Structure-activity relationships of 4-hydroxy-4-biaryl-proline acylsulfonamide tripeptides: A series of potent NS3 protease inhibitors for the treatment of hepatitis C virus

The design and synthesis of a series of tripeptide acylsulfonamides as potent inhibitors of the HCV NS3/4A serine protease is described. These analogues house a C4 aryl, C4 hydroxy-proline at the S2 position of the tripeptide scaffold. Information relating to structure-activity relationships as well as the pharmacokinetic and cardiovascular profiles of these analogues is provided.     

Synthesis and Biological Activity of 4′-Thio-2′-deoxy Purine Nucleosides

Abstract

Coupling of 1-O-acetyl-2-deoxy-3,5-di-O-toluoyl-4-thio-_d-ribofuranose with 6-chloropurine and 2,6-dichloropurine gave a mixture of 9α and 9β anomers as major products. These anomers were separated and converted to 2′-deoxy-4′-thio analogues of adenosine, inosine, guanosine, 2-amino-adenosine, and 2-chloro adenosine as well as their α-anomers.     

Synthesis and potency of novel uracil nucleotides and derivatives as P2Y2 and P2Y6 receptor agonists

The phosphate, uracil, and ribose moieties of uracil nucleotides were varied structurally for evaluation of agonist activity at the human P2Y(2), P2Y(4), and P2Y(6) receptors. The 2-thio modification, found previously to enhance P2Y(2) receptor potency, could be combined with other favorable modifications to produce novel molecules that exhibit high potencies and receptor selectivities. Phosphonomethylene bridges introduced for stability in analogues of UDP, UTP, and uracil dinucleotides markedly reduced potency. Truncation of dinucleotide agonists of the P2Y(2) receptor, in the form of Up(4)-sugars, indicated that a terminal uracil ring is not essential for moderate potency at this receptor and that specific SAR patterns are observed at this distal end of the molecule. Key compounds reported in this study include 9, alpha,beta-methylene-UDP, a P2Y(6) receptor agonist; 30, Up(4)-phenyl ester and 34, Up(4)-[1]glucose, selective P2Y(2) receptor agonists; dihalomethylene phosphonate analogues 16 and 41, selective P2Y(2) receptor agonists; 43, the 2-thio analogue of INS37217 (P(1)-(uridine-5')-P(4)-(2'-deoxycytidine-5')tetraphosphate), a potent and selective P2Y(2) receptor agonist.     

Synthesis of 4-epi-2-deoxy-2-Heq-N-acetylneuraminic acid and 2,4-dideoxy-2-Heq N-acetylneuraminic acid

We have continued our work to develop novel analogues of sialic acid [1–4] that may specifically modulate the interaction between endogenous sialic acid and influenza virus haemagglutinin [3,5,6]. Functional groups of sialic acid that have been implicated for this virus-host recongnition are the glycerol side chain, N-acetyl group and the axially oriented carboxylic acid function In this report we describe the synthesis of two analogues, namely, 4-epi-2-deoxy-2-H_eq-N-acetylneuraminic acid (4-epi-2-d-2-H_eq-Neu5Ac) and 2,4-dideoxy-2-H_eq-N-acetylneuraminic acid (2,4-d₂-2-H_eq-Neu5Ac).     

Utilizations of various uridine 5'-triphosphate analogues by DNA-dependent RNA polymerases I and II purified from liver nuclei of the cherry salmon (Oncorhynchus masou)

Various 5-substituted UTPs (methyl, ethyl, n-propyl, n-butyl, fluoro, chloro, bromo, and iodo) and sulfur-containing UTP analogues (4-thio-, 2-thio-, 5-methyl-2-thio-, and 5-methyl-4-thio-) were synthesized chemically and their utilization by DNA-dependent-RNA polymerases I and II of the cherry salmon (Oncorhynchus masou) were studied in substitution experiments under the condition of limited RNA synthesis in vitro. RNA polymerase I utilized the 5-methyl-, chloro, bromo, and iodo derivatives of UTP more efficiently than unmodified UTP, but RNA polymerase II utilized UTP most efficiently. 5-Methyl-4-thiouridine 5'-triphosphate (4-thio TTP) was utilized more efficiently than UTP by RNA polymerase I. On the other hand, it was found that 4-thio TTP was a selective substrate for RNA polymerase I and that its incorporation by RNA polymerase II was very slow. Thus recognition of UTP analogues as substrates by RNA polymerase I and II was different. These observation were attributed from kinetic analyses to differences in catalytic activity (Vmax).     

