RESUMEN
Vitamin D deficiency might cause a wide variety of human disorders. As a prerequisite for appropriate diagnosis and therapy, medicinally relevant vitamin D metabolites have to be assayed most accurately and with high specificity. It has been demonstrated, that vitamin D conjugates, linked via a hydroxyl group at C11, might be promising for the development of highly specific antibodies to be employed in competitive protein binding assays. The connective synthesis of 3-TBDMS-11α,25-dihydroxyvitamin D3 and D2 ethers in 500â¯mg scale, starting from vitamin D2, is described. For installation of a hydroxyl group at C11 a sequence of Pd(OAc)2 mediated oxidation of an enone, epoxidation and subsequent epoxide ring opening was applied to obtain a suitable CD-ring precursor, that was connected with an A-ring diphenylphosphine oxide by Wittig-Horner reaction. Finally, an appropriate side chain was installed, respectively.
Asunto(s)
Colecalciferol/análogos & derivados , Colecalciferol/síntesis química , Ergocalciferoles/síntesis química , Éteres/síntesis químicaRESUMEN
Experimental data indicate that low-calcemic vitamin D derivatives (VDDs) exhibit anticancer properties, both in vitro and in vivo. In our search for a vitamin D analog as potential anticancer agent, we investigated the influence of chirality in the side chain of the derivatives of 1,25-dihydroxyergocalciferol (1,25D2) on their activities. In this study, we synthesized modified analogs at the side chain and the A-ring, which differed from one another in their absolute configuration at C-24, namely (24S)- and (24R)-1,25-dihydroxy-19-nor-20a-homo-ergocalciferols (PRI-5105 and PRI-5106, respectively), and evaluated their activity. Unexpectedly, despite introducing double-point modifications, both analogs served as very good substrates for the vitamin D-hydroxylating enzyme. Irrespective of their absolute C-24 configuration, PRI-5105 and PRI-5106 showed relatively low resistance to CYP24A1-dependent metabolic deactivation. Additionally, both VDDs revealed a similar antiproliferative activity against HT-29 colorectal cancer cells which was higher than that of 1,25D3, the major biologically active metabolite of vitamin D. Furthermore, PRI-5105 and PRI-5106 significantly enhanced the cell growth-inhibitory activity of 5-fluorouracil on HT-29 cell line. In conclusion, although the two derivatives showed a relatively high anticancer potential, they exhibited undesired high metabolic conversion.
Asunto(s)
Antineoplásicos/síntesis química , Neoplasias Colorrectales/metabolismo , Ergocalciferoles/síntesis química , Vitamina D3 24-Hidroxilasa/metabolismo , Vitamina D/análogos & derivados , Antineoplásicos/química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Sinergismo Farmacológico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Ergocalciferoles/química , Ergocalciferoles/farmacología , Fluorouracilo/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HCT116 , Células HT29 , Humanos , Estructura Molecular , Transducción de Señal/efectos de los fármacos , Vitamina D/químicaRESUMEN
Camptothecin (CPT), a potent anticancer drug with known antiviral activity, is halted of clinical use. Few drug delivery systems of CPT are approved for therapy. Hereby, we propose the encapsulation of hydrophobic CPT in the inner core of cellulose nanoaggregates for sustained release with retaining of antiproliferative activity. Cellulose conjugates were synthesized by esterification of methyl cellulose, hydroxyethyl cellulose and (hydroxypropyl)methyl cellulose with testosterone, ergocalciferol and dl-α-tocopherol hemisuccinates. The degree of substitution attained ranged from 0.004 to 0.025 and no depolymerization was observed by size exclusion chromatography. ATR-FTIR and NMR spectroscopies confirmed grafting of testosterone and vitamins to celluloses. According to dynamic light scattering, it resulted in their self-assembly in aqueous medium as stable and slightly negatively charged nanoaggregates of 213 to 731 nm. Nanoaggregates formation was also assessed using transmission electron and atomic force microscopies. CPT was encapsulated in the cellulose nanoaggregates, achieving a content of 1.7-13.0 wt %. Sustained release of camptothecin over 150 h was observed in simulated physiological conditions. CPT-loaded cellulose nanoparticles appeared to be possible candidates for chemotherapy, according to observed cytotoxicity against MCF-7 cancer cells.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Camptotecina/farmacología , Celulosa/análogos & derivados , Preparaciones de Acción Retardada/química , Testosterona/análogos & derivados , Vitaminas/química , Antineoplásicos Fitogénicos/química , Camptotecina/química , Celulosa/síntesis química , Preparaciones de Acción Retardada/síntesis química , Liberación de Fármacos , Ergocalciferoles/síntesis química , Ergocalciferoles/química , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Células MCF-7 , Nanoestructuras/química , Tamaño de la Partícula , Testosterona/síntesis química , Vitamina E/análogos & derivados , Vitamina E/síntesis química , Vitaminas/síntesis químicaRESUMEN
