iii) cellular proliferation with minimal or no effects on cell mortality or apoptosis. In conclusion, this study provides preclinical and biological/mechanistic data highlighting the potential of DAB-1 as a safe and efficient therapeutic agent for the treatment of patients with NMIBC and MIBC.

Asunto(s)

Aminobenzoatos/farmacología , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Aminobenzoatos/química , Aminobenzoatos/farmacocinética , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones Endogámicos C57BL , Metástasis de la Neoplasia , Transducción de Señal/efectos de los fármacos , Carga Tumoral/efectos de los fármacos , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología

RESUMEN

Prostate cancer is the most diagnosed type of cancer in men in Canada. One out of eight men will be stricken with this disease during the course of his life. It is noteworthy that, at initial diagnoses 80-90% of cancers are androgen dependent. Hence, the androgen receptor is a viable biological target to be considered for drug targeting. We have developed a new generation of testosterone-Pt(II) hybrids for site-specific treatment of hormone-dependent prostate cancer. The hybrid molecules are made from testosterone using an eight-step reaction sequence with about 7% overall yield. They are linked with a stronger tether chain between the testosterone moiety and the Pt(II) moiety in comparison to our first generation hybrids. The new hybrids were tested on hormone-dependent and -independent prostate cancer cell lines. The hybrid 3a presents the best antiproliferative activity and was selective on hormone-dependent prostate cancer with IC50 of 2.2 µM on LNCaP (AR+) in comparison to 13.3 µM on PC3 (AR-) and 8.8 µM on DU145 (AR-) prostate cancer cells. On the same cell lines, CDDP displayed IC50 of 2.1 µM, 0.5 µM and 1.0 µM, respectively. Remarkably, hybrid 3a was inactive on both colon carcinoma (HT-29) and normal human adult keratinocyte cells (HaCat) with an IC50 of >25 µM. This is not the case for CDDP showing IC50 of 1.3 µM and 5.1 µM on HT-29 and HaCat cells, respectively. The potential for selective activity on androgen-receptor positive prostate cancer cells is confirmed with hybrid 3a giving new hope for an efficient and less toxic platinum-based treatment of prostate cancer patients.

Asunto(s)

Antineoplásicos/farmacología , Diseño de Fármacos , Compuestos Organoplatinos/farmacología , Platino (Metal)/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/metabolismo , Testosterona/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Estructura Molecular , Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/química , Platino (Metal)/química , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Relación Estructura-Actividad , Testosterona/química

Asunto(s)

Antineoplásicos/farmacología , Descubrimiento de Drogas/métodos , Neoplasias/tratamiento farmacológico , Animales , Desarrollo de Medicamentos/métodos , Industria Farmacéutica/organización & administración , Humanos

RESUMEN

BACKGROUND: Amaryllidaceae alkaloids (AAs) are a large group of plant-specialized metabolites displaying an array of biological and pharmacological properties. Previous investigations on AA biosynthesis have revealed that all AAs share a common precursor, norbelladine, presumably synthesized by an enzyme catalyzing a Mannich reaction involving the condensation of tyramine and 3,4-dihydroxybenzaldehyde. Similar reactions have been reported. Specifically, norcoclaurine synthase (NCS) which catalyzes the condensation of dopamine and 4-hydroxyphenylacetaldehyde as the first step in benzylisoquinoline alkaloid biosynthesis. RESULTS: With the availability of wild daffodil (Narcissus pseudonarcissus) database, a transcriptome-mining search was performed for NCS orthologs. A candidate gene sequence was identified and named norbelladine synthase (NBS). NpNBS encodes for a small protein of 19 kDa with an anticipated pI of 5.5. Phylogenetic analysis showed that NpNBS belongs to a unique clade of PR10/Bet v1 proteins and shared 41% amino acid identity to opium poppy NCS1. Expression of NpNBS cDNA in Escherichia coli produced a recombinant enzyme able to condense tyramine and 3,4-DHBA into norbelladine as determined by high-resolution tandem mass spectrometry. CONCLUSIONS: Here, we describe a novel enzyme catalyzing the first committed step of AA biosynthesis, which will facilitate the establishment of metabolic engineering and synthetic biology platforms for the production of AAs.

