Minimum structure requirement of immunomodulatory glycolipids for predominant Th2 cytokine induction and the discovery of non-linear phytosphingosine analogs

Analogs of immunomodulatory glycolipid OCH (2) were prepared and minimum structure requirement to exhibit equivalent profiles was disclosed. Analogs bearing non-linear hydrocarbon chain in the phytosphingosine moiety (18, 19) were shown for the first time to possess comparable cytokine inducing profile to 2. Molecular modeling of 2/hCD1d complex based on the crystal structure of alpha-GalCer (1)/hCD1d complex is also described.     

Synthesis and activity of novel analogs of hemiasterlin as inhibitors of tubulin polymerization: modification of the A segment

Analogs of hemiasterlin (1) and HTI-286 (2), which contain various aromatic rings in the A segment, were synthesized as potential inhibitors of tubulin polymerization. The structure-activity relationships related to stereo- and regio-chemical effects of substituents on the aromatic ring in the A segment were studied. Analogs, which carry a meta-substituted phenyl ring in the A segment show comparable activity for inhibition of tubulin polymerization to 2, as well as in the cell proliferation assay using KB cells containing P-glycoprotein, compared to those of 1 and 2.     

4-(Alkylthio)- and 4-(arylthio)-benzonitrile derivatives as androgen receptor antagonists for the topical suppression of sebum production

The first examples of thioether-substituted benzonitriles as potential soft-drug androgen receptor antagonists are reported. A number of 4-(alkylthio)- and of 4-(arylthio)-benzonitrile analogs were evaluated in human androgen receptor binding and cellular functional assays. Analogs with potent in vitro binding and cellular activities were evaluated for topical in vivo efficacy in the Golden Syrian hamster ear model. Analogs from both the 4-(alkylthio)- and of 4-(arylthio)-benzonitrile series showed moderate reduction of wax esters in vivo.     

Analogs of thyrotropin-releasing hormone using an aminoglycine-based template

Novel thyrotropin-releasing hormone (TRH, pGlu-His-Pro-NH₂) analogs, made by solid phase, were derived from the general scaffold pGlu-(D/L)Agl(X)-Pro-NH₂ where Agl = aminoglycine. Analogs ranged from X being a proton to an acylating agent derived from substituted (aromatic heterocyclic rings) formic or acetic acids or an aminotriazolyl moiety (3′-amino-1H-1′,2′,4′-triazolyl) built on N of aminoglycine or N^β of ,β-diaminoproprionic acid (Dpr). X was expected to mimic the electronic and structural characteristics of the imidazole ring of histidine. Analogs were purified by HPLC, characterized by mass spectrometry and isolated as either diastereoisomeric mixtures or pure isomers. Analogs, tested for their binding affinity to mouse pituitary TRH receptors, have apparent equilibrium inhibitory constants >1 μM.     

Synthesis and antiviral evaluation of 9-(S)-[3-alkoxy-2-(phosphonomethoxy)propyl]nucleoside alkoxyalkyl esters: inhibitors of hepatitis C virus and HIV-1 replication

We reported previously that octadecyloxyethyl 9-(S)-[3-hydroxy-2-(phosphonomethoxy)-propyl]adenine (ODE-(S)-HPMPA) was active against genotype 1b and 2a hepatitis C virus (HCV) replicons. This is surprising because acyclic nucleoside phosphonates have been regarded as having antiviral activity only against double stranded DNA viruses, HIV and HBV. We synthesized octadecyloxyethyl 9-(S)-[3-methoxy-2-(phosphonomethoxy)propyl]-adenine and found it to be active in genotype 1b and 2a HCV replicons with EC?? values of 1-2 μM and a CC?? of > 150 μM. Analogs with substitutions at the 3'-hydroxyl larger than methyl or ethyl, or with other purine bases were less active but most compounds had significant antiviral activity against HIV-1 in vitro. The most active anti-HIV compound was octadecyloxyethyl 9-(R)-[3-methoxy-2-(phosphonomethoxy)propyl]guanine with an EC?? < 0.01 nanomolar and a selectivity index of > 4.4 million.     