In recent years the apparent impact of vitamin D deficiency on human health has gained increased awareness. Consequently, the development of appropriate assays to measure the status of medicinally most relevant vitamin D metabolites in human blood, serum or relevant tissue is continuously being improved. Particularly, assaying of 1α,25-dihydroxyvitamin D3, in turn considered as the most active metabolite, is mainly indicated in disorders leading to calcaemia or those resulting from an impaired 1α-hydroxylation of 25-hydroxyvitamin D3. Thus, in some competitive protein binding and ELISA assays, biotin-linked 1α,25-dihydroxyvitamin D3 (1α,25-dihydroxyvitamin D3 LC-biotin) is employed for measurement of actual calicitriol concentration. A new efficient synthesis of 1α,25-dihydroxyvitamin D3 LC-biotin is described, starting with readily available vitamin D2, and combining a classical approach to access 1α,25-dihydroxyvitamin D3, appropriate OH-protective group transformations, and a C-3-O-alkylation, suitable to connect the biotin-linker in a reliable, selective and high yielding strategy. The developed methodology is applicable to the synthesis of a wide variety of C-3-OH-linked vitamin D3 and D2 derivatives.
Asunto(s)
Biotina/síntesis química , Calcitriol/síntesis química , Técnicas de Química Sintética/métodos , Alquilación , Biotina/química , Calcitriol/química , Ergocalciferoles/síntesis química , Ergocalciferoles/químicaRESUMEN
As part of our program on search for vitamin D analogs with selective biological properties, such as low or negligible calcemic action, we describe here an efficient and versatile synthetic approach to derivatives of 1α,25-dihydroxyvitamin D2 with homologated side-chains and substitution at C24 for biological evaluation.
Asunto(s)
Técnicas de Química Sintética/métodos , Ergocalciferoles/síntesis química , Vitaminas/síntesis química , Ergocalciferoles/química , Estereoisomerismo , Vitaminas/químicaRESUMEN
A synthesis of hortonones A-C has been accomplished from vitamin D2via the Inhoffen-Lythgoe diol without the use of protective groups. Key steps in the syntheses include a TMS-diazomethane mediated regioselective homologation of the cyclohexanone ring to a cycloheptanone moiety and a sodium naphthalenide-mediated allylic alcohol transposition. It has been found that the absolute configuration of the natural hortonones is opposite that of the synthetic material prepared from vitamin D2.
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Diterpenos/síntesis química , Alcoholes/síntesis química , Alcoholes/química , Antineoplásicos Fitogénicos/química , Ciclohexanonas/síntesis química , Ciclohexanonas/química , Diazometano/síntesis química , Diazometano/química , Diterpenos/química , Ergocalciferoles/síntesis química , Ergocalciferoles/química , Monimiaceae/química , EstereoisomerismoRESUMEN
Due to the widespread impact of vitamin D on human health, the development of appropriate assays to detect deficiency of all vitamin D metabolites of pharmacological interest is being continuously improved. Although over 50 naturally-occurring metabolites of vitamin D are known to date, only very few are routinely detected in commercially available assays. This is particularly true regarding C3-epimers of vitamin D3 and D2, which not only may interfere in analytical measurements with other metabolites of interest, but also have controversial and not yet fully understood physiological functions. In this study we optimized a synthetic method to obtain various vitamin D3 and D2 C3-epimers in order to make them available in gram quantities for further evaluation and for their use in assay development or drug discovery. Particularly, the inversion of the C3-OH group at the A-ring of vitamin D2, which, in turn, serves as a suitable starting material for most of chemical syntheses of vitamin D metabolites, can be converted to the corresponding C3-epimer under so-called "Mitsunobu conditions". Thus, the C3-OH group is converted into the corresponding ester by treatment with an aromatic acid, subsequent addition of an azodicarboxlate and triphenylphoshine, leading to the corresponding ester, concomitant to the inversion of the stereogenic center at C3. Reduction or saponification of the resulting ester finally leads to the corresponding C3-epimer, that may serve as starting material for a wide variety of vitamin D3 and D2 C3-epimers.