Asunto(s)

Alcaloides de Amaryllidaceae/metabolismo , Amaryllidaceae/enzimología , Proteínas de Plantas/metabolismo , Tiramina/análogos & derivados , Amaryllidaceae/genética , Amaryllidaceae/metabolismo , Secuencia de Aminoácidos , Benzaldehídos/metabolismo , Ligasas de Carbono-Nitrógeno/genética , Ligasas de Carbono-Nitrógeno/metabolismo , Catecoles/metabolismo , Clonación Molecular , Filogenia , Proteínas de Plantas/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Alineación de Secuencia , Tiramina/biosíntesis , Tiramina/metabolismo

RESUMEN

A series of 7α-linked testosterone dimers were made and tested for biological activity on both androgen-dependent (LNCaP) and androgen-independent (DU-145 and PC3) prostate cancer cell lines. The synthesis proceeds through the formation of a trans-4-(17ß-acetoxy-4-androsten-3-one-7α-yl)-but-2-enoic acid 4-hydroxy-alkyl ester intermediate of various length (7a-d) followed by the final dimerization step. The dimers showed interesting biological activity in comparison to the ω-hydroxyalkyl ester intermediates 7a-d. The most active dimer 8a (n=1) showed IC50 of 3.8, 1.4 and 1.8µM, respectively on LNCaP, DU-145 and PC3 cancer cell lines. On these cell lines, this dimer is about 12, 70 and 47 times more powerful than cyproterone acetate (CPA) the reference antiandrogen. Furthermore, dimers 8b-d (n=2, 3, 4) were less active than 8a but showed selective activity on androgen-dependent LNCaP prostate cancer cells. This indicates possible application for the treatment of androgen-dependent prostate cancer.

Asunto(s)

Andrógenos/metabolismo , Neoplasias de la Próstata/metabolismo , Testosterona/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Estructura Molecular , Testosterona/química

RESUMEN

Cytochrome P450 CYP3A4 is the main drug-metabolizing enzyme in the human liver, being responsible for oxidation of 50% of all pharmaceuticals metabolized by human P450 enzymes. Possessing a large substrate binding pocket, it can simultaneously bind several substrate molecules and often exhibits a complex pattern of drug-drug interactions. In order to better understand structural and functional aspects of binding of multiple substrate molecules to CYP3A4 we used resonance Raman and UV-VIS spectroscopy to document the effects of binding of synthetic testosterone dimers of different configurations, cis-TST2 and trans-TST2. We directly demonstrate that the binding of two steroid molecules, which can assume multiple possible configurations inside the substrate binding pocket of monomeric CYP3A4, can lead to active site structural changes that affect functional properties. Using resonance Raman spectroscopy, we have documented perturbations in the ferric and Fe-CO states by these substrates, and compared these results with effects caused by binding of monomeric TST. While the binding of trans-TST2 yields results similar to those obtained with monomeric TST, the binding of cis-TST2 is much tighter and results in significantly more pronounced conformational changes of the porphyrin side chains and Fe-CO unit. In addition, binding of an additional monomeric TST molecule in the remote allosteric site significantly improves binding affinity and the overall spin shift for CYP3A4 with trans-TST2 dimer bound inside the substrate binding pocket. This result provides the first direct evidence for an allosteric effect of the peripheral binding site at the protein-membrane interface on the functional properties of CYP3A4.

