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1.
J Med Chem ; 63(18): 10188-10203, 2020 09 24.
Article in English | MEDLINE | ID: mdl-32407112

ABSTRACT

Toll-like receptor 8 (TLR8) recognizes pathogen-derived single-stranded RNA fragments to trigger innate and adaptive immune responses. Chronic hepatitis B (CHB) is associated with a dysfunctional immune response, and therefore a selective TLR8 agonist may be an effective treatment option. Structure-based optimization of a dual TLR7/8 agonist led to the identification of the selective TLR8 clinical candidate (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (GS-9688, (R)-7). Potent TLR8 agonism (IL-12p40 EC50 = 220 nM) and >100-fold TLR7 selectivity (IFN-α EC50 > 50 µM) was observed in human peripheral blood mononuclear cells (PBMCs). The TLR8-ectodomain:(R)-7 complex confirmed TLR8 binding and a direct ligand interaction with TLR8 residue Asp545. Oral (R)-7 had good absorption and high first pass clearance in preclinical species. A reduction in viral markers was observed in HBV-infected primary human hepatocytes treated with media from PBMCs stimulated with (R)-7, supporting the clinical development of (R)-7 for the treatment of CHB.


Subject(s)
Antiviral Agents/pharmacology , Hepatitis B, Chronic/drug therapy , Hexanols/pharmacology , Pyridines/pharmacology , Pyrimidines/pharmacology , Toll-Like Receptor 8/agonists , Administration, Oral , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Crystallography, X-Ray , Dogs , Drug Discovery , Hepatitis B virus/drug effects , Hexanols/administration & dosage , Hexanols/chemical synthesis , Hexanols/metabolism , Humans , Macaca fascicularis , Molecular Structure , Protein Domains , Pyridines/administration & dosage , Pyridines/chemical synthesis , Pyridines/metabolism , Pyrimidines/administration & dosage , Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Rats , Structure-Activity Relationship , Toll-Like Receptor 8/metabolism
2.
Org Biomol Chem ; 10(37): 7510-26, 2012 Oct 07.
Article in English | MEDLINE | ID: mdl-22885896

ABSTRACT

Transmetallation of the 5-benzyloxy-4-methylpent-2-en-1-yl(tributyl)- and -(triphenyl)stannanes 1 and 8 using tin(iv) chloride generates an allyltin trichloride that reacts with aldehydes to give (Z)-1,5-anti-6-benzyloxy-5-methylhex-3-en-1-ols 2. The allyltin trichloride believed to be the key intermediate in these reactions has been trapped by phenyllithium to give anti-5-benzyloxy-4-methylpent-1-en-3-yl(triphenyl)stannane 9. Transmetallation of this anti-5-benzyloxy-4-methylpent-1-en-3-yl(triphenyl)stannane 9 generated an allyltin trichloride that reacted with aldehydes to give the (Z)-1,5-syn-6-benzyloxy-5-methylhex-3-en-1-ols 23 and was trapped by phenyllithium to give syn-5-benzyloxy-4-methylpent-1-en-3-yl(triphenyl)stannane 24. Similar stereoselectivity was observed for tin(iv) chloride promoted reactions of this syn-5-benzyloxy-4-methylpent-1-en-3-yl(triphenyl)stannane 24 with aldehydes and with phenyllithium. The allyltin trichlorides generated by transmetallation of 4-hydroxy- and 4-benzyloxy-pent-2-enyl(triphenyl)stannanes 34 and 35 were similarly trapped by phenyllithium to give 4-hydroxy- and 4-benzyloxy-pent-1-en-3-ylstannanes 36 and 37 whose configurations were established by correlation with known compounds. This work confirmed the configurations of the intermediate allyltin trichlorides involved in tin(iv) chloride promoted reactions of 4- and 5-alkoxypent-2-enylstannanes with aldehydes and showed that the high levels of remote stereocontrol were due mainly to kinetically controlled transmetallation. A fuller mechanistic scheme is proposed for the reactions in the 5-benzyloxy-4-methylpent-2-enylstannane series together with relevant (119)Sn NMR data.


