RESUMEN
In the search for innovative approaches to cancer chemotherapy, a chemical library of 49 cyanochalcones, 1a-r, 2a-o, and 3a-p, was designed as dual inhibitors of human farnesyltransferase (FTIs) and tubulin polymerization (MTIs) (FTIs/MTIs), two important biological targets in oncology. This approach is innovative since the same molecule would be able to interfere with two different mitotic events of the cancer cells and prevent these cells from developing an emergency route and becoming resistant to anticancer agents. Compounds were synthesized by the Claisen-Schmidt condensation of aldehydes with N-3-oxo-propanenitriles under classical magnetic stirring and under sonication. Newly synthesized compounds were screened for their potential to inhibit human farnesyltransferase, tubulin polymerization, and cancer cell growth in vitro. This study allowed for the identification of 22 FTIs and 8 dual FTIs/MTIs inhibitors. The most effective molecule was carbazole-cyanochalcone 3a, bearing a 4-dimethylaminophenyl group (IC50 (h-FTase) = 0.12 µM; IC50 (tubulin) = 0.24 µM) with better antitubulin activity than the known inhibitors that were previously reported, phenstatin and (-)-desoxypodophyllotoxin. The docking of the dual inhibitors was realized in both the active site of FTase and in the colchicine binding site of tubulin. Such compounds with a dual inhibitory profile are excellent clinical candidates for the treatment of human cancers and offer new research perspectives in the search for new anti-cancer drugs.
RESUMEN
In the incessant search for innovative cancer control strategies, this study was devoted to the design, synthesis and pharmacological evaluation of dual inhibitors of farnesyltransferase and tubulin polymerization (FTI/MTIs). A series of indolizine-phenothiazine hybrids 16 (amides) and 17 (ketones) has been obtained in a 4-step procedure. The combination of the two heterocycles provided potent tubulin polymerization inhibitors with similar efficiency as the reference phenstatin and (-)-desoxypodophyllotoxin. Ketones 17 were also able to inhibit human farnesyltransferase (FTase) in vitro. Interestingly, three molecules 17c, 17d and 17f were very effective against both considered biological targets. Next, nine indolizine-phenothiazine hybrids 16c, 16f, 17a-f and 22b were evaluated for their cell growth inhibition potential on the NCI-60 cancer cell lines panel. Ketones 17a-f were the most active and displayed promising cellular activities. Not only they arrested the cell growth of almost all tested cancer cells, but they displayed cytotoxicity potential with GI50 values in the low nanomolar range. The most sensitive cell lines upon treatment with indolizine-phenothiazine hybrids were NCI-H522 (lung cancer), COLO-205 and HT29 (colon cancer), SF-539 (human glioblastoma), OVCAR-3 (ovarian cancer), A498 (renal cancer) and especially MDA-MB-435 (melanoma). Demonstrating the preclinical effectiveness of these dual inhibitors can be crucial. A single dual molecule could induce a synergy of antitumor activity, while increasing the effectiveness and reducing the toxicity of the classical combo treatments currently used in chemotherapy.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Farnesiltransferasa/antagonistas & inhibidores , Indolizinas/farmacología , Fenotiazinas/farmacología , Moduladores de Tubulina/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Farnesiltransferasa/química , Farnesiltransferasa/metabolismo , Humanos , Indolizinas/síntesis química , Indolizinas/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Fenotiazinas/síntesis química , Fenotiazinas/metabolismo , Unión Proteica , Relación Estructura-Actividad , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/metabolismoRESUMEN
In this article, we report the synthesis and biological properties of a series of novel oxazepines related to isoCA-4 having significant antitumor properties. Among them, three oxazepin-9-ol derivatives display a nanomolar or a sub-nanomolar cytotoxicity level against five human cancer cell lines (HCT116, U87, A549, MCF7, and K562). It was demonstrated that the lead compound in this series inhibits tubulin assembly with an IC50 value of 1â µM and totally arrests the cellular cycle in the G2/M phase at the low concentration of 5â nM in HCT116 and K562 cells. Molecular modeling studies perfectly corroborates these promising results.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Aza/farmacología , Oxazepinas/farmacología , Moduladores de Tubulina/farmacología , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/química , Compuestos Aza/química , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Modelos Moleculares , Estructura Molecular , Oxazepinas/síntesis química , Oxazepinas/química , Relación Estructura-Actividad , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/química , Células Tumorales CultivadasRESUMEN
A broad range of chalcones and derivatives were easily and rapidly synthesized, following Claisen-Schmidt condensation of (hetero)aryl ketones and (hetero)aryl aldehydes using a ultrasound probe. A comparison was made with classical magnetic stirring experiments, and an optimization study was realized, showing lithium hydroxide to be the best basic catalyst of the studied condensations. By-products of the reactions (ß-hydroxy-ketone, diketones, and cyclohexanols) were also isolated. All compounds were evaluated in vitro for their ability to inhibit human farnesyltransferase, a protein implicated in cancer and rare diseases and on the NCI-60 cancer cell lines panel. Molecules showed inhibitory activity on the target protein and cytostatic effect on different cell lines with particular activity against MCF7, breast cancer cells.
