Arotinoids containing a C5,C8-diphenylnaphthalene-2-yl ring linked to a (C3-halogenated) benzoic acid via an ethenyl connector (but not the corresponding naphthamides), which are prepared by Horner–Wadsworth–Emmons reaction of naphthaldehydes and benzylphosphonates, display the rather unusual property of being RXR agonists (15-fold induction of the RXR reporter cell line was achieved at 3- to 10-fold lower concentration than 9- cis-retinoic acid) and RAR antagonists as shown by transient transactivation studies. The binding of such bulky ligands suggests that the RXR ligand-binding domain is endowed with some degree of structural elasticity. All- trans-retinoic acid 1, its isomer 9- cis-retinoic acid 2, and other natural retinoids are important signaling molecules that act in the embryo and throughout adult life. − At the genomic level, retinoids bind the retinoid receptors (RARs, subtypes RARα,β,γ) and retinoic X receptors (RXRs, subtypes RXRα,β,γ) to regulate many important biological activities. Using excess bis-(pyridine)iodonium(I) tetrafluoroborate (Ipy2BF4) and triflic acid, the diiodo derivative 13 was obtained from methyl 2-naphthoate 12 by substitution at both activated positions (C5 and C8, Scheme ). Cross-coupling of the diiodide 13 with phenylboronic acid [Pd(PPh 3) 4, Na 2CO 3, 60 °C, 2 h] afforded compound 14. The preparation of N-arylamides was based on the Cu(I)-diamine-catalyzed amidation of the 4-halo- or 3,4-dihaloderivatives (using, in this case, the more reactive iodides at the C4 position) with the corresponding naphthamides., Saponification of 14 was followed by primary amide formation using EDCI and HOBt in MeOH in the presence of NH 3 to furnish the disubstituted naphthamide 16.

Using CuI as catalyst, (1 S,2 S)-cyclohexane-1,2-diamine as ligand, and K 3PO 4 in dioxane, − the condensation of 16 with halogenated benzoates 17 produced the corresponding amides 18 after CAr-N bond formation at the more reactive position in good yield (64–75%). The sequence was completed with the saponification of the esters using KOH in MeOH at 60 °C, which proceeded in high yield except for the 3-chloro analogue ( 10c; 43%).

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The stilbenoids 22 were prepared by Horner–Wadsworth–Emmons condensation of naphthaldehyde 20 and the corresponding benzylphosphonates 21a,b,d (X = H, F, Br) as previously described. Reduction of naphthoate 14 with DIBAL at −78 °C followed by oxidation of 19 provided aldehyde 20. Reaction of the phosphonate-stabilized anions, obtained by treatment of 21a,b,d with n-BuLi in THF in the presence of DMPU at −78 °C with aldehyde 20 produced the E-isomers ( 3 J H–H between 16 and 18 Hz for the vinyl protons in the 1H NMR spectra) of stilbenoids 22a,b,d in good yield. These esters were used in the next saponification step without further purification, due to their ease of isomerization to the Z isomers, and furnished the final arotinoids 11a,b,d (67–73%). To evaluate the effects of the described retinoids on RARα, RARβ, RARγ, and RXRβ-mediated transactivation, a reporter assay with genetically engineered HeLa cell lines, was used.

A single RXR reporter cell line (expressing RXRβ LBD) is assumed to reveal the ligand responsiveness as a readout for all three RXRs, given the identity of the amino acids constituting the ligand-binding pockets of the RXR subtypes., The reporter cell lines are engineered to express a fusion protein, comprising the ligand-binding domain of the corresponding receptor and the DNA-binding domain of the yeast GAL4 transcription factor. In addition, the cells contain a stably integrated luciferase reporter gene, which is controlled by five Gal4 response elements in front of a β-globin promoter; this is termed (17m)5-βG-Luc., This reporter system is largely insensitive to endogenous receptors, which cannot recognize the GAL4-binding site.

