A new scheme for the synthesis of 5'-nucleotide phosphonate analogs

A convenient and general method is proposed for the synthesis of 5'-nucleotide phosphonate analogs starting from 5-deoxy-1,2-O-isopropylidene-alpha-D-xylo-hexofuranose.     

A new approach for the synthesis of novel 5-substituted isodeoxyuridine analogs

Cyclic sulfates of carbohydrates provide excellent synthons for the preparation of isodeoxyuridines through direct nucleophilic substitution reactions. These substitution reactions have exceptional regioselectivity. The products of the reactions served as key precursors for the synthesis of 5-substituted isodeoxyuridines via the Stille and Heck coupling reactions. Interestingly, unprotected nucleosides could be used in these metal-mediated functionalizations. The methodologies are general and allow ready access to a variety of C-5 functionalized isomeric deoxyuridines, but also have the potential to be extended to other nucleoside analogs.     

Total synthesis and biological evaluation of spirotryprostatin A analogs

Based on the spirotryprostatin A structure, a series of compounds belonging to spiro‐indolyl diketopiperazine structural class were designed and synthesized, which embody an oxindole with an all‐carbon quaternary stereocenter. The total synthesis can efficiently be accessed in a seven‐step reaction sequence with 18–28% overall yield from commercially available materials, and a highly enantioselective 1,3‐dipolar cycloaddition, N ‐acylation of the resulting stereochemically complex spiro[pyrrolidin‐3,3′‐oxindole]s core with Fmoc‐L ‐pro‐Cl and spontaneous ring closure upon N ‐deprotection were obtained. The synthesized compounds 13a–e and 15a–e were evaluated for their antibacterial activities. The result showed that compounds 13b and 15b were active only against Gram‐positive bacteria, and selective antibacterial activity was exhibited by compounds 13d and 13e against Streptococcus lactis . Further, all the remaining compounds showed a certain degree of antibacterial activity. In addition, the structure–activity relationship is also discussed.     

A new method for the synthesis of N3-alkylated analogs of 5-fluorouracil.

5-Fluorouracil (5-FU) is converted to the adducts 1a,b then subjected to Mitsunobu reaction with the secondary alcohols to give the condensates 2a,b. Hydrogenation of 2a,b with Pd/C affords N3-alkyl-5-fluorouracil 3a,b.     

Efficient synthesis of a new L-shaped dimer of naphthalene, and its analogs

Efficient syntheses of 14H-dinaphtho[1,8-bc:1',8'-fg]oxocin-14-one (2), 14H-dinaphtho[1,8-bc:1',2'-f]oxepin-14-one (3), and 2,2'(2H,2'H)-spirobi[naphtho[1,8-bc]furan] (9) are described. The putative structure of 2 has been reported previously, but the synthetic route was not reproducible. 7H-Dibenzo[c,h]xanthen-7-one (4), a known compound, was obtained by a different method. Possible reaction mechanism are proposed.     

4-Aminothiazolyl analogs of GE2270 A: design, synthesis and evaluation of imidazole analogs

Imidazole analogs of the antibiotic natural product GE2270 A (1) were designed, synthesized, and evaluated for Gram positive bacteria growth inhibition. A recently reported, copper-mediated synthesis was exploited to prepare 4-thiazolyl imidazole analogs of 1. The synthesis described represents a structurally complex, natural product-based application of this recently reported synthetic methodology. In addition, the biological evaluation of the imidazole-based analogs further define the SAR of the 4-aminothiazolyl-based antibacterial template.     

Design,synthesis, and biological activity of new endomorphin analogs with multi-site modifications

Endomorphin (EM)-1 and EM-2 are the most effective endogenous analgesics with efficient separation of analgesia from the risk of adverse effects. Poor metabolic stability and ineffective analgesia after peripheral administration were detrimental for the use of EMs as novel clinical analgesics. Therefore, here, we aimed to establish new EM analogs via introducing different bifunctional d-amino acids at position 2 of [(2-furyl)Map⁴]EMs. The combination of [(2-furyl)Map⁴]EMs with D-Arg² or D-Cit² yielded analogs with enhanced binding affinity to the μ-opioid receptor (MOR) and increased stability against enzymatic degradation (t_1/2 > 300 min). However, the agonistic activities of these analogs toward MOR were slightly reduced. Similar to morphine, peripheral administration of the analog [D-Cit², (2-furyl)Map⁴]EM-1 (10) significantly inhibited the pain behavior of mice in multiple pain models. In addition, this EM-1 analog was associated with reduced tolerance, less effect on gastrointestinal mobility, and no significant motor impairment. Compared to natural EMs, the EM analogs synthesized herein had enhanced metabolic stability, bioavailability, and analgesic properties.     