Asunto(s)

Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/metabolismo , Testosterona/análogos & derivados , Sitio Alostérico , Sitios de Unión , Humanos , Unión Proteica , Espectrometría Raman , Testosterona/química , Testosterona/metabolismo

RESUMEN

INTRODUCTION: The hybridization of biologically active molecules is a powerful tool for drug discovery used to target a variety of diseases. It offers the prospect of better drugs for the treatment of a number of illnesses including cancer, malaria, tuberculosis and AIDS. Hybrid drugs can provide combination therapies in a single multi-functional agent and, by doing so, be more specific and powerful than conventional classic treatments. This research field is in great expansion and attracts many researchers worldwide. AREA COVERED: This review covers the main research published between early 2013 to mid-2015 and takes into account several previous reviews on the subject. Its intention is to showcase the most recent advances reported towards the development of molecular hybrids in drug discovery. Particular attention is given to anticancer hybrids throughout the review. EXPERT OPINION: Current advances show that molecular hybrids of biologically active molecules can lead to powerful therapeutics. Natural products play a key role in this field. It is also believed that toxin hybrids present a great opportunity for future progress and should be further explored. Furthermore, the synthesis of hybrid organometallics should be systematically studied as it can lead to potent drugs. The crucial requirement for growth still remains the efficacy of synthesis. Hence, the development of efficient synthetic methods allowing rapid access to diverse series of hybrids must be further investigated by researchers.

Asunto(s)

Antineoplásicos/administración & dosificación , Diseño de Fármacos , Descubrimiento de Drogas/métodos , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Productos Biológicos/administración & dosificación , Productos Biológicos/química , Productos Biológicos/farmacología , Humanos , Neoplasias/tratamiento farmacológico , Compuestos Organometálicos/química

RESUMEN

The search for new specific chemotherapeutic drugs designed to minimize the toxic side effects resulting from chemotherapy is still a subject of intense research. The objective of the current study was to design a non-steroidal-platinum(II) derivative that would target the estrogen receptor alpha (ERα) without triggering estrogenic cell proliferation. For this purpose, the amino acid L-tyrosine was modified and attached to a cisplatin analog. Hence, the L-tyrosine portion of the molecule could possibly act as a transporter to target the ERα protein and, by doing so concentrate the cytotoxic moiety to hormone-dependent breast cancer cells. Herein, we describe three different alternative methodologies that were used to make these new anticancer molecules. The L-tyrosine-Pt(II) hybrid 5b was made in four steps with 36% overall yield by the first method, in six steps with 11% overall yield by the second method and, in four steps with 23% overall yield by the third method. Preliminary biological activity on breast cancer cell lines indicated that the final hybrids (5a and 5b) were unfortunately inactive but their platinum(II) precursors (14a and 14b) showed activity similar to that of cisplatin.

Asunto(s)

Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Compuestos Organoplatinos/química , Compuestos Organoplatinos/farmacología , Tirosina/química , Tirosina/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células MCF-7 , Estructura Molecular , Compuestos Organoplatinos/síntesis química , Relación Estructura-Actividad

RESUMEN

Inflammation plays a crucial role in many types of cancer and is known to be involved in their initiation and promotion. As such, it is presently recognized as an important risk factor for several types of cancers such as bladder, prostate and breast cancers. The discovery of novel anti-inflammatory compounds can have a huge implication not only for the treatment of cancer but also as preventive and protective treatment modalities. We have recently identified a new compound (1) that presents interesting anti-inflammatory activity. In order to better understand its biological action, we have divided the molecule in its basic components and verified their respective contribution towards the anti-inflammatory response of the whole molecule. We have discovered that only the combination of the maleimide function together with the tert-butyloxycarbonylhydrazinamide function lead to important anti-inflammatory properties. The main derivative 1 can decrease the activating effects of INFγ or IL6 on human (hMϕs) macrophages by 38% or by 64% at a concentration of 10 µM as indicated by a decrease of STAT1 or STAT3 activation. The expression of pro-inflammatory markers CD40 and MHCII in INFγ stimulated hMϕs were reduced by 87% and 49%, respectively with a 3 h pretreatment of 1 at 10 µM. The cell motility assay revealed that 1 at 10 µM can reduce relative cell motility induced by IL6 by 92% in comparison with the untreated control hMϕ monolayers. Compound 1 reduced by 91% the inflammatory response induced by the cytokines (INFγ + TNFα) in the macrophage-like J774A.1 cells at a concentration of 25 µM, as measured by the detection of NO production with the Griess reagent. Furthermore, upon removal of the tert-butyloxycarbonyl protective group the unprotected derivative as a hydrochloride salt (1A) retains interesting anti-inflammatory activity and was found to be less toxic than the parent compound (1).