Asunto(s)
Colecalciferol/síntesis química , Ergocalciferoles/síntesis química , HumanosRESUMEN
An improved convergent strategy was developed for the synthesis of the previously obtained side-chain extended and rigidified analogs of 1α,25-dihydroxyvitamin D2, PRI-1906 and PRI-1907. New (24Z) geometric isomers of the analogs, PRI-1916 and PRI-1917, were also obtained and identified. These side-chain isomers were separable by flash chromatography, as C-25 alcohols, from the synthetic precursors of PRI-1906 and PRI-1907, respectively. The structures of new analogs were determined by advanced techniques of 1H and 13C NMR, including COSY, HSQC and HMBC sequences. Binding affinities of the geometric analogs PRI-1906 and PRI-1916 and their respective C-26, C-27 homologs PRI-1907 and PRI-1917 for the full-length human vitamin D receptor were determined by a fluorescence polarization competition assay. The binding affinity of (24Z) methyl analog PRI-1906 was much higher than that of (24E) analog PRI-1906, while the affinity of (24Z) ethyl analog PRI-1917 was lower than that of the respective PRI-1907. Investigation of the metabolism of these compounds by human CYP24A1 revealed they are much more resistant to CYP24A1 than 1α,25-dihydroxyvitamin D2, indicating they could have longer-term biological effects on target tissues.
Asunto(s)
Ergocalciferoles/química , Ergocalciferoles/síntesis química , Unión Competitiva , Cromatografía Líquida de Alta Presión , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Escherichia coli/metabolismo , Ésteres/química , Humanos , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Isoformas de Proteínas , Receptores de Calcitriol/genética , Proteínas Recombinantes/química , Espectrometría de Fluorescencia , Resultado del Tratamiento , Vitamina D3 24-Hidroxilasa/genética , Vitamina D3 24-Hidroxilasa/metabolismoRESUMEN
1α,25-Dihydroxyvitamin D3 [1,25(OH)2D3] is known to act as a powerful differentiation inducer in various types of cancer cells, including acute myeloid leukemia (AML) cells. However, supraphysiological concentrations of 1,25(OH)2D3 required to induce terminal maturation of AML cells can cause lethal hypercalcemia in vivo. Here we characterized the differentiation-inducing effects of novel double-point modified analogs of 1,25-dihydroxyvitamin D2 [1,25(OH)2D2], PRI-5201 and PRI-5202 [Pietraszek et al. (2013) Steroids, 78:1003-1014], on HL60, U937 and MOLM-13 human AML cells in comparison with their direct precursors (PRI-1906 and PRI-1907, respectively) and 1,25(OH)2D3. The results demonstrated the following order of potency for the tested compounds: PRI-5202>PRI-1907>PRI-5201>PRI-1906≥1,25(OH)2D3, as determined by measuring the expression of cell surface markers of myeloid differentiation. Particularly, the sensitivity of different AML cell lines to PRI-5201 and PRI-5202 was 3-15-fold and 13-50 fold higher, respectively, compared to that of 1,25(OH)2D3. Importantly, all the analogs tested at 0.25-1nM concentrations retained the ability of 1,25(OH)2D3 to cooperate with the rosemary polyphenol carnosic acid, which strongly potentiated their prodifferentiation activity in a cell type-dependent manner. These synergistic effects were associated with increased induction of the vitamin D receptor (VDR) protein expression. However, surprisingly, carnosic acid was able to significantly enhance only 1,25(OH)2D3-induced transactivation of the direct repeat 3 (DR3)-type vitamin D response element (VDRE), whereas no such cooperation was seen with 1,25(OH)2D2 analogs. Furthermore, dose-response analysis revealed that 1,25(OH)2D3 was more efficacious than the analogs in inducing VDRE activation. This suggests that the superior prodifferentiation activity of the analogs, as compared to 1,25(OH)2D3, may be due to their potential for enhanced activation of the differentiation-related VDRE(s) that differ from the DR3-type element tested in this study. Collectively, the results demonstrate that the new double-point modified 1,25(OH)2D2 analogs are much stronger inducers of myeloid differentiation than 1,25(OH)2D3 and that their efficacy can be further enhanced by combination with plant polyphenols. These combinations warrant their further mechanistic and translational exploration in AML and other types of cancer.