Eukaryotic selenoprotein synthesis: mechanistic insight incorporating new factors and new functions for old factors

Selenium is an essential micronutrient that has been linked to various aspects of human health. Selenium exerts its biological activity through the incorporation of the amino acid, selenocysteine (Sec), into a unique class of proteins termed selenoproteins. Sec incorporation occurs cotranslationally at UGA codons in archaea, prokaryotes, and eukaryotes. UGA codons specify Sec coding rather than termination by the presence of specific secondary structures in mRNAs termed selenocysteine insertion (SECIS) elements, and trans-acting factors that associate with SECIS elements. Herein, we discuss the various proteins known to function in eukaryotic selenoprotein biosynthesis, including several players whose roles have only been elucidated very recently.     

Divergent synthesis of thapsigargin analogs

Thapsigargin (3) is a potent inhibitor of the SERCA-pump protein, with potential for application in a variety of medicinal areas. The efficient and scalable syntheses of thapsigargin (3) and nortrilobolide (2) have been disclosed previously. To demonstrate the modularity of the previous routes, three natural products (compounds 6, 13, 15) and four analogs (compounds 17–20) have been divergently prepared from a common building block featuring varied acyl chains at the C2, C3, and C8 positions. Biological tests revealed that all of the compounds prepared displayed promising activity profiles.     

Design and synthesis of selenazole-substituted ritonavir analogs

With the help of Surflex-Dock calculation, two ritonavir analogs in which one thioazole unit was replaced by selenazole have been designed and synthesized. The key selenazole structure was constructed from β-azido diselenide through a cascade diselenide cleavage/selenocarbonylation/Staudinger reduction/aza-Wittig reaction and a following MnO₂ oxidation. The accordingly prepared compounds exhibited good anti-HIV-1 (IIIB) activities comparable to that of the original ritonavir, as well as the positive SI values.     

Enantioselective synthesis of ancepsenolide and its analogs

Ancepsenolide (1a-s) and the enantiomer (1a-r) were respectively synthesized from (S)- and (R)-2-[(R)-O-MEM-mandeloyloxylpropanal (3a-s and 3a-r) and diisopropyl hexadecanedioate (5). The analogs (1b, 2a and 2b) were synthesized by a similar method.     

Studies on the synthesis and properties of new PNA analogs consisting of L- and D-lysine backbones

Homopentamers of PNA consisting of L- and D-lysine were synthesized. It was found that the intramolecular hydrogen bonding has no significant influence on intermolecular interaction. These pentamers show a tendency to form complex with polyA in tris(pH 8.0) solution. The L-conformer has more potential than D-isomer.     

A new class of angiotensin inhibitors: N-methylphenylalanine analogs

8-N-methylphenylalanine-; 1-sarcosine, 8-N-methylphenylalanine-; 1-sarcosine, 7-hydroxyproline, 8-N-methylphenylalanine-; 7-alanine, 8-N-methylphenylalanine-; and 1-sarcosine, 7-alanine, 8-N-methylphenylalanine-angiotensins II have been synthesized by the solid-phase method. Their agonist activity in several assays is greatly diminished. Three analogs have inhibitory properties, and 1-sarcosine, 8-N-methylphenylalanine-angiotensin II is more potent than the previously described 1-sarcosine, 8-isoleucine-angiotensin as an inhibitor of the pressor action of angiotensin in the rat.     

8-Methyladenosine-substituted analogs of 2-5A: synthesis and properties

Four 8-methyladenosine-substituted analogs of 2-5A were obtained by a synthesis which involved a modification of the lead ion-catalyzed ligation reaction. Substituent of an 8-methyladenosine residue at the third position (2'-terminal) of the oligonucleotides increased the stability to snake venom phosphodiesterase digestion.     