Asunto(s)
Antineoplásicos/síntesis química , Chalconas/química , Inhibidores Enzimáticos/síntesis química , Farnesiltransferasa/antagonistas & inhibidores , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Sitios de Unión , Dominio Catalítico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Chalconas/metabolismo , Chalconas/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Farnesiltransferasa/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Sonicación , Relación Estructura-ActividadRESUMEN
The majority of cancers detected every year are treated with anti-cancer compounds. Unfortunately, many tumors become resistant to antineoplastic drugs. One option is to use cocktails of compounds acting on different targets to try to overcome the resistant cells. This type of approach can produce good results, but is often accompanied by a sharp increase of associated side effects. The strategy presented herein focuses on the use of a single compound acting on two different biological targets enhancing potency and lowering the toxicity of the chemotherapy. In this light, the approach presented in the current study involves the dual inhibition of human pyruvate dehydrogenase kinase-1 (PDHK1) and tubulin polymerization using mono-, di- and tri-chloroacetate-loaded benzophenones and benzothiophenones. Synthesized molecules were evaluated in vitro on tubulin polymerization and on pyruvate dehydrogenase kinase 1. The cell cycle distribution after treatment of DA1-3b leukemic cells with active compounds was tested. Twenty-two benzo(thio)phenones have been selected by the National Cancer Institute (USA) for evaluation of their anti-proliferative potential against NCI-60 cancer cell lines including multidrug-resistant tumor cell lines. Seventeen molecules proved to be very effective in combating the growth of tumor cells exhibiting inhibitory activities up to nanomolar range. The molecular docking of best antitumor molecules in the study was realized with GOLD in the tubulin and PDHK1 binding sites, and allowed to understand the positioning of active molecules. Chloroacetate-loaded benzo(thio)phenones are dual targeted tubulin- and pyruvate dehydrogenase kinase 1 (PDHK1)-binding antitumor agents and exhibited superior antitumor activity compared to non-chlorinated congeners particularly on leukemia, colon, melanoma and breast cancer cell lines.
Asunto(s)
Acetatos/farmacología , Antineoplásicos/farmacología , Benzofenonas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/antagonistas & inhibidores , Moduladores de Tubulina/farmacología , Acetatos/química , Antineoplásicos/química , Benzofenonas/química , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/química , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/metabolismo , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/químicaRESUMEN
Five new dibenzocyclooctynes bearing different substituents on their aryl moieties were synthesized and evaluated for their reactivity toward strain-promoted alkyne-azide cycloaddition (SPAAC). The dinaphthylcyclooctynes proved to be poorly reactive with azides, and the formation of triazole required many days compared to a few hours for the other cyclooctynes. Fluoride atoms and methoxy groups were also introduced to the aryl rings, leading to more active compounds. Oxidation of the alcohol on the cyclooctyne ring also increased the reaction rates by 3.5- to 6-fold. 3,9-Difluoro-4,8-dimethoxy-dibenzocyclooctyne-1-one thus displayed a SPAAC kinetic rate of 3.5 M-1 s-1, which is one of the highest rates ever described. Furthermore, the dibenzocyclooctyn-1-one displayed fluorescence properties that have allowed their detection in the protozoan parasites Plasmodium falciparum and Trypanosoma brucei by microscopy imaging, proving that they can cross cell membranes and that they are stable enough in biological media.
