Comparative Structure-activity Study Research Articles

Tetrahydrocurcumin Has Similar Anti-Amyloid Properties as Curcumin: In Vitro Comparative Structure-Activity Studies.

Despite its potent anti-amyloid properties, the utility of curcumin (Cur) for the treatment of Alzheimer’s disease (AD) is limited due to its low bioavailability. Tetrahydrocurcumin (THC), a more stable metabolite has been found in Cur-treated tissues. We compared the anti-amyloid and neuroprotective properties of curcumin, bisdemethoxycurcumin (BDMC), demethoxycurcumin (DMC) and THC using molecular docking/dynamics, in-silico and in vitro studies. We measured the binding affinity, H-bonding capabilities of these compounds with amyloid beta protein (Aβ). Dot blot assays, photo-induced cross linking of unmodified protein (PICUP) and transmission electron microscopy (TEM) were performed to monitor the Aβ aggregation inhibition using these compounds. Neuroprotective effects of these derivatives were evaluated in N2a, CHO and SH-SY5Y cells using Aβ42 (10 µM) as a toxin. Finally, Aβ-binding capabilities were compared in the brain tissue derived from the 5× FAD mouse model of AD. We observed that THC had similar binding capability and Aβ aggregation inhibition such as keto/enol Cur and it was greater than BDMC and DMC. All these derivatives showed a similar degree of neuroprotection in vitro and labeled Aβ-plaques ex vivo. Overall, ECur and THC showed greater anti-amyloid properties than other derivatives. Therefore, THC, a more stable and bioavailable metabolite may provide greater therapeutic efficacy in AD than other turmeric derivatives.

Bisphenol-C is the strongest bifunctional ERα-agonist and ERβ-antagonist due to magnified halogen bonding.

We reported that bisphenol AF (BPAF) works as an agonist for estrogen receptor (ER) ERα but as an antagonist for ERβ. Similar results were observed for bisphenol E analogs (BPE-X) such as BPE-F, BPE-Cl, and BPE-Br, each consisting of a series of a tri-halogenated methyl group CX3 in the central alkyl moiety. It was demonstrated that the electrostatic halogen bond based on the dispersion force of halogen atoms is a major driving force in the activities of bifunctional ERα-agonist and ERβ-antagonist. Since the chlorine atoms present in bisphenol C (BPC) exist in a π-π conjugated system due to the presence of an adjacent C = C double bond, we intended to prove that BPC is also a bifunctional ERα-agonist and ERβ-antagonist exhibiting greatly enhanced agonist/antagonist activities. BPC was evaluated for its ability to activate ERα and ERβ in the luciferase reporter gene assay using HeLa cells. With high receptor-binding ability to both ERs, BPC was found to be fully active for ERα but inactive for ERβ. BPC’s definite antagonist activity in ERβ was revealed by its inhibitory activity against 17β-estradiol. Thus, BPC is a bifunctional ERα-agonist and ERβ-antagonist. These agonist/antagonist activities were discovered to be extremely high among series of halogen-containing bisphenol compounds. This comparative structure-activity study revealed that the ascending order of ERα-agonist and ERβ-antagonist activities was BPE-F ≪ BPE-Cl ≲ BPAF < BPE-Br ≪ BPC. The highly intensified receptor interaction of BPC is attributable to the presence of an n-π-π-n conjugation system mediated through the >C = CCl2 double bond.

Synthesis and Comparative Structure-Activity Study of Carbohydrate-Based Phenolic Compounds as α-Glucosidase Inhibitors and Antioxidants.