5-Fluoro-4-thiouridine phosphoramidite: new synthon for introducing photoaffinity label into oligodeoxynucleotides

The synthesis of phosphoramidite of 5-fluoro-4-thio-2'-O-methyluridine is described. An appropriate set of protecting groups was optimized including the 4-thio function introduced via 4-triazolyl as the 4-(2-cyanoethyl)thio derivative, and the t-butyldimethyl silyl for 2' and 3' hydroxyl protection, enabling efficient synthesis of the phosphoramidite. These protecting groups prevented unwanted side reactions during oligonucleotide synthesis. The utility of the proposed synthetic route was proven by the preparation of several oligonucleotides via automated synthesis. Photochemical experiments confirmed the utility of the synthon.     

Ring-substituted quinolines. Part 2: Synthesis and antimycobacterial activities of ring-substituted quinolinecarbohydrazide and ring-substituted quinolinecarboxamide analogues

Additional structural modifications of the new chemical entity, 2,8-dicyclopentyl-4-methylquinoline (DCMQ; MIC = 6.25 μg/mL, M. tuberculosis H37Rv) resulted in the synthesis of four new series of the ring-substituted quinolinecarbohydrazides (series 1–4) constituting 22 analogues. All new derivatives were evaluated for in vitro antimycobacterial activities against drug-sensitive M. tuberculosis H37Rv strain. Certain ring-substituted-2-quinolinecarbohydrazide analogues described herein showed good inhibitory activity. In particular, analogues 4-(1-adamantyl)-2-quinolinecarbohydrazide (2d), 4,5-dicyclopentyl-2-quinolinecarbohydrazide (2e), 4,8-dicyclopentyl-2-quinolinecarbohydrazide (2f), and 4,5-dicyclohexyl-2-quinolinecarbohydrazide (2g) have exhibited the MIC value of 6.25 μg/mL. Further investigation of the most suitable lead prototype, 4-(1-adamantyl)-2-quinolinecarbohydrazide (2d, series 1) led to the synthesis of N2-alkyl/N2,N2-dialkyl/N2-aryl-4-(1-adamantyl)-2-quinolinecarboxamides (series 5) consisting of 13 analogues. Some of the synthesized carboxamides 7a, 7h, and 7m reported herein have exhibited excellent antimycobacterial activities in the range of 6.25–3.125 μg/mL against drug-sensitive and drug-resistant M. tuberculosis H37Rv strains.     

Synthesis of a novel class of some 1,3,4-oxadiazole derivatives as antimicrobial agents

In an effort to discover new candidates with improved antimicrobial activities we report here the synthesis and in vitro biological evaluation of various series of 2-{(3,4,5-trimethoxy phenyl-1,3,4-oxadiazolyl)-5-thio}-4-(morpholino)-6-(phenyl ureido)-s-triazine (7a-i) and 2-{(3,4,5-trimethoxy phenyl-1,3,4-oxadiazolyl)-5-thio}-4-(morpholino)-6-(phenyl thioureido)-s-triazine (8a-g). Antimicrobial properties of the title compounds were investigated against two Gram ( + ve) bacteria (S. aureus, B. subtilis), two Gram ( ? ve) bacteria (P. aeruginosa, E. coli) and yeast-like fungi (C. albicans) using the broth microdilution method.     

TRPV1 antagonist with high analgesic efficacy: 2-Thio pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides

A series of 2-thio pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Among them, compound 24S showed stereospecific and excellent TRPV1 antagonism of capsaicin-induced activation. Further, it demonstrated strong anti-allodynic in a rat neuropathic pain model. Consistent with its action in vitro being through TRPV1, compound 24S blocked capsaicin-induced hypothermia in mice. Docking analysis of 24S with our hTRPV1 homology model was performed to identify its binding mode.     

