RESUMEN
Since the discovery of anticancer properties of a naturally occurring hexacyclic marine alkaloid Lamellarin D, the attempts have been made to prepare its synthetic analogues and elucidate the effects of each structural component on their activity profile. While F-ring-free, A-ring-free and B-ring-open lamellarins are known, E-ring-free analogues have never been investigated. In this work, we developed a facile and straightforward synthetic method toward E-ring-free lamellarin analogues based on the [3+2]-cycloaddition. For the first time, we prepared several pentacyclic lamellarin analogues without E-ring in their structure and assessed their cytotoxicity in a panel of cancer cell lines in comparison with several hexacyclic lamellarins. E-ring-free lamellarins were devoid of cytotoxicity due to their poor solubility in cellular environment.
Asunto(s)
Alcaloides , Antineoplásicos , Neoplasias , Humanos , Antineoplásicos/química , Neoplasias/tratamiento farmacológico , Alcaloides/química , Línea Celular , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Cumarinas/química , Relación Estructura-ActividadRESUMEN
Derivatives of natural allylpolyalkoxybenzenes conjugated to triphenylphosphonium (TPP) cations by aliphatic linkers of three, six, seven, and eight atoms were synthesized to examine the role of the polyalkoxybenzene pharmacophore, TPP fragment, and linker length in antiproliferative activities. The key synthetic procedures included (i) hydroboration-oxidation of apiol, dillapiol, myristicin, and allyltetramethoxybenzene; (ii) acylation of polyalkoxybenzyl alcohols or amines; and (iii) condensation of polyalkoxybenzaldehydes followed by hydrogenation and cyclopropyl-homoallyl rearrangement. The targeted TPP conjugates as well as the starting allylbenzenes, the corresponding alkylpolyalkoxybenzenes, and the respective alkyl-TPP salts were evaluated for cytotoxicity in a panel of human cancer cell lines using MTT and Click-iT-EdU assays and in a sea urchin embryo model. The linker of three carbon atoms was identified as favorable for selective cancer cell growth inhibition. Although the propyl-TPP salt was cytotoxic at low micromolar concentrations, the introduction of a polyalkoxybenzene moiety significantly potentiated inhibition of both cell growth and de novo DNA synthesis in several human cancer cell lines, HST-116 colon cancer, A375 melanoma, PC-3 prostate cancer, and T-47D breast carcinoma cells, while it failed to produce any developmental abnormalities in the sea urchin embryos.
RESUMEN
1,3-Substituted pyrazolo[3,4-b]pyridinones 11-18 were synthesized by a three-component condensation of Meldrum's acid with aryl aldehydes and 1,3-substituted 5-aminopyrazoles. Their biological activity was evaluated using the in vivo phenotypic sea urchin embryo assay and the in vitro cytotoxicity screen against human cancer cell lines. In the sea urchin embryo model, 1-benzimidazolyl-pyrazolo[3,4-b]pyridinones 11 caused inhibition of hatching and spiculogenesis at sub-micromolar concentrations. These compounds also selectively and potently inhibited growth of the MOLT-4 leukemia cell line. Subsequent structure-activity relationship studies determined the benzimidazolyl fragment as an essential pharmacophore for both effects. We applied numerous techniques for target identification. A preliminary QSAR target identification search did not result in tangible leads. Attempts to prepare a relevant photoaffinity probe that retained potency in both assays were not successful. Compounds 11 were further characterized for their activity in a wild-type versus Notch-mutant leukemia cell lines, and in in vitro panels of kinases and matrix metalloproteinases. Using a series of diverse modulators of spiculogenesis as standards, we excluded multiple signaling networks including Notch, Wnt/ß-catenin, receptor tyrosine kinases (VEGF/VEGFR, FGF/FGFR), PI3K, and Raf-MEK-ERK as possible targets of 11. On the other hand, matrix metalloproteinase-9/hatching enzyme was identified as one potential target.