The transcriptional activity of the various compounds was compared with that of the pan-RAR agonists 3 and 2 (Figure ) as positive controls for RAR and RXR activation, respectively. In the antagonist assays the positive controls are challenged with increasing amounts of putative antagonists, resulting in decreased transactivation of the reporter. Note that depending on their receptor binding affinities weak agonists can appear in this in vivo competition assay as antagonists, albeit they retain at high concentration their weak agonist activity. The transcriptional data of the naphthamide and stilbene arotinoids with the RAR subtypes is presented in Figures (agonist activity) and (antagonist activity). Proposed docking site for 11a (as blue sticks).

The Cα trace of the RARα LBD is displayed as a ribbon, colored in gray. The side chains of Phe228, Leu269, Ile270, Arg272, Ile273, Arg276, Phe286, and Phe302 (which show consistent favorable. Similar docking experiments with RXRα failed to provide stable solutions without severe distortion of the protein-binding pocket, and no binding poses could be found due to the bulky phenyl extensions protruding from both sides of the ligand naphthyl core, in particular the C5 phenyl group interacting with H11 (see ).

Extended pockets in the LBD of nuclear receptors to allow binding of bulky agonists have been noted by X-ray crystalography of ligand-bound estrogen receptor α (ERα). This precedent suggests that the RXR ligand-binding domain is also endowed with some degree of structural elasticity to allow binding of bulky stilbenes such as 11a or 11b.

To summarize, diphenylsubstituted ( E)-4-(2-(naphthalen-2-yl)vinyl)benzoic acids and the corresponding 4-(2-naphthamido)benzoic acids with the same substitution pattern have been prepared and evaluated as retinoid receptor modulators. Transactivation studies in this series revealed that, whereas the amides are poor ligands, the corresponding stilbenes exhibited dual modulatory activities, with both strong activation of RXRβ and strong antagonism of the RAR-subtypes, a profile rarely found in retinoids.

Just before the basketball world turns its attention to Milan for the 2014 Turkish Airlines Euroleague Final Four, Euroleague Basketball is pleased to honor 10 of the stars that made this season so spectacular, the 2013-14 All-Euroleague First and Second Teams. To select them, tens of thousands of fans from around the globe were able to cast votes for their favorite players, as did media members from each of the countries with Euroleague teams.

The All-Euroleague selections feature players from seven teams and five players who appear among the competition's best for the first time. The features five superstars from four different teams: and from Real Madrid, from EA7 Emporio Armani Milan, from CSKA Moscow and from FC Barcelona. Both Fernandez and Tomic return after appearing on the 2012-13 All-Euroleague First Team. The consists of Ricky Hickman from Maccabi Electra Tel Aviv, Vasilis Spanoulis of Olympiacos Piraeus, Victor Khryapa of CSKA Moscow, Nikola Mirotic of Real Madrid and Stephane Lasme of Panathinaikos Athens. This marks Spanoulis’s fifth straight All-Euroleague selection and seventh overall, which ties him with FC Barcelona great Juan Carlos Navarro for the most in competition history. Khryapa is selected to an All-Euroleague Team for the third time and Mirotic for the second time.

Although he did not start a single game, Sergio Rodriguez had as much of an impact as any player on Real Madrid leading the Euroleague in victories this season and scoring more points than any team this century. The playmaker came off the bench in all 29 games to lead Madrid in both scoring (13.5 ppg.) and assists (5 apg.) despite playing just the fourth-most minutes on the team. Rodriguez ranked fourth in the league in three-point shooting accuracy (48.8%), fifth in average assistis, seventh in performance index rating (15.7) and was also among the league's top 10 in free throw accuracy (89.2) and steals (1.2 spg.). His true greatness is best viewed in per-minute stats; Rodriguez led the league in assists (8.8 apg. Prorated over 40 minutes), was second in performance index rating (27.7 per 40) and third in scoring (23.9 ppg. During the regular season, Rodriguez set Madrid club records for most assists (11) in a Euroleague game this century and most three-pointers without a miss, 6, in one game.

This marks the first All-Euroleague selection of Rodriguez's career. This season's winner of the Alphonso Ford Top Scorer Trophy, Keith Langford was the force that led EA7 Emporio Armani Milan to the brink of the Final Four. Langford, 30, not only led the competition in scoring (17.6 ppg.), but thanks to his all-around contributions, also had the highestaverage performance index rating (17. Install Ubuntu From Usb Windows 10. 7) among all Euroleague players.