Asunto(s)
Hidrocarburos Cíclicos/síntesis química , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Antiprotozoarios/farmacología , Azidas , Reacción de Cicloadición , Fluorescencia , Hidrocarburos Cíclicos/química , Hidrocarburos Cíclicos/metabolismo , Estructura Molecular , Plasmodium falciparum/metabolismo , Trypanosoma brucei brucei/metabolismoRESUMEN
Unprecedented triazinyl-isoxazoles were afforded via an effective cycloaddition reaction between nitrile oxides and the scarcely described 2-ethynyl-4,6-dimethoxy-1,3,5-triazine as dipolarophile. The biological evaluation of the newly synthesized compounds showed that the inhibition of human farnesyltransferase by zinc complexation could be improved with triazine-isoxazole moieties. The replacement of the isoxazole unit by a pyrrolidin-2-one was detrimental to the inhibitory activity while the pyrrolidin-2-thione derivatives conserved the biological potential. The potential of selected compounds to disrupt protein farnesylation in Chinese hamster ovary (CHO) cells transfected with pEGFP-CAAX was also evaluated.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Farnesiltransferasa/antagonistas & inhibidores , Isoxazoles/farmacología , Pirrolidinonas/farmacología , Triazinas/farmacología , Animales , Células CHO , Cricetulus , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Farnesiltransferasa/metabolismo , Humanos , Isoxazoles/química , Estructura Molecular , Pirrolidinonas/química , Relación Estructura-Actividad , Triazinas/químicaRESUMEN
The synthesis and evaluation of a series of N,N-bis-heterocyclic-methylamines 1 as isoazaerianin analogues are described. It was demonstrated that the replacement of the 3,4,5-trimethoxyphenyl A-ring present in CA-4, isoCA-4 and isoazaerianin by a quinoline or a quinazoline ring is possible and often beneficiary for a high level of cytotoxicity. We have also showed that a carbazole or an indole nucleus are very effective as B-rings in this series, leading to anti-cancer drugs 1 having a sub-nanomolar level of cytotoxicity (1a: IC50â¯=â¯70 pM against HCT116â¯cells). 1a also display a high level of cytotoxicity against four other human cancer cells and inhibited tubulin assembly at a micromolar level. Moreover, at a concentration of 5â¯nM, 1a arrested the cellular cycle in G2/M phase of the cellular cycle and induced apoptosis of HCT116â¯cells. It was also showed that after few hours 1a at a concentration of 10â¯nM totally disrupted endothelial network formation on Matrigel.
Asunto(s)
Antineoplásicos/farmacología , Citotoxinas/farmacología , Metilaminas/farmacología , Mitosis/efectos de los fármacos , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Citotoxinas/síntesis química , Citotoxinas/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Metilaminas/síntesis química , Metilaminas/química , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Based on N-acyliminium species, two efficient and rapid approaches to diversify spirocyclic systems connected by two different carbon centers to the isoindole ring have been developed. The imide reduction and the tandem oxidative cleavage of olefin/formyl-amide equilibration were at first selected as the key steps for these strategies. Ultimately the intramolecular α-amidoalkylation reaction was achieved through the arylation of α-acetoxy lactams or α-hydroxy lactams using, respectively, a Lewis acid or a Brønsted acid depending on the nature of N-acyliminium precursors. The latter led, in addition to the spiro-6-membered aza-heterocycles, to the formation of scarce spiro-5-membered analogues which show promising inhibitory activities on human farnesyltransferase in the nanomolar range demonstrating improved IC50 values of up to 1.5 nM.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Farnesiltransferasa/antagonistas & inhibidores , Isoindoles/química , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Modelos Moleculares , Conformación MolecularRESUMEN
We report the synthesis and metabolic and biological evaluation of a series of 17 novel heterocyclic derivatives of isocombretastatin-A4 (iso-CA-4) and their structure-activity relationships. Among these derivatives, the most active compound, 4f, inhibited the growth of a panel of seven cancer cell lines with an IC50 in the low nanomolar range. In addition, 4f showed interesting activity against CA-4-resistant colon-carcinoma cells and multidrug-resistant leukemia cells. It also induced G2/M cell-cycle arrest. Structural data indicated binding of 4f to the colchicine site of tubulin, likely preventing the curved-to-straight tubulin structural changes that occur during microtubule assembly. Also, 4f disrupted the blood-vessel-like assembly formed by human umbilical-vein endothelial cells in vitro, suggesting its function as a vascular-disrupting agent. An in vitro metabolism study of 4f showed its high human-microsomal stability in comparison with that of iso-CA-4. The physicochemical properties of 4f may be conducive to CNS permeability, suggesting that this compound may be a possible candidate for the treatment of glioblastoma.
Asunto(s)
Carbazoles/farmacología , Quinaldinas/farmacología , Moduladores de Tubulina/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Carbazoles/síntesis química , Carbazoles/metabolismo , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Polimerizacion/efectos de los fármacos , Unión Proteica , Quinaldinas/síntesis química , Quinaldinas/metabolismo , Ratas , Relación Estructura-Actividad , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/metabolismoRESUMEN
A facile one-pot synthesis of 2-styrylindoles, through Suzuki arylation of ortho-substituted chloroenynes followed by N-cyclization and N-demethylation, has been developed. A variety of 2-styrylindoles were obtained in good to excellent yields and were evaluated for their anticancer properties.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Indoles/síntesis química , Indoles/farmacología , Estireno/química , Antineoplásicos/química , Técnicas de Química Sintética , Células HCT116 , Humanos , Indoles/química , IsomerismoRESUMEN
Five different halofunctionalizations of acyclic monoterpenoids were performed using a combination of a hypervalent iodine(III) reagent and a halide salt. In this manner, the dibromination, the bromo(trifluoro)acetoxylation, the bromohydroxylation, the iodo(trifluoro)acetoxylation or the ene-type chlorination of the distal trisubstituted double bond occurred with excellent selectivity and moderate to good yields.
