Disease relevance of Compound 14

• Employing the photodependent cytotoxicity of compound 14 against HCT116 human colon cancer cells, it was demonstrated that 4-substituted-2,6-dimethylnitrobenzene analogues are useful NO donors for the time- and site-controlled NO treatment [1].
• Of the latter compounds, compound 14 (1,3-benzodioxolane-5-carboxylic acid 4'-benzyloxy-3'-methoxybenzylidene-hydrazide) activated neutrophils at nanomolar concentrations, and Ca(2+) mobilization was inhibited by pertussis toxin and N-t-butoxycarbonyl-Phe-Leu-Phe-Leu-Phe (Boc-2), an antagonist of formyl peptide receptors (FPR/FPRL1) [2].
• Compound 14 retains the in vitro toxicity associated with nitidine (1) but is devoid of antileukemic activity [3].
• Furthermore, compound 14 failed to cause catalepsy in the rat up to 90 mg/kg (po) [4].
• On the basis of the results of these studies, compound 14 is a strong candidate for clinical evaluation as a systemic agent for the treatment of picornavirus infections [5].

High impact information on Compound 14

• In addition, compound 14 maintained potent antiviral activity against acyclovir-resistant HSV-1 strains [6].
• Drug resistance to compound 14 correlated to point mutations in conserved domain III of the herpesvirus DNA polymerase, but these mutations do not confer resistance to existing nucleoside therapy [6].
• Compound 14 showed approximately 5-fold greater selectivity than 1 in vivo and supports the concept that bladder-selective K(ATP) channel openers may have utility in the treatment of overactive bladder [7].
• In search of a backup M(2) muscarinic receptor antagonist to the previously reported compound 1, we discovered compound (+)-14, which showed superior oral efficacy in animal models [8].
• Because this compound is inactive in cells and unstable in plasma, we have stabilized it to metabolic hydrolysis by replacing the ester moiety with a 5-ethyl-substituted oxazole as in compound 14 [9].

Chemical compound and disease context of Compound 14

• The parent N-H compound 14 was several times more active than amantadine against H(2)N(2) and H(3)N(2) influenza A virus [10].
• HClO4 in dioxane to produce principally 4beta,5alpha-diol 11 (80%) of which acetylation followed by dehydration with SOCl2 yielded 4beta,19-diacetoxy-5-ene compound 14 in good yield [11].

Biological context of Compound 14

• The corresponding unsaturated analog of 11, compound 14, showed a slightly weaker receptor affinity (IC50 = 4.0 +/- 2.0 microM) but a significantly higher relative efficacy (50-55%) than 11 [12].
• Hydroxymethyl compound 14 was obtained by deamination of reported 2,4-diaminopyrido[2,3-d]pyrimidine-6-methanol (12a) in refluxing 1 N NaOH [13].
• Alkylation by compound 14, which has a vinyl linker, occurred at the A of 5'-AGTCCA-3' (site 6) and at several minor alkylation sites, including mismatch alkylation at A of 5'-TCACAA-3' (site 2) [14].
• Although the compounds of each series had poor in vitro inhibitory potencies (IC50 >> 100 microM), most of them inhibited the EGF-dependent cellular proliferation of ER 22 cells at relatively low doses (IC50 = 1.1 microM for compound 14) [15].
• Condensation of aldehyde (S)-(-)-17 with nitro compound (S)-(-)-27, both of which were prepared from a common precursor (S)-16, gave the alpha-hydroxynitro compound 28, which upon acetylation afforded alpha-acetoxynitro compound 14 in good yield [16].

Anatomical context of Compound 14

• 1'-Hexylamino-9-anilinoacridine (compound 14) was the least toxic compound to human Jurkat cells, while it retained strong antileishmanial activity [17].
• Binding at the agonist site, using3H-CP 55,940 in assays with mouse brain membranes, is inhibited byO-isopropyl dodecylfluorophosphonate (compound 2), dodecanesulfonyl fluoride (compound 14) and dodecylbenzodioxaphosphorin oxide with IC50 values of 2-11 nM [18].
• Compounds 16 and 17 showed antimalarial activity with EC(50) values of 230 and 240ng/mL, respectively, and compound 14 exhibited an EC(50) of 0.05muM against the Leukemia cell line K-562 [19].

Associations of Compound 14 with other chemical compounds

• The compound 14 was a selective TRA/TSI which exhibited desirable characteristics for oral activity, "shunt" effect to elevate PGI2 level, and absence of agonist activity [20].
• Subsequent condensation and cyclization of alpha-acetoxynitro compound 14 with benzyl isocyanoacetate (15) in the presence of DBU in THF gave the key pyrrole intermediate (S,S)-(-)-12 in 57% yield [16].
• In the rat microdialysis assay, compound 14 showed significantly enchanced levels of acetylcholine after oral administration [21].

Gene context of Compound 14

• Compound 14 was a potent and selective inhibitor of cPLA2 and compound 4 showed a dual inhibitory profile against both types of PLA2 while no cytotoxicity at 10 microM on human neutrophils or on murine macrophage line was observed for both [22].
• Compound 14 was 15-fold more potent in inhibiting human renin than porcine renin [23].
• Compound 14 (MRPP) exhibited enhanced activity against L1210 in vivo, when compared to ARPP (8) [24].
• Compound 14-inhibited CB1 in mouse brain requires about 3-4 days for recovery of 50% activity, suggesting covalent derivatization [18].
• The most interesting compound (14) is simultaneously a highly potent H(3) receptor ligand (K(i)=4.1nM) and a highly potent HMT inhibitor (IC(50)=24nM), which makes this derivative a valuable pharmacological tool for further development [25].

Analytical, diagnostic and therapeutic context of Compound 14

• Compounds 4, 9, 11, and 14 were most effective in the anti-angiogenesis assays run at Emory. In the assays conducted by the NCI, compound 14 was almost as potent as the anti-angiogenic drug TNP-470, which has undergone clinical trials [26].

References