Asunto(s)
Ergocalciferoles/química , Ergocalciferoles/síntesis química , Leucemia Mieloide Aguda/patología , Polifenoles/química , Abietanos/química , Antineoplásicos/química , Diferenciación Celular , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Ensayos de Selección de Medicamentos Antitumorales , Genes Reporteros , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Mutación Puntual , Receptores de Calcitriol/metabolismo , Activación Transcripcional/efectos de los fármacosRESUMEN
There is a long lasting controversy over the biological activity of vitamin D2 as compared to vitamin D3 in terms of maintaining of calcium homeostasis and raising the level of circulating 25-OH-D. To shed more light on this relationship we synthesized 1α,25-dihydroxyvitamin D2, by a novel convergent strategy, to compare this compound directly with the activity of 1α,25-dihydroxyvitamin D3. The same synthetic strategy also provided a series of (5E,7E) geometric isomers of the natural 1α,25-dihydroxyvitamin D2 as well as a series of double point modified analogs of its (24R)-epimer, including C-22 hydroxy derivatives. The structure of the new analogs was determined by 1H and 13C NMR as well as by mass spectrometry. The influence of (5E,7E) modification, alone or in combination with additional modifications in the side chain, on the activity profile and metabolic deactivation of analogs of 1α,25-dihydroxyvitamin D2 still remains unknown. (5E,7E) modification in the structure of new analogs of 1α,25-dihydroxyvitamin D2 is expected to give analogs with no influence on calcium level, as was previously obtained for the analogs of 1α,25-dihydroxyvitamin D3. Investigation of the affinities for the vitamin D receptor and cell differentiation, transcriptional and calcium activities of the most active form of vitamin D2 and of (5E,7E) analogs, compared to 1α,25-dihydroxyvitamin D3, is underway in the collaborating laboratories.
Asunto(s)
Ergocalciferoles/química , Ergocalciferoles/síntesis química , Calcitriol/análogos & derivados , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Isomerismo , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Oxígeno/química , Isoformas de Proteínas , Receptores de Calcitriol/metabolismoRESUMEN
1,25-dihydroxyvitamin D3 (1,25D), a steroid hormone which regulates calcium/phosphate homeostasis, has a broad spectrum of anti-cancer activities, including differentiation of acute myeloid leukemia (AML) cells. In order to avoid undesirable side effects such as hypercalcemia, low-calcemic analogues should be produced for therapeutic purposes. In this paper, we describe biological activities of double-point modified analogues of vitamin D2 and we compare them to 1,25D and to paricalcitol, the drug used to treat secondary hyperparathyroidism. In vivo, our new analogues have lower calcemic effects, and lower toxicity in comparison to 1,25D. They have enhanced pro-differentiating and transcription-inducing activities in AML cells. Interestingly, differentiation effects do not correlate with the affinities of the analogues to the vitamin D receptor (VDR).
Asunto(s)
Ergocalciferoles/química , Ergocalciferoles/síntesis química , Transporte Activo de Núcleo Celular , Animales , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Diferenciación Celular , Evaluación Preclínica de Medicamentos , Ergocalciferoles/genética , Células HL-60 , Homeostasis , Humanos , Hipercalcemia/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Receptores de Lipopolisacáridos/metabolismo , Ratones , Mutación Puntual , Receptores de Calcitriol/metabolismo , Activación Transcripcional/efectos de los fármacos , Regulación hacia Arriba , Vitamina D3 24-Hidroxilasa/metabolismoRESUMEN
The hybrid analogs of 1,25-dihydroxyergocalciferol (PRI-5201 and PRI-5202) were synthesized as potential anticancer agents using a convergent strategy. The analogs were designed by combining a 19-nor modification of the A-ring with the homologated and rigidified ergocalciferol-like side-chain of the previously obtained analogs PRI-1906 and PRI-1907. The strategy also allowed the novel efficient synthesis of 19-nor-1,25-dihydroxyergocalciferol (paricalcitol, PRI-5100) and its (24R)-diastereomer (PRI-5101). The single crystal X-ray structures of the 19-nor analogs (PRI-5100 and PRI-5101) were solved and refined. The A-ring of both analogs adopts exclusively chair ß-conformation in the solid state. The side-chain of these analogs is coplanar with the CD-ring plane, while it is perpendicular in 1,25-dihydroxycholecalciferol.
