The first members of the pectenotoxin family of marine natural products were isolated off the northeastern coast of Japan in 1985. Subsequently, ten members of this group have been identified. [1] The structural diversity within the pectenotoxins stems from variations in the oxidation state at C43, as well as the differing configurations of the AB spiroketal portion of the structures. Pectenotoxin-2 (C43 ¼ Me) is cytotoxic towards human lung, colon, and breast cancer cell lines with LC 50 values in the nanomolar range. [1c] Pectenotox-COMMUNICATIONS 4569 5'-amino and 3'-acetaldehyde groups remain at the end of the reaction.As in the polymerase chain reaction (PCR), [20±22] S(dAp) 8 templates the ligation of multiple monomers in a single reaction cycle. Unlike PCR, where both strands of the DNA duplex are amplified to give exponential growth, the DNAtemplated polymerization reactions employ only a single strand as the template and growth is presumably linear with each reaction cycle. In addition, the requirement for primers compatible with the double-strand-binding polymerase is avoided, and short sequences of DNA are amplified efficiently.Finally, the reaction does not synthesize native DNA, but a backbone analogue. Therefore, solid-supported oligomeric DNA can be used to catalyze the rapid synthesis of polymers containing different backbones simply by changing the structure of the reactant, in this case (T) 1 and (T N ) 2 , Quite unlike other solid-supported syntheses, S(dAp) n can be used repeatedly both to catalyze the polymerization as well as purify the product, which greatly reduces the time and effort for the synthesis of modified DNA-analogues. The extension of this chemistry to mixed-sequence templates should enable the rapid amplification of DNA sequence information into specific backbone-modified analogues. Moreover, this general strategy for solid-phase synthesis can now be extended more broadly, through other molecular recognition elements, to accomplish chain-length-specific polymerizations. Experimental SectionDNA Synthesis: All native DNA oligomers were prepared by the Emory University Microchemical Facility on a PE-Biosystems 394 DNA Synthesizer. The DNA S(dAp) 8 template was synthesized on OAS-PS (Glen Research, Batch No. G008062, Cat. No. 26-4001) solid supports by standard cyanoethyl phosphoramidite chemistry. The linker of OAS-PS is stable to the last step of ammonium hydroxide deprotection treatment in the automated synthesis. To confirm purity, the DNA oligomers were removed from the resin and analyzed by Rainin HPXL RP-HPLC: Phenomenex Prodigy 5 analytical ODS(2) C18; Rainin Dynamax UV detector at 260 nm, and eluted with MeOH in H 2 O (0±100 % in 50 min), and the structure confirmed by MALDI-MS: C 80 H 97 N 40 O 38 P 7 calcd m/z: 2443.69 [MþH þ ]; found 2444.87.Polymerization: The substrates, 8 mm for (T N ) 2 and 16 mm for (T) 1 , were mixed with S(dAp) 8 at the indicated stoichiometry, heated to 75 8C for 2±3 min, and cooled to 4 8C for 3 h. [23] NaBH 3 CN (20 equiv) was added at room...
