Lupus erythematosus profundus involving the ear lobe.
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
R Vig
Publications and source records attributed to R Vig.
Enhancing effects of a mono-bromo substitution at the para position of the phenyl moiety on the metabolism and anti-HIV activity of d4T-phenyl methoxyalaninyl phosphate derivatives.
d4T-5'-[p-Bromophenyl methoxyalaninyl phosphate] (d4T-pBPMAP), a novel phenyl phosphate derivative of 2',3'-didehydro-2',3'-dideoxythymidine (d4T) that has an enhanced ability to undergo hydrolysis due to the electron withdrawing properties of its single bromo substituent at the para-position of the phenyl moiety, was found to yield substantially more of the key metabolite alaninyl d4T monophosphate (A-d4T-MP) than the unsubstituted d4T-5'-phenyl methoxyalaninyl phosphate or para-methoxy substituted d4T-5'-phenyl methoxyalaninyl phosphate. d4T-pBPMAP was tested for its anti-HIV-1 activity in peripheral blood mononuclear cells (PBMNC) and thymidine kinase (TK)-deficient CEM T-cells. d4T-pBPMAP was 12.6-fold more potent than the parent compound d4T in inhibiting p24 production (IC50 values: 44 nM vs 556 nM) and 41.3-fold more potent than d4T in inhibiting the reverse transcriptase (RT) activity (IC50 values: 57 nM vs 2355 nM) in HIV-1-infected TK-deficient CEM cells. Similarly, d4T-pBPMAP was more potent than the unsubstituted or para-methoxy substituted phenyl methoxyalaninyl phosphate derivatives of d4T. d4T-pBPMAP did not exhibit any detectable cytotoxicity to PBMNC or CEM cells at concentrations as high as 10,000 nM. Notably, d4T-pBPMAP was capable of inhibiting the replication of a zidovudine (ZDV/AZT)-resistant HIV-1 strain as well as HIV-2 in PBMNC at nanomolar concentrations. To our knowledge, this is the first demonstration that the potency of the d4T-aryl-phosphate derivatives can be substantially enhanced by introducing a single para-bromo substituent in the aryl moiety.
Anti-HIV Agents↗
Structure-based design of N-[2-(1-piperidinylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea and N-[2-(1-piperazinylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea as potent non-nucleoside inhibitors of HIV-1 reverse transcriptase.
A novel computer model of the HIV reverse transcriptase (RT) non-nucleoside inhibitor (NNI) binding pocket, which was generated using high resolution crystal structure information from 9 individual RT/NNI complexes, revealed previously unrecognized ligand derivatization sites for phenethylthiazolylthiourea (PETT) derivatives. Spatial gaps surrounding the pyridyl ring of the active PETT derivative trovirdine were discovered during modeling procedures. Docking studies using the computer-generated model of the binding pocket (composite binding pocket) suggested that the replacement of the planar pyridyl ring of trovirdine with a nonplanar piperidinyl or piperazinyl ring, which occupy larger volumes, would better fill the spacious Wing 2 region of the butterfly-shaped NNI binding pocket. The anti-HIV activity of the synthesized heterocyclic compounds N-[2-(1-piperidinylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea and N-[2-(1-piperazinylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea was examined in HTLVIIIB-infected peripheral blood mononuclear cells. Both compounds were more potent than trovirdine and abrogated HIV replication at nanomolar concentrations without any evidence of cytotoxicity.
Antiviral Agents↗
5-Alkyl-2-[(methylthiomethyl)thio]-6-(benzyl)-pyrimidin-4-(1H)-ones as potent non-nucleoside reverse transcriptase inhibitors of S-DABO series.
Novel dihydroalkoxybenzyloxopyrimidine (S-DABO) derivatives targeting the non-nucleoside inhibitor (NNI) binding site of human immunodeficiency virus (HIV) reverse transcriptase (RT) have been synthesized using a novel computer model for the NNI binding pocket and tested for their RT inhibitory activity in cell-free assays using purified recombinant HIV RT as well as for their anti-HIV activity in HTL VIIIB-infected peripheral blood mononuclear cells. Our computational approach allowed the identification of several ligand derivatization sites for the generation of more potent S-DABO derivatives. Our lead S-DABO derivative, 5-isopropyl-2-[(methylthiomethyl)thio]-6-(benzyl)-pyrimidin-4-(1H)-one (compound 3), elicited potent anti-HIV activity with an IC50 value of less than 1nM for inhibition of HIV replication without any evidence of cytotoxicity and an unprecedented selectivity index of > 100,000.