Design and synthesis of a new generation of substituted purine hydroxamate analogs as histone deacetylase inhibitors

Histone deacetylase inhibitors have been proved to be great potential for the treatment of cancer. Recently, we designed and modified a series of substituted purine hydroxamate analogs as potent HDAC inhibitors based on our previous studies. The target compounds were investigated for their in vitro HDAC inhibitory activities and anti-proliferative activities. Results indicated that these compounds could effectively inhibit HDAC and possess obvious anti-proliferative activity against tumor cells. Promisingly, target compounds 4m and 4n outperformed SAHA in both enzymatic inhibitory activity and cellular anti-proliferative activity assay.     

A new and efficient strategy for the synthesis of shimofuridin analogs: 2'-O-(4-O-stearoyl-alpha-L-fucopyranosyl)thymidine and -uridine

Two shimofuridin analogs: 2'-O-(4-O-stearoyl-alpha-L-fucopyranosyl)thymidine (2) and -uridine (3) have been synthesized using D-arabinose, L-fucose, thymine, uracil, and stearoyl chloride as the starting materials. The synthetic procedures involve the facile preparation of 1-(3,5-di-O-benzyl-beta-D-ribofuranosyl)thymine (9) and -uracil (10) by coupling of 1,2-anhydro-3,5-di-O-benzyl-alpha-D-ribofuranose (8) with silylated thymine and uracil, and then stereoselective formation of the 1,2-cis (alpha) interglycoside bonds through condensation of the nucleoside derivatives 9 and 10 with 2-(2,3-di-O-benzyl-4-O-stearoyl-beta-L-fucopyranosylsulfonyl) pyrimidine (18). The 1,2-anhydro-3,5-di-O-benzyl-alpha-D-ribofuranose (8) was prepared by an improved procedure from D-arabinose.     

Enzymatic synthesis of novel glutathione analogs

A strain of Escherichia coli enriched in its content of gamma-glutamylcysteine synthetase and glutathione synthetase by recombinant DNA techniques has been immobilized in a carrageenan matrix and used for the synthesis of various types of isotopically labeled glutathione (L-gamma-glutamyl-L-cysteinyl-glycine) (K. Murata, W. A. Abbott, R. J. Bridges, and A. Meister (1985) Anal. Biochem. 150, 235-237). In the present work, this E. coli matrix was used as the basis of a method for the synthesis of glutathione analogs. Thus, amino acid analogs were used in place of the corresponding amino acid constituents of glutathione (e.g., 4-fluoroglutamate was substituted for glutamate) in the reaction mixtures. Using this method we have synthesized several analogs of glutathione including L-gamma-glutamyl-(beta-chloro)-L-alanyl-glycine, (R,S)-4-fluoro-DL-gamma-glutamyl-L-cysteinyl-glycine, D-gamma-glutamyl-L-cysteinyl-glycine, and L-gamma-glutamyl-L-homocysteinyl-glycine. This method may also be used for the synthesis of a number of L- and D-gamma-glutamyl amino acids. The analogs are purified by gel-filtration and ion-exchange chromatography. The analogs are used to examine the substrate specificity and mechanisms of action of glutathione-utilizing enzymes and for studies on glutathione metabolism and function. Fluorine-containing analogs may be used for NMR studies. The enzymatically prepared compounds may also be used as intermediates in the chemical synthesis of other analogs of glutathione and glutathione disulfide.     

Improved synthesis and purification of Alzheimer's Aβ 1–42 and analogs

Fmoc-amino acid fluorides are highly efficient coupling agents for solution and solid-phase peptide synthesis and this property was used advantageously for the manual solid-phase assembly of the Alzheimer's Aβ 1–42 peptide [Milton et al., In Marshak, D. (Ed.) Techniques in Protein Chemistry, Vol. VIII, Academic Press, Orlando, FL, 1997, pp. 865–873]. Further studies comparing this methodology in the preparation of Aβ 1–42 peptide analogs employing a fully automated continuous-flow peptide synthesizer are reported.