In the preceding communication, [1] the proposed synthesis plan identified the two principal pectenotoxin-4 subunits II and III (Figure 1). It was our intention to couple these fragments through the alkylation of the metalloenamine derived from hydrazone III, readily available from the coupling of advanced intermediates IV and V (transform T 2 ), by epoxide II. However, this investigation revealed that the above bond construction was not feasible due to the decomposition of metalloeneamine III under the reaction conditions. [2] Accordingly, the objective in the present communication is the synthesis of the subunits IV and V, and the completion of the syntheses of pectenotoxin-4 (1) and pectenotoxin-8 by a revised fragment coupling strategy, where epoxide alkylation (transform T 1 ) precedes diene formation (transform T 2 ).The plan for the construction of the F-ring tetrahydrofuran IV was to involve a C37 hydroxy-directed epoxidation of olefin VI with a subsequent ring closure by the C32 hydroxy moiety (transform T 3 ). Finally, the stereoselective formation of the E-ring tetrahydrofuran V from its acyclic precursor VII was based on an iodoetherification precedent provided by Bartlett and Rychnovsky (transform T 4 ). [3] The synthesis of the ring-E synthon V began with the known aldol adduct adduct 2 (Scheme 1). [4] Reduction of 2 (LiBH 4 , THF, 0 8C), and selective protection of the primary alcohol (TBSCl, Im, CH 2 Cl 2 , 100 % over two steps) afforded allylic alcohol 3. [5] Acylation of 3 with the PMB-protected lactic acid 4 [6] (DCC, DMAP, CH 2 Cl 2 , 52 %), followed by carbonyl olefination of 5 a with Tebbe reagent [7] afforded the 1,5-diene 5 b. Claisen rearrangement of 5 b in refluxing toluene gave the desired rearrangement product 6 in 82 % yield for the two steps. Chelate-controlled reduction of the resulting ketone (Zn(BH 4 ) 2 , Et 2 O, À78 8C, 86 %, d.r. 86:14) provided the precursor for the key iodoetherification reaction. In spite of the modest selectivity that was observed for the formation of the desired tetrahydrofuran 7 (NIS, CH 3 CN, À40 8C, 89 %, d.r. 72:28), this outcome proved sufficient to pursue the planned route.Successive radical dehalogenation of 7 (Bu 3 SnH, AIBN, toluene, 100 %) and deprotection of the primary TBS ether (TBAF, THF, 95 %) afforded alcohol 8. Oxidation with Dess± Martin reagent [8] (py, CH 2 Cl 2 , 99 %), Wittig homologation (EtOC(O)CC(CH 3 )PPh 3 , THF, 65 8C; 100 % E:Z > 95:5), and ester reduction (LiAlH 4 , Et 2 O, 0 8C, 92 %) completed the carbon assembly of the E-ring fragment. Benzyl protection (NaH, BnBr, TBAI, THF/DMF, 94 %) followed by PMB deprotection (DDQ, CH 2 Cl 2 /pH 7 buffer, 95 %) gave alcohol 10. Oxidation to the methyl ketone [8] (Dess±Martin periodinane, py, CH 2 Cl 2 , 93 %), and hydrazone formation (TMSCl, CH 2 Cl 2 /Me 2 NNH 2 , 100 %) completed the synthesis of hydrazone 11.As summarized in Figure 1, the first stage of the synthesis of the ring-F fragment IV will be simplified to the construction of the C31±C35 phosphonium salt, the C36±C40 aldehyd...
No abstract
Orexin A and B (also known as hypocretins), two recently discovered neuropeptides, play an important role in food intake, sleep/wake cycle and neuroendocrine functions. Orexins are endogenous ligands of two G-protein-coupled receptors, termed OX 1 and OX 2 . This work presents the first short orexin A and B analogues, orexin A 23-33 and orexin B 18-28, with high affinity (119 ± 49 and 49 ± 23 nM) for OX 1 receptors expressed on SK-N-MC cells and indicates the importance of the C-terminal part of the orexin peptides for this ligand-receptor interaction. However, these C-terminal fragments of orexin did not displace the 125 I-labelled orexin B from the recombinant orexin 1 receptor stably expressed in Chinese hamster ovary cells. To examine the role of the shortened orexin A 23-33 in feeding, its effects in mimicking or antagonizing the effects of orexin A were studied in rats after administration via the lateral hypothalamus. In contrast with orexin A, which potently induced feeding up to 4 h after administration, orexin A 23-33 neither induced feeding nor inhibited orexin A-induced feeding. Modafinil (VigilÒ), which was shown earlier to activate orexin neurons, displayed binding neither to the orexin receptor expressed on SK-N-MC cells nor to the recombinant orexin 1 receptor, which indicates that modafinil displays its antinarcoleptic action via another yet unknown mechanism. PCR and subsequent sequencing revealed expression of the full-length orexin 1 receptor mRNA in SK-N-MC and NT-2 cells. Interestingly, sequencing of several cDNA clones derived from RNA of both SK-N-MC and NT-2 cells differed from the published nucleotide sequence at position 1375. Amino acid prediction of this AfiG change results in an isoleucinefivaline substitution at the protein level, which may provide evidence for an editing process.
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