Anti-HIV Agents↗
Rational design and synthesis of phenethyl-5-bromopyridyl thiourea derivatives as potent non-nucleoside inhibitors of HIV reserve transcriptase.
A series of novel phenethylthiazolylthiourea (PETT) derivatives targeting the nonnucleoside inhibitor (NNI) binding site of HIV reverse transcriptase (RT) have been designed based on the structure of the NNI binding pocket. The structure-based design and synthesis of these new PETT derivatives were complemented by biological assays of their anti-HIV activity. Modeling studies for rational drug design included the construction of a composite NNI binding pocket from nine RT-NNI crystal structures, the analyses of surface complementarity between NNI and RT, and application of Ki calculations combined with a docking procedure involving the novel PETT derivatives. The use of the composite NNI binding pocket allowed the identification and structure-based design of three promising PETT derivatives with ortho-F (2), ortho-Cl (3), and meta-F (5) substituents on the phenyl ring. These novel PETT derivatives were more active than AZT or trovirdine and showed potent anti-HIV activity with IC50[p24] values of < 1 nM and selectivity indices of > 100,000.
Anti-HIV Agents↗
Structure-based design of novel dihydroalkoxybenzyloxopyrimidine derivatives as potent nonnucleoside inhibitors of the human immunodeficiency virus reverse transcriptase.
Two highly potent dihydroalkoxybenzyloxopyrimidine (DABO) derivatives targeting the nonnucleoside inhibitor (NNI) binding site of human immunodeficiency virus (HIV) reverse transcriptase (RT) have been designed based on the structure of the NNI binding pocket and tested for anti-HIV activity. Our lead DABO derivative, 5-isopropyl-2-[(methylthiomethyl)thio]-6-(benzyl)-pyrimidin-4-(1H)-on e, elicited potent inhibitory activity against purified recombinant HIV RT and abrogated HIV replication in peripheral blood mononuclear cells at nanomolar concentrations (50% inhibitory concentration, <1 nM) but showed no detectable cytotoxicity at concentrations as high as 100 microM.
Binding Sites↗
Aryl phosphate derivatives of 3'-deoxythymidine are not potent anti-human immunodeficiency virus agents.
Aryl phosphate derivatives of 3'-deoxythymidine (3dT), albeit more active than 3dT in thymidine kinase (TK)-deficient cells, are not potent anti-human immunodeficiency virus (HIV) agents and are capable of inhibiting HIV replication only at micromolar concentrations.
Anti-HIV Agents↗
D4T-5'-[p-bromophenyl methoxyalaninyl phosphate] as a potent and non-toxic anti-human immunodeficiency virus agent.
Three aryl phosphate derivatives of 2',3'-didehydro-2',3'-dideoxythymidine (d4T) were tested for their anti-human immunodeficiency virus (HIV) activity in peripheral blood mononuclear cells (PBMC) and thymidine kinase (TK)-deficient CEM T cells. Compared to the parent compound d4T, the lead compound d4T-5'-[p-bromophenyl methoxyalaninylphosphate] with a para-bromo substituent in the aryl moiety was 12.6-fold more potent in inhibiting p24 production (IC50 values: 44 nM versus 556 nM) and 41.3-fold more potent in inhibiting the reverse transcriptase (RT) activity (IC50 values: 57 nM versus 2355 nM) in HIV-infected TK-deficient CEM cells. None of the compounds exhibited any detectable cytotoxicity to PBMC or CEM cells at concentrations as high as 10,000 nM. To our knowledge, this is the first demonstration that the potency as well as selectivity index of the d4T aryl phosphate derivatives in TK-deficient cells can be substantially enhanced by introducing a single para-bromo substituent in the phenyl moiety.
Alanine↗
Selectin inhibition: synthesis and evaluation of novel sialylated, sulfated and fucosylated oligosaccharides, including the major capping group of GlyCAM-1.