Subject(s)
Hexanols/chemical synthesis , Organometallic Compounds/chemistry , Organotin Compounds/chemistry , Organotin Compounds/chemical synthesis , Tin Compounds/chemistry , Crystallography, X-Ray , Hexanols/chemistry , Models, Molecular , Molecular Structure
3.
Parasitol Int ; 60(4): 488-92, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21924377

ABSTRACT

Malaria is one of the world's deadliest diseases and is becoming an increasingly serious problem as malaria parasites develop resistance to most of the antimalarial drugs used today. We previously reported the in vitro and in vivo antimalarial potencies of 1,2,6,7-tetraoxaspiro[7.11]nonadecane (N-89) and 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) against Plasmodium falciparum and Plasmodium berghei parasites. To improve water-solubility for synthetic peroxides, a variety of cyclic peroxides having carboxyl functionality was prepared based on the antimalarial candidate, N-251, and their antimalarial activities were determined. The reactions of N-89 and its derivatives with Fe(II) demonstrated a highly efficient formation of the corresponding carbon radical which may be suspected as a key for the antiparasitic activity.


Subject(s)
Antimalarials/administration & dosage , Hexanols/administration & dosage , Malaria, Falciparum/drug therapy , Malaria/drug therapy , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Spiro Compounds/administration & dosage , Animals , Antimalarials/chemical synthesis , Antimalarials/therapeutic use , Carbon/chemistry , Carbon/metabolism , Carboxylic Acids/chemistry , Drug Evaluation, Preclinical , Ferrous Compounds/metabolism , Free Radicals/chemistry , Free Radicals/metabolism , Hexanols/chemical synthesis , Hexanols/therapeutic use , Humans , Inhibitory Concentration 50 , Malaria/parasitology , Malaria, Falciparum/parasitology , Mice , Mice, Inbred ICR , Oxidation-Reduction , Peroxides/chemistry , Peroxides/metabolism , Plasmodium berghei/growth & development , Plasmodium falciparum/growth & development , Spiro Compounds/chemical synthesis , Spiro Compounds/therapeutic use , Structure-Activity Relationship
4.
J Nanosci Nanotechnol ; 9(4): 2660-3, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19438017

ABSTRACT

An approach to reject stray light and improve glucose adsorption was presented. With a self-assembled monolayer (SAM) and a confocal optical configuration applied in this approach, the adsorption and signal to noise ratio (SNR) have been improved respectively. Our experimental results demonstrated that the surface enhanced Raman scattering (SERS) spectroscopy with 9 feature peaks for 100 mM aqueous glucose is successfully obtained in a dry environment in response time as fast as 40 s only. This approach could improve glucose detection in response time and sensitivity effectively in atmosphere environment.


Subject(s)
Glucose/analysis , Hexanols/chemical synthesis , Nanospheres/chemistry , Polystyrenes/chemistry , Silver/chemistry , Spectrum Analysis, Raman/methods , Sulfhydryl Compounds/chemical synthesis , Adsorption , Glucose/chemistry , Hexanols/chemistry , Spectrum Analysis, Raman/instrumentation , Sulfhydryl Compounds/chemistry , Surface Properties , Time Factors
5.
J Agric Food Chem ; 56(10): 3758-63, 2008 May 28.
Article in English | MEDLINE | ID: mdl-18461959

ABSTRACT

The individual diastereoisomers of the cysteine conjugate of 3-mercaptohexanol (4) were synthesized with high isomeric purity (>98%). On treatment with Apotryptophanase enzyme, the 3R diastereoisomer of 4 gave an 82% yield of the R enantiomer of 1, with no trace of the 3S enantiomer present. Conversely, the 3S diastereoisomer of 4 gave the 3S enantiomer of 1 (43%) accompanied by a trace of the 3R form (S/R = 98.5:1.5), reflecting the diastereomeric purity of the cysteine conjugate. The same stereochemical outcome was observed when the individual diastereoisomers of 4 were added to fermentations with the Saccharomyces cerevisiae AWRI 1655 yeast strain, which gave 1 in 1% yield. A d(10)-analogue of 1 was synthesized and used as an internal standard to determine, by gas chromatography-mass spectrometry (GC-MS), the amounts of 1 formed in these transformations.