Asunto(s)
Antineoplásicos/síntesis química , Ergocalciferoles/síntesis química , Antineoplásicos/química , Cristalografía por Rayos X , Ergocalciferoles/química , Enlace de Hidrógeno , Modelos Moleculares , Conformación Molecular , Oxidación-ReducciónRESUMEN
A new vitamin D(2) analogue was synthesized using the Julia-Kocienski olefination. It has antiproliferative effects on cell lines from squamous cell carcinomas of colon and head and neck, but is also as hypercalcaemic as calcitriol in vivo.
Asunto(s)
Ergocalciferoles/síntesis química , Ergocalciferoles/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Calcio/sangre , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Ergocalciferoles/química , Células HCT116 , Humanos , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Three ferrocene complexes vectorized with estrogens and vitamin D(2) were synthesized and fully characterized by spectroscopic, electrochemical and computational methods. The synthesis of these esters was accomplished by reacting ferrocenoyl chloride with the corresponding ROH groups (R = ergocalciferol, estradiol, estrone). The cytotoxicity of these complexes in HT-29 colon cancer and MCF-7 breast cancer cell lines was investigated in vitro. Only ferrocenoyl 17ß-hydroxy-estra-1,3,5(10)-trien-3-olate showed good cytotoxic activity in both cell lines, exceeding those of ferrocenium and ferrocene. In MCF-7, ferrocenoyl 17ß-hydroxy-estra-1,3,5(10)-trien-3-olate exhibited remarkable IC(50), in the low micromolar range. This may be attributed to the presence of the estradiol vector. Docking studies between alpha-estrogen receptor ligand binding site and ferrocenoyl 17ß-hydroxy-estra-1,3,5(10)-trien-3-olate revealed some key hydrophobic interactions that might explain the cytotoxic activity of this ester.
Asunto(s)
Antineoplásicos/química , Ergocalciferoles/química , Estrógenos/química , Compuestos Ferrosos/química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Ergocalciferoles/síntesis química , Ergocalciferoles/farmacología , Receptor alfa de Estrógeno/metabolismo , Estrógenos/síntesis química , Estrógenos/farmacología , Femenino , Compuestos Ferrosos/síntesis química , Compuestos Ferrosos/farmacología , Humanos , Metalocenos , Modelos Moleculares , Unión ProteicaRESUMEN
We characterized a structure-function relationships of four analogs of vitamin D(2) with extended and branched side-chains. We tested their ability to induce differentiation of human acute myeloid leukemia (AML) cells both in vitro and ex vivo. Our experiments on five human cell lines revealed substantial differences among tested analogs. Analogs with side-chains extended by one (PRI-1906) or two carbon units (PRI-1907) displayed similar or elevated cell-differentiating activity in comparison to 1,25-dihydroxyvitamin D(3) (1,25D), whereas further extending side-chain resulted in substantially lower biological activity (PRI-1908 and PRI-1909). Similar pattern of cell-differentiating activities to that observed in human cell lines has also been shown in blast cells isolated from patients diagnosed with AML. The ability of the analogs to activate expression of CYP24A1 gene has been studied in HL60 cell line. The analog PRI-1906 activated expression of CYP24A1 similarly to 1,25D, while PRI-1907 weaker than 1,25D. In addition, the analogs PRI-1906 and PRI-1907 were able to moderately inhibit proliferation and significantly activate expression of CYP24A1 mRNA in prostate cancer cells PC-3. Finally, we examined the molecular actions triggered by these analogs and found that their biological activity was related to their ability to induce expression and nuclear translocation of VDR and C/EBPß.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ergocalciferoles/química , Ergocalciferoles/farmacología , Leucemia Mieloide Aguda/metabolismo , Neoplasias de la Próstata/metabolismo , Transporte Activo de Núcleo Celular/efectos de los fármacos , Anciano , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Ergocalciferoles/síntesis química , Femenino , Células HL-60 , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/biosíntesis , Receptores de Calcitriol/metabolismo , Esteroide Hidroxilasas/genética , Esteroide Hidroxilasas/metabolismo , Relación Estructura-Actividad , Vitamina D3 24-HidroxilasaRESUMEN
We have investigated the oxidative behavior of sterols such as cholesteryl acetate (1), 7-dehydrocholesteryl acetate (2), ergosteryl acetate (3), cholecalciferol acetate (Vitamin D(3) acetate) (4) and ergocalciferol acetate (Vitamin D(2) acetate) (5) with the oxidant system methyltrioxorhenium/H(2)O(2)/pyridine in order to check potential parameters controlling the selectivity. The reactions, performed in CH(2)Cl(2)/H(2)O at 25 degrees C, have shown good regio- and stereoselectivity. All oxidation products were isolated by high-performance liquid chromatography (HPLC) and characterized by MS(EI) or FAB, (1)H NMR, (13)C NMR, APT, COSY, HSQC, HMBC, ROESY and NOEDS measurements. Seven new oxygenated compounds were also obtained. Under the experimental conditions adopted in this work, only the diene steroids, i.e. 7-dehydrocholesteryl acetate and ergosteryl acetate, undergo hydrolytic oxirane ring opening, whereas Vitamin D(2) and D(3) acetates, containing the triene system and cholesteryl acetate yield only epoxides. The selectivity seems to be controlled by the nucleophilicity of double bonds and by stereoelectronic and steric effects.