Selectins interact with glycoconjugate ligands in important normal and pathological situations. While high affinity recognition of natural ligands is associated with alpha 1-3(4)fucosylated, alpha 2-3sialylated (and/or sulfated) lactosamine sequences, small oligosaccharides that potently inhibit the selectins have not been found. One possibility suggested by other investigators is that high affinity may require unusual sequences not yet tested, for example, the "major capping group" (6'-sulfo-sialyl Le(x)) of the L-selectin ligand GlyCAM-1. To explore this possibility, we synthesized a spectrum of novel synthetic and semisynthetic oligosaccharides related to those on natural ligands. In studying these molecules, we noted that binding of recombinant soluble selectins to immobilized sialyl Le(a) or 3'-sulfo-Le(x) is markedly inhibited by concentrations of chloride above the physiological range. This indicates the ionic nature of the interactions, and shows that buffers typically used in screening assays for inhibitors are not optimal. Using parameters that more closely approximate physiological conditions, we confirmed that alpha 2-3-linked sialic acids, and alpha 1-3(4)fucosylation are important for recognition. Similar results obtained with both types of immobilized targets for the three selectins indicated that the binding sites for sialic acid and sulfate are very close, or identical. While O-sulfate esters mostly improved L- and P-selectin recognition, effects depended upon their position and number. Furthermore, sulfation can also impart some "negative" specificity: the major capping group does not interact with E-selectin. The branched Core 2 sequence seemed to enhance L- and P-selectin binding, however, the best inhibitors still appeared to be sialyl Le(a) and 3'-sulfo-Le(x), with the aglycone group of the latter affecting binding. Of particular note, the "major capping group" of GlyCAM-1 was not an unusually potent nor highly selective inhibitor of L-selectin, even when studying the interaction of L-selectin with native GlyCAM-1 itself.
Carbohydrate Sequence↗
The enzymatic sulfation of glycoprotein carbohydrate units: blood group T-hapten specific and two other distinct Gal:3-O-sulfotransferases as evident from specificities and kinetics and the influence of sulfate and fucose residues occurring in the carbohydrate chain on C-3 sulfation of terminal Gal.
Enzymatic 3-O-sulfation of terminal beta-Gal residues was investigated by screening sulfotransferase activity present in 37 human tissue specimens toward the following synthesized acceptor moieties: Galbeta1,3GalNAc alpha-O-Al, Galbeta1,4GlcNAcbeta-O-Al, Galbeta1,3GlcNAcbeta-O-Al, and mucin-type Galbeta1,4GlcNAcbeta1,6(Galbeta1,3)GalNAc alpha-O-Bn structures containing a C-3 methyl substituent on either Gal. Two distinct types of Gal: 3-O-sulfotransferases were revealed. One (Group A) was specific for the Galbeta1, 3GalNAc alpha- linkage and the other (Group B) was directed toward the Galbeta1,4GlcNAc branch beta1,6 linked to the blood group T hapten. Enzyme activities found in breast tissues were unique in showing a strict specificity for the T-hapten. Galbeta-O-allyl or benzyl did not serve as acceptors for Group A but were very active with Group B. An examination of activity present in six human sera revealed a specificity of the serum enzyme toward beta1,3 linked Gal, particularly, the T-hapten without beta1,6 branching. Group A was highly active toward T-hapten/acrylamide copolymer, anti-freeze glycoprotein, and fetuin O-glycosidic asialo glycopeptide; less active toward fetuin triantennary asialo glycopeptide; and least active toward bovine IgG diantennary glycopeptide. Group B was moderately and highly active, respectively, with the latter two glycopeptides noted and least active with the first two. Competition experiments performed with Galbeta1,3GalNAc alpha-O-Al and Galbeta1,4GlcNAcbeta1,6(Galbeta1,3)GalNAc alpha-O-Bn having a C-3 substituent (methyl or sulfate) on either Gal reinforced earlier findings on the specificity characteristics of Group A and Group B. Group A displayed a wider range of optimal activity (pH 6.0-7.4), whereas Group B possessed a peak of activity at pH 7.2. Mg2+ stimulated Group A 55% and Group B 150%, whereas Mn+2 stimulated Group B 130% but inhibited Group A 75%. Ca2+ stimulated Group B 100% but inhibited Group A 35%. Group A and Group B enzymes appeared to be of the same molecular size (<100,000 Da) as observed by Sephacryl S-100 HR column chromatography. The following effects upon Gal: 3-O-sulfotransferase activities by fucose, sulfate, and other substituents on the carbohydrate chains were noted. (1) A methyl or GlcNAc substituent on C-6 of GalNAc diminished the ability of Galbeta1,3GalNAc alpha-O-Al to act as an acceptor for Group A. (2) An alpha1,3-fucosyl residue on the beta1,6 branch in the mucin core structure did not affect the activity of Group A toward Gal linked beta1,3 to GalNAc alpha-. (3) Lewis x and Lewis a terminals did not serve as acceptors for either Group A or B enzymes. (4) Elimination of Group B activity on Gal in the beta1,6 branch owing to the presence of a 3-fucosyl or 6-sulfo group on GlcNAc did not hinder any action toward Gal linked beta1,3 to GalNAc alpha. (5) Group A activity on Gal linked beta1,3 to GalNAc remained unaffected by 3'-sulfation of the beta1,6 branch. The reverse was true for Group B. (6) The acceptor activity of the T-hapten was increased somewhat upon C-6 sulfation of GalNAc, whereas, C-6 sialylation resulted in an 85% loss of activity. (7) A novel finding was that Galbeta1,4GlcNAcbeta-O-Al and Galbeta1,3GlcNAcbeta-O-Al, upon C-6 sulfation of the GlcNAc moiety, became 100% inactive and 5- to 7-fold active, respectively, in their ability to serve as acceptors for Group B.