RESUMEN
Designing multitarget drugs have raised considerable interest due to their advantages in the treatment of complex diseases such as cancer. Their design constitutes a challenge in antitumor drug discovery. The present study reports a dual inhibition of tubulin polymerization and HDAC activity. On the basis of 1,1-diarylethylenes ( isoCA-4) and belinostat, a series of hybrid molecules was successfully designed and synthesized. In particular compounds, 5f and 5h were proven to be potent inhibitors of both tubulin polymerization and HDAC8 leading to excellent antiproliferative activity.
Asunto(s)
Diseño de Fármacos , Histona Desacetilasas/metabolismo , Estilbenos/química , Estilbenos/farmacología , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Técnicas de Química Sintética , Células HCT116 , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/química , Humanos , Células K562 , Conformación Proteica , Estilbenos/síntesis química , Tubulina (Proteína)/químicaRESUMEN
A novel series of tubulin polymerization inhibitors, based on fluorinated derivatives of isocombretastatin A-4 was synthesized with the goal of evaluating the effect of these compounds on the proliferative activity. The introduction of fluorine atom was performed on the phenyl ring or at the linker between the two aromatic rings. The modification of isoCA-4 by introduction of difluoromethoxy group at the para-position (3i) and substitution of the two protons of the linker by two fluorine atoms (3m), produced the most active compounds in the series, with IC50 values of 0.15-2.2 nM (3i) and 0.1-2 nM (3m) respectively, against a panel of six cancer cell lines. Compounds 3i and 3m had greater antiproliferative activity in comparison with references CA-4 or isoCA-4, the presence of fluorine group leads to a significant enhancement of the antiproliferative activity. Molecular docking studies indicated that compounds 3i and 3m occupy the colchicine binding site of tubulin. Evaluation of cytotoxicity in Human noncancer cells indicated that the compounds 3i and 3m were practically ineffective in quiescent peripheral blood lymphocytes, and may have a selective antiproliferative activity against cancer cells. Analyses of cell cycle distribution, and morphological microtubules organization showed that compound 3m induced G2/M phase arrest and, dramatically disrupted the microtubule network.
Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Flúor/química , Estilbenos/farmacología , Tubulina (Proteína)/metabolismo , 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 , Modelos Moleculares , Estructura Molecular , Polimerizacion/efectos de los fármacos , Estilbenos/síntesis química , Estilbenos/química , Relación Estructura-ActividadRESUMEN
In the current context of lack of emergence of innovative human farnesyltransferase inhibitors families, and given all new therapeutic perspectives that open up for such molecules in rare diseases (e.g. Hutchinson-Gilford progeria syndrome), and in delta hepatitis, cardiovascular or neuroinflammatory diseases, we have just discovered a new series of powerful inhibitors. These molecules are pyroglutamic acid derivatives, and were evaluated on human farnesyltransferase in vitro then modeled in silico on the active site of the protein. Three main points of the pyroglutamic acid cycle have undergone chemical modulations pyroglutamides in position 5 (compounds 7a-h), constrained bicyclic analogues of pyrroloimidazoledione type (compounds 1a-h), modulation of the position 3 (compounds 2-5 and 8), and allowed the first SAR in the field. Five derivatives in the current work have IC50 values in the small nanomolar range (2-5 nM). These new lead compounds open the way for the next generation of farnesyltransferase inhibitors.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Farnesiltransferasa/antagonistas & inhibidores , Ácido Pirrolidona Carboxílico/análogos & derivados , Sitios de Unión , Simulación por Computador , Inhibidores Enzimáticos/química , Humanos , Modelos Biológicos , Estructura Molecular , Conformación Proteica , Ácido Pirrolidona Carboxílico/metabolismoRESUMEN
Mild oxidation of bromides by iodine(III) reagents generated active electrophilic bromination species that were reacted with polyprenoids. By simple and minor variations of an I(III)/Br combination, the reactivity could be selectively steered toward dibromination, oxybromination, or bromocyclization, giving access to a wide array of brominated motifs.