Asunto(s)
Peróxido de Hidrógeno/química , Compuestos Organometálicos/química , Oxidantes/química , Esteroles/química , Colecalciferol/síntesis química , Colecalciferol/química , Ésteres del Colesterol/síntesis química , Ésteres del Colesterol/química , Cromatografía Líquida de Alta Presión , Ergocalciferoles/síntesis química , Ergocalciferoles/química , Peróxido de Hidrógeno/metabolismo , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Compuestos Organometálicos/síntesis química , Oxidación-Reducción , Estereoisomerismo , Esteroles/síntesis químicaRESUMEN
A heteroatom-tethered regioselective ring-closing metathesis reaction was used for the C-19 functionalization of 1alpha-hydroxy-5,6-trans-vitamin D(2) analogues. Applications of the reaction to form a range of analogues by manipulation of the tether using both organolithium reagents and Diels-Alder cycloadditions are described.
Asunto(s)
Ergocalciferoles/química , Ciclización , Ergocalciferoles/síntesis química , Indicadores y Reactivos , Metaloporfirinas/química , Estereoisomerismo , ZincRESUMEN
A series of analogs of 1,25-dihydroxyergocalciferol (1-4) was synthesized and screened for their antiproliferative activity in vitro. The structure of new analogs was designed based on biological activity of the previously obtained side-chain modified analogs of vitamin D(2) and D(3). The analogs were obtained by the Julia olefination of C(22)-vitamin D sulfone 11 with side-chain aldehyde 15. The analogs were tested for their antiproliferative activity against the cells of human breast cancer lines T47D and MCF7 as well as human and mouse leukemia lines, HL-60 and WEHI-3, respectively. Analog 2 (PRI-1907) showed the strongest antiproliferative activity out of the present series of analogs of 1,25-dihydroxyvitamin D(2) with the mono homologated and double unsaturated side chain. The activity of 2 was 3-150 times stronger, depending on the cell line, than that of 1,25-dihydroxycholecalciferol (calcitriol), used as standard.
Asunto(s)
Ergocalciferoles/síntesis química , Ergocalciferoles/farmacología , Animales , Neoplasias de la Mama/patología , División Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Ergocalciferoles/administración & dosificación , Ergocalciferoles/química , Humanos , Leucemia/patología , Ratones , Estructura Molecular , Células Tumorales CultivadasRESUMEN
OBJECTIVE: In order to find out more effective method for the synthesis of the A-ring synthon, (-)-1-acetylenyl-3-tert-butyldiphenylsily-loxy-exo-bicyclo [3. 1. 0] hexane (3), for 19-nor-1 alpha, 25-dihydroxyvitamin D3(2)with commercial value. METHODS: We synthesized the A-ring synthon (+/-)(3) via nine steps with good yield starting from 3-cyclopentenyl alcohol(4). RESULTS: The spectral data of compound (+/-)(3) is the same as the spectral data of (-)(3) which reported preciously by us. CONCLUSION: The method is an effective method for synthesis of the A-ring synthon (3).
Asunto(s)
Compuestos Bicíclicos con Puentes/síntesis química , Ergocalciferoles/síntesis química , Siloxanos/síntesis química , AlquinosRESUMEN
Synthesis of a 1 alpha,25-dihydroxyvitamin D2 analog (3), in which the double bond in the side-chain is replaced by an amide group, is described. Condensation of a carboxylic acid (8) with an amine (6) gave an amide (9), which in turn led to 3 via several steps. The analog (3) could not bind to the chick cytosol vitamin D receptor, which indicated the importance of the hydrophobic interaction of the C(22)-C(23) double bond in 1 alpha,25-dihydroxyvitamin D2 (2) with the vitamin D receptor.