Bioorganic & medicinal chemistry
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A series of 4-(3-aryloxyaryl)quinolines with alcohol substituents on the terminal aryl ring was prepared as potential LXR agonists, in which an alcohol group replaced an amide in previously reported amide analogs. High affinity LXR ligands with excellent agonist potency and efficacy in a functional model of LXR activity were identified, demonstrating that alcohols can substitute for amides while retaining LXR activity. The most potent compound was 5b which had an IC(50)=3.3 nM for LXRbeta binding and EC(50)=12 nM (122% efficacy relative to T0901317) in an ABCA1 mRNA induction assay in J774 mouse cells.
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The voltage-gated sodium channel remains a rich area for the development of novel blockers. In this study we used comparative molecular field analysis (CoMFA), a ligand-based design strategy, to generate a 3D model based upon local anesthetics, hydantoins, and alpha-hydroxyphenylamides to elucidate a SAR for their binding site in the neuronal sodium channel. Correlation by partial least squares (PLS) analysis of in vitro sodium channel binding activity (expressed as pIC(50)) and the CoMFA descriptor column generated a final non-cross-validated model with q(2)=0.926 for the training set. ⋯ Synthesis and evaluation of these compounds for their ability to inhibit [(3)H]-batrachotoxin revealed that these compounds have potent sodium channel blockade. Furthermore, the CoMFA model was able to accurately predict the binding of these compounds to the neuronal sodium channel. Synthesis and subsequent sodium channel evaluation of compound 37 (predicted IC(50)=7 microM, actual IC(50)=6 microM), established that novel compounds based on overlapping regions of phenytoin and lidocaine are better binders to the sodium channel than phenytoin itself (IC(50)=40 microM).
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Pharmacophore modelling, docking and virtual screening have become important tool in drug discovery process. Serotonin 2C (5-HT(2C)) receptor ligands have got major attention for their therapeutic uses as antidepressant and anorectic agents. Two step pharmacophore and docking based virtual screening was done using 5-HT(2C) agonists. ⋯ Refined pharmacophore with excluded volumes was constructed and combined with homology model based docking. Best hit from this virtual screening showed IC(50) of 20.1 nM. Similarity search of this hit compound resulted more active ligand with 7.8 nM activity.
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Tobacco cembranoids were reported to inhibit tumorigenesis. Biocatalysis of (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (1) using the symbiotic Bacillus sp. NC5, Bacillus sp. ⋯ The use of symbiotic marine bacteria as biocatalysts for bioactive natural product scaffolds is very rare. Cembranoid 1 carbamate analogs 9-11 were prepared by its reaction with corresponding isocyanates. Cembranoid 1 and its bioconversion and carabamate products show anti-invasive activity against the human highly metastatic prostate PC-3M cancer cell line at 10-50 nM doses in Matrigel assay.
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Simple modifications to the anhydride moiety of norcantharidin have lead to the development of a series of analogues displaying modest PP1 inhibition (low muM IC(50)s) comparable to that of norcantharidin (PP1 IC(50)=10.3+/-1.37 microM). However, unlike norcantharidin, which is a potent inhibitor of PP2A (IC(50)=2.69+/-1.37 microM), these analogues show reduced PP2A inhibitory action resulting in the development of selective PP1 inhibitory compounds. Data indicates that the introduction of two ortho-disposed substituents on an aromatic ring, or para-substituent favours PP1 inhibition over PP2A inhibition. ⋯ The latter shows a 7-fold improvement in PP1 versus PP2A selectivity when compared with norcantharidin. Subsequent analysis of 23 and 35 as potential PP2B inhibitors revealed modest inhibition with IC(50)s of 89+/-6 and 42+/-3 microM, respectively, and returned with PP1/PP2B selectivities of 0.54 and 0.15. Thus, these analogues are the simplest and most selective PP1 inhibitors retaining potency reported to date.