Synthesis and activity of substituted heteroaromatics as positive allosteric modulators for α4β2α5 nicotinic acetylcholine receptors

The design and synthesis of a series of substituted heteroaromatic α4β2α5 positive allosteric modulators is reported. The optimization and development of the heteroaromatic series was carried out from NS9283, and several potent analogues, such as 3-(5-(pyridin-3-yl)-2H-tetrazol-2-yl)benzonitrile (5k) and 3,3′-(2H-tetrazole-2,5-diyl)dipyridine (12h) with good in vitro efficacy were discovered.     

Nucleoside 3′-O-(2-Oxo-“Spiro”-4.4-Pentamethylene-1.3.2-Oxathiaphospholane)S: Monomers For Stereocontrolled Synthesis Of Oligo(Nucleoside Phosphorothioate/Phosphate)S

Abstract

Attempts at synthesis of “chimeric” oligonucleotide constructs (PO/PS-Oligos) possessing phosphate and P-stereodefined phosphorothioate internucleotide linkages via combined phosphoramidite/oxathiaphospholane methods were unsuccessful. Therefore, novel monomers for oxathiaphospholane method, namely 5′-O-DMT-deoxyribonucleoside 3′-O(2-oxo-.spiro-4.4-pentamethylene-1.3.2-oxathiaphospholane)s, were prepared and used together with their diastereomerically pure 2-thio analogues for the stereocontrolled synthesis of “chimeric” oligonucleotide constructs (PO/PS-Oligos).     

Synthesis and properties of oligonucleotides containing 4-thiothymidine, 5-methyl-2-pyrimidinone-1-beta-D(2''-deoxyriboside) and 2-thiothymidine.

Methods are given for the synthesis of derivatives of 4-thiothymidine (4ST), 5-methyl-2-pyrimidinone-1-beta-D(2'-deoxyriboside) (4HT) and 2-thiothymidine (2ST) suitable for incorporation into oligodeoxynucleotides by the cyanoethyl phosphoramidite method. 4HT and 2ST are incorporated with no base protection but the sulphur atom in 4ST is protected with an S-sulphenylmethyl (-SCH3) function. This can be removed with dithiothreitol after synthesis. These T analogues have been incorporated into GACGATATCGTC, a self-complementary dodecamer containing the Eco RV recognition site (underlined), in place of the two T residues within this site. Although pure dodecamers are obtained in each case the syntheses are not as efficient as those seen when normal unmodified bases are used mainly due to the chemical reactivity of 4ST, 4HT and 2ST. Some of the chemical properties of oligonucleotides containing these bases (reactivity towards NH3) as well as their physical properties (melting temperatures, U.V., fluorescence and circular dichroism spectra) have been determined and are discussed.     

The synthesis and antiviral activity of some 4'-thio-2'-deoxynucleoside analogues.

A practical 7-step synthesis of benzyl 3,5-di-O-benzyl-2-deoxy-1,4-dithio-D-erythro-pentofuranoside is described and the product has been used in the synthesis of some 4'-thio-2'-deoxynucleosides. These novel nucleoside analogues have potentially useful biological activity and are resistant to phosphorolysis.     

mt-tRNA Components: Synthesis of (2-Thio)Uridines Modified with Blocked Glycine/Taurine Moieties at C-5,1

In this paper, we discuss the usefulness of reductive amination of 5-formyl-2′,3′-O-isopropylidene(-2-thio)uridine with glycine or taurine esters in the presence of sodium triacetoxyborohydride (NaBH(OAc)₃) for the synthesis of the native mitochondrial (mt) tRNA components 5-carboxymethylaminomethyl(-2-thio)uridine (cmnm⁵(s²)U) and 5-taurinomethyl(-2-thio)uridine (τm⁵(s²)U) with a blocked amino acid function. 2-(Trimethylsilyl)ethyl and 2-(p-nitrophenyl)ethyl esters of glycine and 2-(2,4,5-trifluorophenyl)ethyl ester of taurine were selected as protection of carboxylic and sulfonic acid residues, respectively. The first synthesis of 5-formyl-2′,3′-O-isopropylidene-2-thiouridine is also reported.     