Subject(s)
Cysteine/chemistry , Hexanols/chemical synthesis , Sulfhydryl Compounds/chemical synthesis , Cysteine/metabolism , Fermentation , Gas Chromatography-Mass Spectrometry , Hexanols/metabolism , Magnetic Resonance Spectroscopy , Odorants/analysis , Saccharomyces cerevisiae/metabolism , Stereoisomerism , Sulfhydryl Compounds/metabolism
6.
Anal Biochem ; 351(2): 273-81, 2006 Apr 15.
Article in English | MEDLINE | ID: mdl-16455035

ABSTRACT

A universal reagent 1-O-(4,4'-dimethoxytrityl)-6-aminohexanol (DTAH) is described for the estimation of surface-bound functionalities (epoxy, aldehyde, and carboxyl) required for preparation of oligonucleotide arrays (biochips). The method involves the reaction of universal reagent DTAH with surface-bound functionality under microwaves for 10 min, followed by washings to remove the excess reagent. In the subsequent step, a weighed amount of DTAH-treated surface is exposed to acid to liberate 4,4'-dimethoxytrityl cation, which is measured at 505 nm to determine the functional group loading on the surface.


Subject(s)
Hexanols , Oligonucleotide Array Sequence Analysis/methods , Spectrophotometry/methods , Trityl Compounds , Aldehydes/analysis , Carboxylic Acids/analysis , Epoxy Compounds/analysis , Hexanols/chemical synthesis , Hexanols/chemistry , Kinetics , Microwaves , Oligonucleotide Array Sequence Analysis/instrumentation , Trityl Compounds/analysis , Trityl Compounds/chemical synthesis , Trityl Compounds/chemistry
7.
J Org Chem ; 69(25): 8775-9, 2004 Dec 10.
Article in English | MEDLINE | ID: mdl-15575756

ABSTRACT

We developed a stereocontrolled route allowing potential access to the eight isomers of 4-benzylaminohex-5-ene-1,2,3-triol in two or four steps and ca. 50% yield from readily available chiral nonracemic cis- or trans-alpha,beta-epoxyimine precursors. A new (NH(4))(2)CO(3)-based carboxylation/intramolecular cyclization sequence allowed regio- and stereocontrolled C-3 epoxide opening while neat C-2 hydrolysis was ensured by simple aqueous acidic treatment.


Subject(s)
Hexanols/chemical synthesis , Cyclization , Epoxy Compounds/chemical synthesis , Epoxy Compounds/chemistry , Hydrolysis , Molecular Conformation , Stereoisomerism
8.
Appl Biochem Biotechnol ; 119(2): 171-80, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15531787

ABSTRACT

The main objective of this work was to improve the selective synthesis of a volatile compound: aldehyde or alcohol using a coupled-enzyme system. A novel method of synthesis of C6-aldehyde or alcohol was carried out in the presence of hydroperoxide lyase (HPLS) activity coupled to alcohol dehydrogenase (ADH) activity. After cleavage of the initial substrate, hydroperoxy fatty acid catalyzed by HPLS, the second enzyme, ADH, can catalyze the reduction of the aldehyde to the corresponding alcohol, or the oxidation of contaminating alcohol into aldehyde, depending on the cofactor present in the medium (oxidized or reduced form). We succeeded in improving the synthesis of one of the products. When coupling HPLS to NADP, the selectivity of hexanal production from 13-hydroperoxy linoleic acid was improved, and hexanol production was reduced 5 to 10 times after 15 min of reaction at 15 degrees C and pH 7.0. In another experiment, HPLS was coupled to ADH in the presence of NADH. The production of alcohol (hexenols) was then favored especially when using 13-hydroperoxy linolenic acid as substrate at concentrations >15 mM, reaching 95% of the products. Coupling of the enzymatic reactions (cleavage reduction) not only reduced the number of steps but also allowed us to increase the conversion rate of the initial substrate (hydroperoxy fatty acid). Structures of the compounds produced in this work were confirmed using gas chromatography-mass spectroscopy analysis. Each of these products has its own delicately different fresh odor that can be used in various applications.


Subject(s)
Alcohol Dehydrogenase/chemistry , Aldehyde-Lyases/chemistry , Aldehydes/chemical synthesis , Cytochrome P-450 Enzyme System/chemistry , Hexanols/chemical synthesis , Alcohols/chemical synthesis , Coenzymes/chemistry , Enzyme Activation , Multienzyme Complexes/chemistry , Substrate Specificity
9.
J Am Chem Soc ; 124(10): 2106-7, 2002 Mar 13.
Article in English | MEDLINE | ID: mdl-11878951

ABSTRACT

A new two-step procedure for the synthesis of cyclohexenols has been developed. A nickel-catalyzed three-component addition of an enal, alkyne, and acetylenic tin affords substituted hept-4-en-6-ynals. The products of this first step then undergo a second nickel-catalyzed reaction with organozincs or organoboranes to afford densely functionalized cyclohexenols. Variation in each of the four components is tolerated to provide access to a wide range of versatile building blocks.