Langford led the league in fouls drawn (163), free throws attempted (156) and made (119) and was second on his team in assists (2.9 apg.). His calling card, though, was scoring. He recorded three of the 10 best scoring games in the league this season – a trio of 29-point performances. Langford scored in the 20s nine times, five of which came on the road. He scored in double figures in every Top 16 and playoffs game in which he played and led the Euroleague in scoring in both of those phases. For Langford, who has averaged more points than any other Euroleague player over the past five seasons, this is his first All-Euroleague selection. Rudy Fernandez was at his best again in 2013-14, helping to lead Real Madrid's record-breaking attack with acrobatic baskets, rim-rocking alley-oop slams, strong outside shooting and stellar defense that often triggered fast breaks.

Fernandez, 29, was a model of consistency, as he started every game and was among Madrid's leaders in nearly every major statistical category. He led the team and was fifth in the Turkish Airlines Euroleague in steals (1.4 spg.). Fernandez was second on Madrid in scoring (13.2 ppg.) and third in assists (3.3 apg.) and defensive rebounding (3.1 drpg.). A terror to guard, Fernandez ranked 11th in the Euroleague with 3.8 fouls drawn per game and ninth in free throw accuracy (88.6%).

As a result, Fernandez ranked third in the league with an average performance index rating of 17.1. He was the bwin MVP for the round twice during the Top 16, including a career-high 28-point performance against fellow Final Four side CSKA Moscow. This is the second straight All-Euroleague First Team selection for Fernandez, who was also the Rising Star Trophy winner in 2007. In his second season with CSKA Moscow, Sonny Weems reaffirmed his status as one of the best clutch scorers in the Turkish Airlines Euroleague. Weems, 27, was a major factor in his team's success, both as its top scorer and the go-to guy with games on the line. He led CSKA this season in scoring (12.6 ppg), steals (0.9 spg) and average index rating (13.3), while ranking second in assists (3.6 apg) and third in rebounds (3.5 rpg). He almost singlehandedly authored one of the great comebacks this season with 10 points in the last three minutes of regulation to help CSKA force overtime and eventually beat Panathinaikos in a memorable opening game in the playoffs.

Weems was always at his best against top competition; he put up 28 points against one of the league's best defenses, Real Madrid, among his averages of 14.8 points and an 18.8 index rating in five games against the other three Final Four teams. In his third Euroleague season, this is the first first All-Euroleague selection for Weems. For much of the season, big man Ante Tomic was the centerpiece of FC Barcelona's attack. He also dominated in the pressure-cooker of the Top 16 like no player in recent Euroleague history. In facct, Tomic, 27, became the first player to earn the monthly bwin MVP honor twice in one season when he did so back-to-back in February and March. Tomic led Barcelona in scoring (11.8 ppg.) and rebounding (6.3 rpg.), was second in two-point shooting (63.3%) and blocks (0.9 bpg.) and averaged more assists (2.2 apg.) than any other center in the competition. That all added to his performance index rating average of 16, which was sixth-best in the Turkish Airlines Euroleague.

Moreover, his per-minute index rating (28.5 prorated over 40 minutes) was the best in the league. He had two of the top 10 performances in the league this season with index ratings of 36 and 40 on the road at EA7 Milan and Anadolu Efes, respectively, in back-to-back weeks in February. For Tomic this is a second straight All-Euroleague First Team honor, which coincides with his only two seasons wearing a Barcelona uniform. Ricky Hickman, Maccabi Electra Tel Aviv He may have taken a longer road to stardom than the rest on this list, but Maccabi combo-guard Ricky Hickman is certainly reaping the fruits of his dedication and hard work. Hickman is only three seasons removed from playing in lower-division European clubs, but today he is a key player in Maccabi's run to the biggest event in European basketball – the Turkish Airlines Euroleague Final Four. Hickman, 28, led Maccabi this season in scoring (12.1 ppg.) and average performance index rating (11.3).

Only two players attempted more foul shots than Hickman this season (116) and he ranked seventh in the Euroleague in fouls drawn (4.0 per game). Hickman was honored as the bwin MVP for his role in the crucial road playoff victory in Game 1 of the series against would-be Final Four hosts EA7 Emporio Armani Milan. He finished as the playoffs leader in index rating (22.3) and fouls drawn (7.3), while ranking among the top five in scoring (16.5 ppg.) and assists (4.5 apg.) to bring Maccabi to the Final Four in style.