Asunto(s)

Antiinflamatorios no Esteroideos/farmacología , Antineoplásicos/farmacología , Ácidos Carboxílicos/farmacología , Hidrazinas/farmacología , Macrófagos/efectos de los fármacos , Maleimidas/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Hidrazinas/síntesis química , Hidrazinas/química , Maleimidas/síntesis química , Maleimidas/química , Ratones , Estructura Molecular , Óxido Nítrico/biosíntesis , Relación Estructura-Actividad , Neoplasias de la Vejiga Urinaria/metabolismo

RESUMEN

Prostate cancer (PC) is a major health issue in the world. Treatments of localized PC are quite efficient and usually involve surgery, radiotherapy and/or hormonal therapy. Metastatic PC is however rarely curable to this day. Treatments of metastatic PC involve radiotherapy, chemotherapy and hormonal treatment such as orchiectomy, antiandrogens and luteinizing hormone-releasing hormone agonists. The suppression of tumor growth by hormonal treatment is efficient but overtime resistance still occurs and the disease progresses. Thus, more urgently than ever there is a need for discovery of new treatment options for castration-resistant PC (CRPC). Hence, we designed and tested a series of amide derivatives located at position 7α of testosterone as prospective "natural" or "semisynthetic" anticancer agents against CRPC with the goal of discovering therapeutic alternatives for the disease. This manuscript describes an efficient path towards the target molecules that are made in only 6 or 7 chemical steps from testosterone in good overall yields. This strategy can be used to make several compounds of interest that present higher biological activity than the classic antiandrogen; cyproterone acetate (3). The best testosterone-7α-amide was the N-2-pyridylethylamide (25) which was as active as the antiandrogen cyproterone acetate (3) on androgen-dependent LNCaP cells and 2.7 times more active on androgen-independent PC3 prostate cancer cells. The results obtained show the synthetic feasibility and the potential for future development of this unique class of semi-synthetic anticancer agents that offer the premise of new treatment modalities for patients afflicted with CRPC.

Asunto(s)

Antineoplásicos/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Testosterona/análogos & derivados , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Estructura Molecular , Neoplasias de la Próstata/patología , Relación Estructura-Actividad , Testosterona/química , Testosterona/farmacología

RESUMEN

The intercalation of antitumor drug doxorubicin (DOX) and its analogue N-(trifluoroacetyl) doxorubicin (FDOX) with DNA duplex was investigated, using FTIR, CD, fluorescence spectroscopic methods and molecular modeling. Both DOX and FDOX were intercalated into DNA duplex with the free binding energy of -4.99 kcal for DOX-DNA and -4.92 kcal for FDOX-DNA adducts and the presence of H-bonding network between doxorubicin NH2 group and cytosine-19. Spectroscopic results showed FDOX forms more stable complexes than DOX with KDOX-DNA=2.5(± 0.5)× 10(4)M(-1) and KFDOX-DNA=3.4(± 0.7)× 10(4)M(-1). The number of drug molecules bound per DNA (n) was 1.2 for DOX and 0.6 for FDOX. Major alterations of DNA structure were observed by DOX intercalation with a partial B to A-DNA transition, while no DNA conformational changes occurred upon FDOX interaction. This study further confirms the importance of unmodified daunosamine amino group for optimal interactions with DNA. The results of in vitro MTT assay carried out on SKC01 colon carcinoma corroborate the observed DNA interactions. Such DNA structural changes can be related to doxorubicin antitumor activity, which prevents DNA duplication.