Animals↗
Nucleoside conjugates. 15. Synthesis and biological activity of anti-HIV nucleoside conjugates of ether and thioether phospholipids.
A series of the anti-HIV nucleoside conjugates of either (1-O-alkyl) and thioether (1-S-alkyl) lipids linked by a pyrophosphate diester bond has been synthesized as micelle-forming prodrugs of the nucleosides to improve their therapeutic efficiency. These include AZT 5'-diphosphate-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (1), 3'-azido-2',3'-dideoxyuridine 5'-diphosphate-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (2) 2',3'-dideoxycytidine 5'-diphosphate-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (3), and AZT 5'-diphosphate-rac-1-O-tetradecyl-2-O-palmitoylglycerol (4). The conjugates form micelles by sonication (mean diameters ranging 6.8-55.5 nm). Conjugate 1 protected 80% of HIV-infected CEM cells as low as 0.58 microM and lost the protection at 180 microM due to prevailing cytotoxicity, while the conjugate started to show the cytotoxicity at 100 microM. Pharmacokinetics studies showed a significant increase of half-life values (t1/2) of AZT and AZddU2 (respective t1/2 = 5.69 and 6.5 h) after administration of conjugates 1 and 2, while those after administration of AZT and AZddU were 0.28 and 0.89 h, respectively. The fractions of the prodrugs 1 and 2 converted to the parent compounds AZT and AZddU were 36% and 55%, respectively. The results indicate that AZT and AZddU thioether lipid conjugates 1 and 2 warrant further investigation.
Animals↗
Nucleoside conjugates. 14. Synthesis and antitumor activity of 1-beta-D-arabinofuranosylcytosine conjugates of ether lipids with improved water solubility.
A series of ara-CDP-rac-1-O-alkyl-2-O-acylglycerols (9a-f), analogues of highly active ara-CDP-rac-1-O-hexadecyl-2-O-palmitoylglycerol (1) and Cytoros2 (2), was prepared, and solubility, lipophilicity, and structure-activity relationships of these conjugates were investigated. Conjugates 9a-f containing sn-1 alkyl (< C16) and sn-2 fatty acyl (< C14) and sn-1 alkyl (< C14) and sn-2 fatty acyl (< C16) substituents of the glycerol were water-soluble by shaking, while those with the sn-1 alkyl (> C16) and the sn-2 fatty acyl (> C16) such as conjugate 1 were sparingly soluble. Conjugates 9a-c,e were almost completely solubilized in water by shaking. However, a large portion of conjugates 9d and 9f in water by shaking exist in micelles with mean diameters ranging 7.0-55.2 nm. The partition coefficients (1-octanol/PBS) of the water-soluble conjugates were about 9-18 times greater than that of ara-C. A single dose (300 mg/kg) of conjugates 9d and 9f produced a significant increase in life span (ILS 206 to > 543%) with 17-67% long-term survivors (> 45 days) in mice bearing ip-implanted L1210 lymphoid leukemia. These results were comparable to those of the previous conjugate 1 and Cytoros (2). In contrast, conjugates 9a-c,e at single doses were less effective (ILS 69-178% with no long-term survivors). However, two (qd, 1, 7) or three (qd 1, 5, 9) divided doses of these conjugates were found to be as effective as a single dose of the previous conjugates. The three divided doses (150 mg/kg per day) of conjugates 9d, 9e, and 9f produced a remarkable antitumor activity in L1210 leukemic mice (ILS > 350% with > 50% long-term survivors). Because of the convenient formulation and the significant antitumor activities, the water-soluble conjugates 9d, 9e, and 9f warrant further investigation.
Animals↗
Synthesis of methyl O-(beta-D-galactopyranosyl)-(1-->3)-O- [alpha-L-fucopyranosyl-(1-->4)]-2-acetamido-2-deoxy-6-O-sulfo-beta-D- glucopyranoside sodium salt as a potential ligand for selectin molecules.
Explore the source record for details and available documents.