Vassilis Spanoulis, Olympiacos Piraeus For the fourth year in a row – and fourth wearing an Olympiacos uniform – Vassilis Spanoulis lived up to high expectations with an incredible season. Although the Reds fell short of the Final Four by one game after a great playoffs series against Real Madrid, Spanoulis masterfully orchestrated his team's attempt to retain the Turkish Airlines Euroleague trophy it held for two years. A combo-guard difficult to contain due to both his scoring instincts and passing ability, Spanoulis did both the entire season, finishing with some of the best numbers of his illustrious career. Spanoulis, 31, ranked third in Euroleague in scoring (15.1 ppg.), and eighth in assists (4.6 apg.). He was also among the league's best in three-pointers made and fouls drawn. Spanoulis finished the season second on Olympiacos in average performance index rating (13.0) and claimed a pair of weekly bwin MVP awards along the way.

This marks the fourth consecutive All-Euroleague selection – and sixth overall – for the 2013 Euroleague MVP, who adds the trophy to those earned as a three-time Euroleague champion and three-time Final Four MVP. Victor Khryapa, CSKA Moscow A constant force at on both ends of the floor, versatile CSKA forward Victor Khryapa again did many things so well throughout the season to lead his team to another Final Four appearance. Khryapa, 31, led CSKA and ranked among league's top 15 players in assists (4.2 apg.).

He also led CSKA in rebounding (5.2 rpg.), was second in steals (0.9 spg.) and average performance index rating (12.2). In Top 16 Round 7 against Maccabi Electra Tel Aviv, Khryapa came within 2 assists of becoming just the second man to record a triple-double in a Euroleague game, racking up 10 points, 10 rebounds, 8 assists and 4 steals. He later became the first player ever to lead the Euroleague playoffs in both rebounding (7.6) and assists (5.6). Khryapa, a Euroleague champion with CSKA in 2008, will take part in his eighth Final Four this season. This is his third All-Euroleague selection after earning First Team honors in 2009-10, the same year he also won the Best Defender Trophy. He received Second Team honors last season. Nikola Mirotic, Real Madrid Producing memorable, award-winning performances in every one of his full Euroleague campaigns, Nikola Mirotic continued his trend of delivering the goods in 2013-14 to help take Real Madrid to their third Final Four together.

Both crafty around the rim and deadly from long range, the 23-year-old forward was a vital part of Real Madrid's success and its having one of the best-ever offenses in the competition. Mirotic ranked among the top three on his team in scoring (12.2 ppg.), rebounding (4.6 rpg.), fouls drawn (3.3 per game), three-point shooting (46.3%), steals (1.1 spg.) and blocks (0.8 bpg.). His versatility led to Mirotic recording the eighth-best average performance index rating in the competition (15.5). He was the only player in the Turkish Airlines Euroleague to rank among the top 15 this season in scoring, steals, blocks and index rating. This is his second time on the All-Euroleague Team, after a Second Team selection last season. Mirotic is also the only two-time winner of the Euroleague Rising Star Trophy, which he took home in 2011 and 2012. Stephane Lasme, Panathinaikos Athens Most often found elevating above big crowds in the paint for a soaring dunk, monster block, or a sky-high rebound, Stephane Lasme did plenty in his second season with Panathinaikos Athens to bring the Greens within one victory of a Final Four berth.

Lasme, 31, was a cornerstone of the only defense in the competition that held opponents to fewer than 70 points per night in the Top 16. Lasme intimidated opponents with an average of 1 block per night, which was eighth-best in the competition, and helped control the paint with 4.8 rebounds per contest. Lasme ranked first on the team in both categories, but he was also a main contributor on the Greens' offense, too, as their leading scorer with 8.9 points per game.

Moreover, Lasme was among the best big men in the Euroleague at getting to the free throw line. He ranked among the league's top 10 with 97 free throw attempts and knocked them down with admirable 82.5% accuracy. It all led to his first All-Euroleague selection, a year after earning Euroleague Best Defender honors. Nokia C6 01 Themes Free Download.