Synthesis and biological evaluation of 4-[3-biphenyl-2-yl-1-hydroxy-1-(3-methyl-3H-imidazol-4-yl)-prop-2-ynyl]-1-yl-benzonitrile as novel farnesyltransferase inhibitor

Farnesyltransferase inhibitors (FTIs) have emerged as a novel class of anti-cancer agents. Analogues of the potent FTI, 4-[3-biphenyl-1-hydroxy-1-(3-methyl-3H-imidazol-4-yl)-prop-2-ynyl]-1-yl-benzonitrile, were synthesized and tested in vitro for their inhibitory activities. The synthesis and detailed biological data of this series of analogues are presented.     

Studies on the N-acetyl-beta-D-hexosaminidase B from germinating Lupinus luteus L. seeds. II. Mechanism and inhibition with some 2-acetamido-2-deoxyaldono(1----4)lactones

The N-acetyl-beta-D-hexosaminidase B of germinating yellow lupin seeds catalyzed the hydrolysis of both p-nitrophenyl-N-acetyl-beta-D-glucosaminide and -galactosaminide substrates. The investigation of the pH dependence of the kinetic parameters (Vmax and Vmax/Km) demonstrated that two common ionizable groups (probably two carboxyl groups) play an essential role in the catalysis. That is, the enzyme has a lysozyme-like splitting mechanism, and the possibility of an anchimeric assistance provided by the acetamido group seems to be negligible. The presence of a deprotonated carboxyl group near the glycosidic linkage was also supported by inhibition with 1-thio substrate analogues. On the other hand, some 2-acetamido-2-deoxyaldono(1----4)lactones proved to be effective inhibitors of the hexosaminidase with the exception of the D-arabinose derivative, which can be explained by high stereospecificity in the binding.     

Sulfoxide-metal exchange for the synthesis of the 2'-tributylstannyl derivative of 2',3'-didehydro-2',3'-dideoxyuridine (d4u): a general entry to 2'-carbon-substituted analogues of d4U

Methods are described for the synthesis of the 2'-tributylstannyl derivative of 2',3'-didehydro-2',3'-dideoxyuridine (d4U). Two approaches were investigated: radical-mediated desulfonylative stannylation of the 2'-benzenesulfonyl derivative of d4U and sulfoxide-metal exchange reaction of the 2'-benzenesulfinyl derivative. The latter approach was found to give the desired 2'-stannyl derivative in good yield. It was also shown that manipulations of the stannyl group allowed the introduction of a variety of carbon-substituents to the 2'-position by applying the Stille reaction. The whole reaction sequence has opened up a highly general entry to 2'-carbon-substituted analogues of d4U.     

An expeditious synthesis of 4-hydroxy-2E-nonenal (4-HNE), its dimethyl acetal and of related compounds

The facile one step synthesis of 4-hydroxy-2(E)-nonenal and its dimethyl acetal via a cross-metathesis reaction between commercially available octen-3-ol and acrolein or its dimethyl acetal is reported. The method was extended to the synthesis of C₆ and C₁₂ 4-hydroxy-2(E)-enals, their dimethyl acetal and of the 4-hydroxy-2(E)-nonenoic acid (4-HNA).     

Synthesis of 3′-O2-(Azaheterocycle)-Thymidines

Abstract

The synthesis of 3′-O ²-(azaheterocycle)-thymidines is presented from 1-thia-3-aza-1,3-butadiene precursors (N-thioacylamidines). A variety of heterocycles is accessible using the dienic, the electrophilic or the nucleophilic reactivity of these thia-azabutadiene systems. 3′-O ²-(azaheterocycle)-thymidine analogues are regarded as potential substrates to interfere with the DNA-polymerization process.