Structure-activity correlations for beta-phenethylamines at human trace amine receptor 1

A cell line in which RD-HGA16 cells were stably transfected with the hTAAR 1 receptor was created and utilized to carry out a systematic evaluation of a series of beta-phenethylamines. Fair agreement was observed with data obtained for aryl and ethylene chain substituted analogs in an AV12-664 cell line in which hemagglutinin-tagged hTAAR 1 was stably co-expressed with rat G alpha(s). Analogs with multiple substituents as well as analogs with bulky groups were found to be partial agonists. Analogs in which the primary amino group was converted to a secondary or a tertiary amino group by N-methylation were also partial agonists. Comparative Molecular Field Analysis (CoMFA) using the potency data yielded a regression coefficient r(2) of 0.824. The steric field contribution to the model was 61% with the balance (39%) contributed by the electrostatic field. The collective results suggest that increasing steric bulk both at the amino nitrogen, particularly by N-dimethylation, and at the 4-position of the aromatic ring leads to low efficacy ligands.     

Beta-amino acid analogs of an insect neuropeptide feature potent bioactivity and resistance to peptidase hydrolysis

Insect neuropeptides of the insect kinin class share a common C-terminal pentapeptide sequence F(1)X(1)(2)X(2)(3)W(4)G(5)-NH(2) (X(2)(3) = P, S, A) and regulate such critical physiological processes as water balance and digestive enzyme release. Analogs of the insect kinin class, in which the critical residues of F(1), P(3), and W(4) were replaced with beta(3)-amino acid or their beta(2)-homo-amino acid variants, have been synthesized by the solid phase peptide strategy. The resulting single- and double-replacement analogs were evaluated in an insect diuretic assay and enzyme digestion trials. Analogs modified in the core P(3) position produce a potent and efficacious diuretic response that is not significantly different from that obtained with the endogenous achetakinin peptides. The analogs also demonstrate enhanced resistance to hydrolysis by ACE and NEP, endopeptidases that inactivate the natural insect neuropeptides. This paper describes the first instance of beta-amino acids analogs of an arthropod peptide that demonstrate significant bioactivity and resistance to peptidase degradation.     

Simplified YM-26734 inhibitors of secreted phospholipase A2 group IIA

Simplified analogs of YM-26734, a known inhibitor of secreted phospholipase A(2) (sPLA(2)) group IIA, were synthesized and found to also display potent inhibition at low nanomolar concentrations. Analogs were based on the didodecanoylphloroglucinol portion of YM-26734 which contains the predicted active site calcium binding group.     

Convenient synthesis and in vitro pharmacological activity of 2-thioanalogs of salvinorins A and B

To study drug-receptor interactions, new thio-derivatives of salvinorin A, an extremely potent natural kappa-opioid receptor (KOR) agonist, were synthesized. Obtained compounds were examined for receptor binding affinity. Analogs with the same configuration at carbon atom C-2 as in natural salvinorin A showed higher affinity to KOR than their corresponding epimers.     

Syntheses and odor descriptions of cyclopropanated compounds, part 6: Analogs of aliphatic monoterpene dienols and non-branched alcohols

Analogs of aliphatic monoterpene dienols (geraniol, nerol, linalool, and lavandulol) and non-branched alcohols (norleaf alcohol, matsutake alcohol, etc.) bearing a cyclopropane ring were synthesized, and their odor characteristics were examined. Most of the analogs show odor properties different from their parent compounds.     

Synthesis and biological evaluation of 1-benzyl-5-(3-biphenyl-2-yl-propyl)-1H-imidazole as novel farnesyltransferase inhibitor

Farnesyltransferase inhibitors (FTIs) have emerged as a novel class of anti-cancer agents. Analogs of the potent FTI, 1-benzyl-5-(3-biphenyl-2-yl-propyl)-1H-imidazole, were synthesized and tested in vitro for their inhibitory activities. The most promising compound identified from this series is analog 29 that possesses potent enzymatic and cellular activities.     