RESUMEN
Marine meroterpenoids, thiaplidiaquinones A and B and their respective non-natural dioxothiazine regioisomers have been shown to inhibit mammalian and protozoal farnesyltransferase (FTase) with the regioisomers exhibiting activity in the nanomolar range. In order to explore the structure-activity relationship (SAR) of this class of marine natural products, analogues of thiaplidiaquinones A and B and their regioisomers were synthesised, with variation in the number of isoprene units present in their side chains to afford prenyl and farnesyl analogues. The previously reported geranyl series of compounds were found to be the most potent FTase inhibitors closely followed by the novel farnesyl series. The prenyl series exhibited the most potent anti-plasmodial activity but the series was also the most cytotoxic. Overall, the farnesyl series exhibited moderate anti-plasmodial activity with one analogue, 14 also exhibiting low cytotoxicity, identifying it as a scaffold worthy of further exploration.
Asunto(s)
Antibacterianos/farmacología , Antimaláricos/farmacología , Farnesiltransferasa/antagonistas & inhibidores , Plasmodium falciparum/efectos de los fármacos , Staphylococcus/efectos de los fármacos , Terpenos/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antimaláricos/síntesis química , Antimaláricos/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Farnesiltransferasa/metabolismo , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Plasmodium falciparum/enzimología , Ratas , Staphylococcus/clasificación , Relación Estructura-Actividad , Terpenos/síntesis química , Terpenos/químicaRESUMEN
The synthesis and evaluation of a new series of IsoCombretaQuinolines (IsoCoQuines) 2 with a 2-substituted-quinoline in place of the 3,4,5-trimethoxyphenyl ring present in isoCA-4 and CA-4 are described. Most of these compounds displayed a potent cytotoxic activity (IC50 < 10 nM) against a panel of five human cancer cell lines and inhibited tubulin assembly at a micromolar level. The most potent analogue 2b, having a 3-hydroxy-4-methoxyphenyl as B-ring, led to cell cycle arrest in G2/M phase. Docking studies indicate that 2b showed a binding mode comparable to those previously observed with quinazoline analogous (IsoCoQ) and with isoCA-4 at the colchicine binding site of tubulin.
Asunto(s)
Diseño de Fármacos , Multimerización de Proteína/efectos de los fármacos , Quinazolinas/síntesis química , Quinazolinas/farmacología , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/farmacología , Tubulina (Proteína)/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Técnicas de Química Sintética , Ensayos de Selección de Medicamentos Antitumorales , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Simulación del Acoplamiento Molecular , Estructura Cuaternaria de Proteína , Quinazolinas/química , Quinazolinas/metabolismo , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismoRESUMEN
The phenothiazine group has been identified as a suitable A ring in the structure of tubulin polymerization inhibitors. In our search to identify more potent inhibitors, a study of different isosteric tricyclic groups as new potential A rings was first realized and permitted to identify 1-azaphenothiazine and iminodibenzyl as favorable modulations providing compounds with improved activity against tubulin. An investigation of the methylene group as the connector between the A and B rings revealed that the "CH2" bridge was tolerated, improving the biological potency when the A unit was of phenothiazine, 1-azaphenothiazine or iminodibenzyl type. Molecules 6-8 and 12 showed increased biological activity in comparison to parent phenstatin 2 on COLO 205 colon cancer cell line. The most antineoplastic agent in the current study was phenothiazine 5 displaying a GI50 of 25nM against the melanoma MDA-MB-435 cell line.
Asunto(s)
Antineoplásicos/farmacología , Fenotiazinas/farmacología , Tubulina (Proteína)/metabolismo , 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 , Modelos Moleculares , Estructura Molecular , Fenotiazinas/síntesis química , Fenotiazinas/química , Polimerizacion/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Biological screening of a library of synthesized benzo[c]chromene-7,10-dione natural products against human farnesyltransferase (FTase) has identified tecomaquinone I (IC50 of 0.065±0.004µM) as being one of the more potent natural product inhibitors identified to date. Anti-plasmodial screening of the same library against a drug-resistant strain of Plasmodium falciparum identified the structurally-related dichromenol tectol as a moderately active growth inhibitor with an IC50 3.44±0.20µM. Two novel series of analogues, based on the benzo[c]chromene-7,10-dione scaffold, were subsequently synthesized, with one analogue exhibiting farnesyltransferase inhibitory activity in the low micromolar range. A preliminary structure-activity relationship (SAR) study has identified different structural requirements for anti-malarial activity in comparison to FTase activities for these classes of natural products. Our results identify tecomaquinone I as a novel scaffold from which more potent inhibitors of human and parasitic FTase could be developed.