Subject(s)
Cyclohexanes/chemical synthesis , Hexanols/chemical synthesis , Nickel/chemistry , Catalysis , Cyclohexenes , Organometallic Compounds/chemistry
10.
J Med Chem ; 41(11): 1909-26, 1998 May 21.
Article in English | MEDLINE | ID: mdl-9599240

ABSTRACT

Water soluble analogues of the lipophilic immunostimulant, octadecyl D-alanyl-L-glutamine, BCH-527, were synthesized and evaluated for the ability to stimulate natural killer (NK) cells. One of these compounds in which the octadecyl chain of BCH-527 was replaced with a shorter chain alcohol, 6-(D-alanyl-L-glutaminylamino)hexan-1-ol, 9, displayed an in vitro stimulation of NK cells comparable to that of interleukin 2 (IL 2). However, when the hydroxyl of 9 was linked to L-fucose to yield 1-beta-[6-(D-alanyl-L-glutaminylamino)hex-1-yl]-L- fucopyranose (BCH-2537, 1), the observed stimulation of NK cells was greater than that observed with IL 2. Further evaluation of these compounds revealed that the improved in vitro activity of BCH-2537 was more pronounced in vivo. That is, while both compounds significantly increased splenic NK cells, only BCH-2537 significantly increased the activity of these cells in vivo. In terms of a structure-activity relationship, NK cell activity was sensitive to minor structural modifications. It was influenced by conservative substitutions within the dipeptide, the length of the hydrocarbon chain, and the functionality at the end of the chain. No other compound enhanced NK cell activity to the extent exhibited by BCH-2537, although a few were equipotent to 9.


Subject(s)
Adjuvants, Immunologic , Dipeptides , Fucose/analogs & derivatives , Hexanols , Killer Cells, Natural/drug effects , Lymphocyte Activation/drug effects , Adjuvants, Immunologic/chemical synthesis , Adjuvants, Immunologic/chemistry , Adjuvants, Immunologic/pharmacology , Animals , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , Dipeptides/chemical synthesis , Dipeptides/chemistry , Dipeptides/pharmacology , Female , Fucose/chemical synthesis , Fucose/chemistry , Fucose/pharmacology , Hexanols/chemical synthesis , Hexanols/chemistry , Hexanols/pharmacology , Immunophenotyping , Killer Cells, Natural/immunology , Lymphocyte Culture Test, Mixed , Mice , Mice, Inbred C57BL , Mitogens/chemical synthesis , Mitogens/chemistry , Mitogens/pharmacology , Phagocytosis/drug effects , Phagocytosis/immunology , Respiratory Burst/drug effects , Respiratory Burst/immunology , Spleen/cytology , Spleen/drug effects , Spleen/immunology , Structure-Activity Relationship , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes, Cytotoxic/drug effects , T-Lymphocytes, Cytotoxic/immunology
11.
Appl Biochem Biotechnol ; 33(1): 15-24, 1992 Apr.
Article in English | MEDLINE | ID: mdl-1416953

ABSTRACT

This paper describes practical enzymatic procedures for the synthesis of (R) and (S) 1-deuterohexanol, a useful building block for chiral poly isocyanated liquid crystals. Alcohol dehydrogenases from horse liver and Pseudomonas catalyzed the reduction of hexanal with deuterated NAD (NADD) resulting in 50% and 89% yields of (R) and (S) 1-deuterohexanol, respectively. The deuterated cofactor was regenerated in situ by alcohol dehydrogenase catalyzed oxidation of ethanol-d6 or 2-propanol-d8. The (S) alcohol was also synthesized by the horse liver alcohol dehydrogenase reduction of 1-deuterohexanal, which was prepared chemically from hexanal. The yields of the reaction were greatly increased by the use of a biphasic system or with the immobilized enzyme in anhydrous organic solvents. Horse liver alcohol dehydrogenase was stabilized by immobilization on PAN or noncovalent entrapment on XAD resin.


Subject(s)
Alcohol Dehydrogenase/chemistry , Hexanols/chemical synthesis , Aldehydes/chemical synthesis , Deuterium , Heterocyclic Compounds/chemical synthesis , Molecular Structure , NAD/chemistry , Oxidation-Reduction , Stereoisomerism
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