Synthesis,conformation, and antiviral activity of 5-methoxymethyl-2'-deoxycytidine analogs

Analogs of 5-methoxymethyl-2'-deoxycytidine, MMdCyd (1) by substitution at N4 were synthesized to impart resistance against deamination. The anti HSV-1 activity and solution conformation of analogs were determined. N4-Butanoyl-MMdCyd (10) was a potent inhibitor of HSV-1 replication while N4-hexanoyl-MMdCyd (11), N4-propanoyl-MMdCyd (9) and N4-acetyl-MMdCyd (8) had good activity against HSV-1 replication. All other analogs were devoid of activity against HSV-1.     

Cyanopyrazoles as analogs of purine precursors--II. Effects on macromolecular synthesis and cell cycle progression

The cytotoxic and cytokinetic effects, and in vitro inhibition of macromolecular synthesis by cyanopyrazoles were studied using Friend leukemia and Ehrlich ascites tumor cells. At concentrations in the range of 2.5 mM to 50 microM analog 3(5)-amino-4-cyano-5(3)-trichloromethylpyrazole (I) was highly cytotoxic and completely inhibited thymidine, uridine and leucine incorporation into macromolecular material. 24 hr incubation of FL cells with cytostatic concentrations of compound I (in the range of 2 to 0.5 microM) resulted in an accumulation of cells in the G2 + M phase. Analogs N-hydroxyethyl-3(5)-amino-4-cyano-5(3)-trichloromethylpyrazole (II) and 3(5)-amino-4-cyanopyrazole (III) were not cytotoxic at concentrations up to 5 mM and did not substantially inhibit precursor incorporation into macromolecules but exhibited a cytostatic activity. These compounds caused a decrease of FL cells in the G2 + M phase and an accumulation in the S phase. Analogs I and II displayed a similar in vivo inhibitory effect on thymidine incorporation into DNA in EAT cells. The results indicate that the cytotoxicity of cyanopyrazoles correlates with their ability to inhibit precursor incorporation into macromolecular material. On the other hand, the cytostatic action of compound I is not coupled to a block of nucleic acid synthesis.     

Effect of tryptophan analogs on derepression of the Escherichia coli tryptophan operon by indole-3-propionic acid.

The abilities of 14 tryptophan analogs to repress the tryptophan (trp) operon have been studied in Escherichia coli cells derepressed by incubation with 0.25 mM indole-3-propionic acid (IPA). trp operon expression was monitored by measuring the specific activities of anthranilate synthase (EC 4.1.3.27) and the tryptophan synthase (EC 4.2.1.20) beta subunit. Analogs characterized by modification or removal of the alpha-amino group or the alpha-carboxyl group did not repress the trp operon. The only analogs among this group that appeared to interact with the trp aporepressor were IPA, which derepressed the trp operon, and d-tryptophan. Analogs with modifications of the indole ring repressed the trp operon to various degrees. 7-Methyl-tryptophan inhibited anthranilate synthase activity and consequently derepressed the trp operon. Additionally, 7-methyltryptophan prevented IPA-mediated derepression but, unlike tryptophan, did so in a non-coordinate manner, with the later enzymes of the operon being relatively more repressed than the early enzymes. The effect of 7-methyltryptophan on IPA-mediated derepression was likely not due to the interaction of IPA with the allosteric site of anthranilate synthase, even though feedback-resistant mutants of anthranilate synthase were partially resistant to derepression by IPA. The effect of 7-methyltryptophan on derepression by IPA was probably due to the effect of the analog-aporepressor complex on trp operon expression.     