Asunto(s)
Antineoplásicos/farmacología , Bencimidazoles/farmacología , Embrión no Mamífero/efectos de los fármacos , Pirazoles/farmacología , Piridonas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Bencimidazoles/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Técnicas Químicas Combinatorias , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Pirazoles/química , Piridonas/química , Erizos de Mar/embriologíaRESUMEN
Free-radical-scavenging capacity antioxidant and membrane-protective properties of natural and related synthetic allylpolyalkoxybenzenes with different numbers of alkoxy/methoxy groups in the aromatic ring were evaluated using several in vitro models. These included the DPPH assay, inhibition of lipid peroxidation products accumulation, inhibition of H2O2-induced hemolysis, and oxidation of oxyhemoglobin. A synthetic protocol for the synthesis of natural nothoapiol (9) from a parsley seed metabolite, apiol (7), was developed. A structure-activity relationship study revealed that both the methylenedioxy fragment and methoxy groups in the aromatic ring are favorable for antioxidant activity. Hydroxyapiol (14), containing a hydroxy group in the aromatic core, was identified as the most potent compound. The pentaalkoxy-substituted nothoapiol (9) showed antioxidant activity in mouse brain homogenates, whereas in mouse erythrocytes it exhibited a marked pro-oxidant effect. Despite their low free-radical-scavenging capacity, allylpolyalkoxybenzenes can contribute to the total antioxidant potencies of plant essential oils.
RESUMEN
A series of both novel and reported combretastatin analogues, including diarylpyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles, were synthesized via improved protocols to evaluate their antimitotic antitubulin activity using in vivo sea urchin embryo assay and a panel of human cancer cells. A systematic comparative structure-activity relationship studies of these compounds were conducted. Pyrazoles 1i and 1p, isoxazole 3a, and triazole 7b were found to be the most potent antimitotics across all tested compounds causing cleavage alteration of the sea urchin embryo at 1, 0.25, 1, and 0.5 nM, respectively. These agents exhibited comparable cytotoxicity against human cancer cells. Structure-activity relationship studies revealed that compounds substituted with 3,4,5-trimethoxyphenyl ring A and 4-methoxyphenyl ring B displayed the highest activity. 3-Hydroxy group in the ring B was essential for the antiproliferative activity in the diarylisoxazole series, whereas it was not required for potency of diarylpyrazoles. Isoxazoles 3 with 3,4,5-trimethoxy-substituted ring A and 3-hydroxy-4-methoxy-substituted ring B were more active than the respective pyrazoles 1. Of the azoles substituted with the same set of other aryl pharmacophores, diarylpyrazoles 1, 4,5-diarylisoxazoles 3, and 4,5-diaryl-1,2,3-triazoles 7 displayed similar strongest antimitotic antitubulin effect followed by 3,4-diarylisoxazoles 5, 1,5-diaryl-1,2,3-triazoles 8, and pyrroles 10 that showed the lowest activity. Introduction of the amino group into the heterocyclic core decreased the antimitotic antitubulin effect of pyrazoles, triazoles, and to a lesser degree of 4,5-diarylisoxazoles, whereas potency of the respective 3,4-diarylisoxazoles was increased.
Asunto(s)
Antimitóticos/síntesis química , Erizos de Mar/embriología , Moduladores de Tubulina/síntesis química , Tubulina (Proteína)/metabolismo , Animales , Antimitóticos/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Embrión no Mamífero/efectos de los fármacos , Humanos , Isoxazoles/síntesis química , Isoxazoles/farmacología , Pirazoles/síntesis química , Pirazoles/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/farmacología , Moduladores de Tubulina/farmacologíaRESUMEN
A series of 1,5-diaryl- and 4,5-diaryl-1,2,3-triazole derivatives of combretastatin A4 were synthesized and evaluated as antimitotic microtubule destabilizing agents using the sea urchin embryo model. Structure-activity relationship studies identified compounds substituted with 3,4,5-trimethoxyphenyl and 3,4-methylenedioxy-5-methoxyphenyl ring A and 4-methoxyphenyl ring B as potent antiproliferative agents with high cytotoxicity against a panel of human cancer cell lines including multi-drug resistant cells. 4,5-Diaryl-1,2,3-triazoles (C-C geometry) were found to be considerably more active than the respective 1,5-diaryl-1,2,3-triazoles (N-C geometry). Compound 10ad' induced G2/M cell cycle arrest and apoptosis in human T-leukemia Jurkat cells via caspase 2/3/9 activation and downregulation of the antiapoptotic protein XIAP. A mitotic catastrophe has been evaluated as another possible cell death mode.