Asunto(s)

Antineoplásicos/química , Antineoplásicos/farmacología , Aductos de ADN/metabolismo , ADN/metabolismo , Doxorrubicina/química , Doxorrubicina/farmacología , Sustancias Intercalantes/química , Carcinoma/tratamiento farmacológico , Carcinoma/metabolismo , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Aductos de ADN/química , Doxorrubicina/metabolismo , Humanos , Conformación de Ácido Nucleico

RESUMEN

Prostate cancer is a major public health problem worldwide and, more specifically, new treatments for hormone-refractory cancers are highly sought by several research groups. Although platinum(II)-based chemotherapy and other strategies grow in interest to treat castration-resistant prostate cancer (CRPC), they still exhibit modest activity on CRPC and overall patient survival. In this study, we designed and prepared new combi-molecules using 17ß-acetyl-testosterone and amino acid platinum(II) complexes linked at the position 7α to target and to improve the antiproliferative activity of platinum(II)-based chemotherapy on prostate cancer cells. Twelve chemical intermediates and six new combi-molecules were prepared and characterized. Structure-activity relationships studies show that the platinum complex moiety is essential for an optimal cytocidal activity. Moreover, stereochemistry of the amino acid involved in the platinum complexes had only minor effects on the antiproliferative activity whereas pyridinyl (10a and b) and thiazolyl (10f) complexes exhibited the highest cytocidal activities that are significantly superior to that of cisplatin used as control on human prostate adenocarcinoma LNCaP (AR+), PC3 (AR-) and DU145 (AR-). Compounds 10a, b and f arrested the cell cycle progression in S-phase and induced double strand breaks as confirmed by the phosphorylation of histone H2AX into γH2AX. Compounds 10a and f showed 33 and 30% inhibition, respectively of the growth of HT-1080 tumors grafted onto chick chorioallantoic membranes. Finally, compounds 10a and 10f exhibited low toxicity on the chick embryos (18 and 21% of death, respectively), indicating that these new combi-molecules might be a promising new class of anticancer agents for prostate cancer.

Asunto(s)

Diseño de Fármacos , Platino (Metal)/química , Neoplasias de la Próstata/tratamiento farmacológico , Testosterona/análogos & derivados , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Bioensayo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Embrión de Pollo , Humanos , Concentración 50 Inhibidora , Masculino , Modelos Animales , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Compuestos Organometálicos/toxicidad , Relación Estructura-Actividad , Testosterona/química , Testosterona/farmacología , Testosterona/toxicidad

RESUMEN

The binding sites of antitumor drug doxorubicin (DOX) and its analogue N-(trifluoroacetyl) doxorubicin (FDOX) with tRNA were located, using FTIR, CD, fluorescence spectroscopic methods and molecular modeling. Different binding sites are involved in drug-tRNA adducts with DOX located in the vicinity of A-29, A-31, A-38, C-25, C-27, C-28, G-30 and U-41, while FDOX bindings involved A-23, A-44, C-25, C-27, G-24, G-42, G-53, G-45 and U-41 with similar free binding energy (-4.44 for DOX and -4.41 kcal/mol for FDOX adducts). Spectroscopic results showed that both hydrophilic and hydrophobic contacts are involved in drug-tRNA complexation and FDOX forms more stable complexes than DOX with K DOX-tRNA=4.7 (± 0.5)× 10(4) M(-1) and K FDOX-tRNA=6.3 (± 0.7)× 10(4) M(-1). The number of drug molecules bound per tRNA (n) was 0.6 for DOX and 0.4 for FDOX. No major alterations of tRNA structure were observed and tRNA remained in A-family conformation, while biopolymer aggregation and particle formation occurred at high drug concentrations.

Asunto(s)

Antineoplásicos/metabolismo , Doxorrubicina/análogos & derivados , Doxorrubicina/metabolismo , ARN de Transferencia/metabolismo , Antineoplásicos/química , Dicroismo Circular , Doxorrubicina/química , Estabilidad de Medicamentos , Concentración de Iones de Hidrógeno , Cinética , Simulación del Acoplamiento Molecular , Conformación de Ácido Nucleico , Estabilidad del ARN , ARN de Transferencia/química , Ribonucleótidos/química , Soluciones , Espectrometría de Fluorescencia , Espectroscopía Infrarroja por Transformada de Fourier , Termodinámica