Synthesis and biological evaluation of cryptophycin analogs with substitution at C-6 (fragment C region)

Analogs of the antitumor agents cryptophycins 1 and 8 with dialkyl substitution at C-6 (fragment C) were synthesized and evaluated for in vitro cytotoxicity against human leukemia cells (CCRF-CEM). The activity of these analogs decreased as the size of the substituents at C-6 increased. The C-6 spirocylopropyl compound (2g) was highly potent in vitro and showed excellent antitumor activity in animal models.     

5-(3-carboxymethoxyphenyl)-2-(4,5-dimethylthiazolyl)-3-(4-sulfophenyl)tetrazolium, inner salt (MTS) and related analogs of 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT) reducing to purple water-soluble formazans As cell-viability indicators

Analogs of MTT, 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide, designed to yield water-soluble formazans upon reduction, have been synthesized and evaluated as cell-viability indicators.     

Structure-activity studies on a novel series of cholinergic channel activators based on a heteroaryl ether framework.

Analogs of compound 1 with a variety of azacycles and heteroaryl groups were synthesized. These analogs exhibited Ki values ranging from 0.15 to > 10,000 nM when tested in vitro for cholinergic channel receptor binding activity (displacement of [3H](-) cytisine from whole rat brain synaptic membranes).     

Identification by gas chromatography-mass spectrometry of intermediates in the aromatization of modified C19 steroids by human placental microsomes

Analogs of 4-androstene-3,17-dione and testosterone were tested as substrates for the aromatizing enzyme complex of human placenta. Compounds modified in rings B, C and D were found to be aromatized via a pathway similar to that postulated for 4-androstene-3,17-dione and testosterone, in which oxidation to the 19-hydroxy and 19-oxo (or corresponding gem-diol) intermediates occurs. No evidence of additional intermediates was obtained.     

Analysis of the pivotal residues of the immunodominant and highly uveitogenic determinant of interphotoreceptor retinoid-binding protein.

Interphotoreceptor retinoid-binding protein (IRBP), a retinal-specific Ag, induces experimental autoimmune uveitis in a variety of animals. We have previously shown that sequence 1169-1191 of bovine IRBP is the immunodominant epitope of this protein in Lewis rats and is highly immunogenic and uveitogenic in these rats. The active site of peptide 1169-1191 was determined by testing its truncated forms. The shortest peptide to be immunologically active was found to be 1182-1190 (WEGVGVVPD). To determine the role of individual residues of this sequence, we have tested the immunologic activities of nine analogs of peptide 1181-1191, in which each of residues 1182-1190 was substituted with alanine (A). The tested activities included the capacity to induce experimental autoimmune uveitis and cellular responses in immunized rats, as well as the capability to stimulate lymphocytes sensitized against IRBP or the parent peptide 1181-1191. Analogs that did not stimulate these lymphocytes were also tested for their capacity to competitively inhibit the proliferative response to 1181-1191. Analogs A(1184), A(1186), and A(1187) resembled 1181-1191 in their activities, whereas the other analogs exhibited remarkably reduced activities, with several patterns being noticed. Analog A(1182) was inactive in all tests. Analog A(1190) was very weakly uveitogenic and non-immunogenic, but it stimulated lymphocytes sensitized against IRBP or 1181-1191 when added at exceedingly high concentrations. Analogs A(1183) and A(1185) resembled A(1190) in being weakly uveitogenic and A(1185) was also found to be poorly immunogenic. In addition, relatively high concentrations of A(1183) and A(1185) were needed to stimulate lymphocytes sensitized against IRBP or 1181-1191. However, a different pattern of activities was exhibited by analogs A(1188) and A(1189). These peptides were uveitogenic and immunogenic, but failed to stimulate lymphocytes sensitized to IRBP or 1181-1191. Furthermore, A(1188) and A(1189), but not A(1182), also inhibited the response to 1181-1191 of a cell line specific toward this parent peptide. The data are interpreted to show that residues 1188 and 1189 are involved in the interaction of the peptide with the TCR, whereas residues 1182 and 1190 and, perhaps, 1183 and 1185, are pivotal for the binding of peptide 1181-1190 to the MHC molecules on APC.