Asunto(s)
Antineoplásicos/farmacología , Bibencilos/farmacología , Erizos de Mar/efectos de los fármacos , Triazoles/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Bibencilos/síntesis química , Bibencilos/química , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Modelos Animales , Conformación Molecular , Fenotipo , Erizos de Mar/embriología , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/química , Células Tumorales CultivadasRESUMEN
5,7-Dinitroquinazoline-4-ones undergo nucleophilic displacement of a nitro group with N-, S-, and O-nucleophiles. In contrast to previously studied dinitro-substituted benzoannulated five- and seven-membered heterocycles (where a high degree of selectivity was observed), these quinazolines mostly yield mixtures of regioisomeric substitution products. At the same time, primary and secondary amines react selectively to afford 5-aminoquinazolones (peri-substitution). A similar effect is observed for some other polynitroaromatic compounds with adjacent nitro and carbonyl groups. This phenomenon is attributed to a stabilization of the intermediate peri-sigma-complex by intramolecular hydrogen bond N(+)-H...O double bond C.
RESUMEN
We have developed a series of novel potent ortho-substituted azole derivatives active against kinases VEGFR-1 and VEGFR-2. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase activity and selectivity could be controlled by varying the arylamido substituents at the azole ring. The most specific molecule (17) displayed > 10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in enzymatic and cell-based assays were in the range of activities for reported clinical and development candidates (IC50 < 100 nM), including Novartis' PTK787 (Vatalanib). High permeability of active compounds across the Caco-2 cell monolayer (> 30x10(-5) cm/min) is indicative of their potential for intestinal absorption upon oral administration.
Asunto(s)
Azoles/síntesis química , Azoles/farmacología , Receptor 1 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Adenosina Trifosfato/metabolismo , Azoles/farmacocinética , Unión Competitiva , Células CACO-2 , Permeabilidad de la Membrana Celular , Humanos , Concentración 50 Inhibidora , Absorción Intestinal , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
[Reaction: see text]. 1,3-dinitrodibenz[b,f][1,4]oxazepin-11(10H)-one, prepared by intramolecular displacement of nitro group in N-(2-hydroxyphenyl)-2,4,6-trinitrobenzamide, reacts with O- and S-nucleophiles to yield the products of mono- or bis-substitution of the nitro groups. The nitro group in position 3 is displaced first. This observation is in contrast with earlier results for the nitro-substituted benzoannulated five-membered heterocycles. This difference in reactivity is likely due to the increased steric hindrance for peri-nitro group displacement in the case of the benzoannulated seven-membered heterocycle. N-Alkylation of the nitro-substituted dibenz[b,f][1,4]oxazepin-11(10H)-ones yields analogues of a known antidepressant drug Sintamil. The structure of the products is confirmed by NOE experiments and alternative synthesis.
Asunto(s)
Dibenzoxazepinas/química , Dibenzoxazepinas/síntesis química , Nitrocompuestos/química , Estructura MolecularRESUMEN
Regioselective Michael addition of nitro and heterocyclic compounds to levoglucosenone, 1, is effectively catalyzed by amines and also by cathodic electrolysis. In comparison to the base-catalyzed reaction, it was found that under electrochemical conditions the reaction proceeds under milder conditions and with higher yields. Cathodically-initiated Michael addition of thiols to levoglucosenone using small currents produces the previously unknown threo addition product in several instances. The normal erythro isomer, identified as the kinetic product, tends to be formed when large currents are used. In contrast, slow, low current electrolyses promote equilibration of the two forms so that erythro can be converted to threo by the retro reaction and readdition. Addition of 2-naphthalenethiol to (R)-(+)-apoverbenone is also reported.