Carbohydrate Sequence↗
Nucleoside conjugates. 13. Synthesis and antitumor activity of 1-beta-D-arabinofuranosylcytosine conjugates of thioether lipids with improved water solubility.
A series of ara-CDP-rac-1-S-alkyl-2-O-acyl-1-thioglycerols (3-12), analogues of highly active Cytoros2 (1), was prepared, and solubility, lipophilicity, and structure-activity relationships of these conjugates were investigated. The conjugates with sn-1 alkyl (< C18) and sn-2 fatty acyl (< C14) substituents of the thioglycerol were water-soluble, while those with the sn-1 alkyl (> C14) and the sn-2 fatty acyl (> C16) were sparingly soluble. The latter formed micelles upon sonication. Conjugate 7 containing the sn-1 tetradecyl and the sn-2 palmitoyl (C16) groups formed micelles by both sonication and shaking. The partition coefficients (1-octanol/PBS) of the water-soluble conjugates were about 20 times greater than that of ara-C. The water-insoluble showed a more than 40 times increase. A single dose of the micelle-forming conjugates 7 and 10 produced a significant increase in life span (ILS > 421%) with 50% long-term survivors (> 45 days) in mice bearing ip-implanted L1210 lymphoid leukemia. These results were comparable to those of previous micelle-forming conjugate 1 (Cytoros). In contrast, the water-soluble conjugates at single doses were less effective (ILS 81-386% with 0-33% long-term survivors). However, three divided doses of the water-soluble conjugates were found to be as effective as a single dose of micellar solution of the water-insoluble. The results indicate that conjugate 7 and most of the water-soluble derivatives warrant further investigation.
Animals↗
Synthesis and antitumor activity of 1-beta-D-arabinofuranosylcytosine conjugates of optical isomers of ether and thioether lipids.
Four 1-beta-D-arabinofuranosylcytosine conjugates (ara-C) (1a, b and 2a, b) of sn-1 and sn-3 isomers of 1-O-octadecyl-2-O-palmitoylglycerol and its 1-S-alkyl analogue have been synthesized, and their antitumor activity against L1210 lymphoid leukemia in mice were compared with those of the previous conjugates (3a, b) of racemates in order to determine the significance of chirality of the glycerol moieties for activity. Administration (i.p.) of a single dose (300 mg/kg) of conjugates of sn-1 (1a), sn-3 (2a) and rac (3a) isomers of the ether lipid increased lifespan of i.p. implanted L1210 lymphoid leukemic DBA/2J mice by 169, 175 and 236%, respectively. The sn-1 (1b), sn-3 (2b), and rac (3b) isomers of the thioether lipid with a single dose of 300 mg/kg produced an increase in lifespan values of 238, 263 and 250%, respectively. The results indicate that chirality of the glycerol moieties appears not to be critical for the activity, and racemates 3a and 3b are promising prodrugs of ara-C for further clinical investigations.
Animals↗
Synthesis of 2-acetamido-2-deoxy-4-O-beta-D-galactopyranosyl-3-O-methyl -D-glucopyranose (N-acetyl-3-O-methyllactosamine) and its benzyl alpha-glycoside.
Benzyl 2-acetamido-2-deoxy-3-O-methyl-alpha-D-glucopyranoside (3) was obtained by deacetalation of its 4,6-O-benzylidene derivative (2). Compound 2 was prepared by methylation of benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-alpha-D-glucopyranoside with methyl iodide-silver oxide in N,N-dimethylformamide. Diol 3 was selectively benzoylated and p-toluenesulfonylated, to give the 6-benzoic and 6-p-toluenesulfonic esters (4 and 5, respectively). Displacement of the sulfonyl group of 5 with sodium benzoxide in benzyl alcohol afforded the 6-O-benzyl derivative (6). Glycosylation of 4 with 2,3,4,6-tetra-O-acetyl-alpha-D-galactopyranosyl bromide (7) in dichloromethane, in the presence of 1,1,3,3-tetramethylurea, furnished the disaccharide derivative 8. Similar glycosylation of compound 6 with bromide 7 gave the disaccharide derivative 10. O-Deacetylation of 8 and 10 afforded disaccharides 9 and 11. The structure of compound 9 was established by 13C-n.m.r. spectroscopy. Hydrogenolysis of the benzyl groups of 11 furnished the disaccharide 2-acetamido-2-deoxy-4-O-beta-D-galactopyranosyl-3-O-methyl-D-glucopyr ano se (N-acetyl-3-O-methyllactosamine).
Amino Sugars↗
The heart of dentistry. Dental clinic for the Apaches. 2.
Explore the source record for details and available documents.
Dental Clinics↗