Twenty-one natural and unnatural phenolic compounds containing a carbohydrate moiety were synthesized and their structure–activity relationship (SAR) was evaluated for α-glucosidase inhibition and antioxidative activity. Varying the position of the galloyl unit on the 1,5-anhydro-d-glucitol (1,5-AG) core resulted in changes in the α-glucosidase inhibitory activity and notably, particularly strong activity was demonstrated when the galloyl unit was present at the C-2 position. Furthermore, increasing the number of the galloyl units significantly affected the α-glucosidase inhibition, and 2,3,4,6-tetra-galloyl-1,5-AG (54) and 2,3,4,6-tetra-galloyl-d-glucopyranose (61) exhibited excellent activities, which were more than 13-fold higher than the α-glucosidase inhibitory activity of acertannin (37). Moreover, a comparative structure-activity study suggested that a hemiacetal hydroxyl functionality in the carbohydrate core and a biaryl bond of the 4,6-O-hexahydroxydiphenoyl (HHDP) group, which are components of ellagitannins including tellimagrandin I, are not necessary for the α-glucosidase inhibitory activity. Lastly, the antioxidant activity increased proportionally with the number of galloyl units.

Protocol for Heterologous Expression of Insect Odourant Receptors in Drosophila

Insect olfactory receptors (ORs) are tuned to volatile chemicals, they are expressed in the membrane of olfactory sensory neurons (OSNs), housed in sensilla on the antenna. The olfactory apparatus is under strong selection and ORs are tuned to vital chemical signals, mediating social communication, feeding and oviposition, and avoidance of predators and pathogens. An emerging technique to reliably and efficiently identify the key ligands of ORs is to express single ORs in heterologous cell systems for subsequent screening. Several in vivo and in vitro platforms have been developed; we here provide a step-by-step protocol for OR expression in Drosophila melanogaster OSNs. Following RNA extraction, molecular cloning of ORs and injection of plasmid vectors into Drosophila embryos to create flies with OR transgenes, single ORs are expressed, via crossing with specific transgene promoters in OSNs of ab3 and T1 antennal sensilla. This approach enables replicable single sensillum electrophysiological recordings (SSR) from readily distinguishable Drosophila sensilla, containing OSNs expressing transgenic ORs. We expect this method to be applicable to ORs across insect orders and to increasingly contribute to chemical ecology research. Heterologous expression enables thorough investigation of single ORs, towards the identification of yet unknown, behaviourally and ecologically relevant chemical signals. It also enables investigations of the functional properties of ORs and their evolutionary diversification, through comparative structure-activity studies across phylogenies.

SAR studies on curcumin's pro-inflammatory targets: discovery of prenylated pyrazolocurcuminoids as potent and selective novel inhibitors of 5-lipoxygenase.

The anticarcinogenic and anti-inflammatory properties of curcumin have been extensively investigated, identifying prostaglandin E2 synthase (mPGES)-1 and 5-lipoxygenase (5-LO), key enzymes linking inflammation with cancer, as high affinity targets. A comparative structure-activity study revealed three modifications dissecting mPGES-1/5-LO inhibition, namely (i) truncation of the acidic, enolized dicarbonyl moiety and/or replacement by pyrazole, (ii) hydrogenation of the interaryl linker, and (iii) (dihydro)prenylation. The prenylated pyrazole analogue 11 selectively inhibited 5-LO, outperforming curcumin by a factor of up to 50, and impaired zymosan-induced mouse peritonitis along with reduced 5-LO product levels. Other pro-inflammatory targets of curcumin (i.e., mPGES-1, cyclooxygenases, 12/15-LOs, nuclear factor-κB, nuclear factor-erythroid 2-related factor-2, and signal transducer and activator of transcription 3) were hardly affected by 11. The strict structural requirements for mPGES-1 and 5-LO inhibition strongly suggest that specific interactions rather than redox or membrane effects underlie the inhibition of mPGES-1 and 5-LO by curcumin.

Ferroelectric Behavior in Metal-Containing Liquid Crystals: A Structure-Activity Study

The synthesis and physical characterization (thermotropic and ferroelectric behavior) of eight ortho-palladated dimers [Pd 2 (μ-Cl) 2 L * 2 ] is reported. They are derived from chiral imines HL * (HL * =p-R 1 OC 6 H 4 CH=NC 6 H 4 -OR 2 -p, with R 1 , R 2 , or both equal to (R)- or (S)-1-methylheptyl). The chiral imines, which contain one or two stereogenic centers, are not liquid crystals themselves. However, the dimeric complexes, which contain two or four stereogenic centers in their structure, exhibit both SmA and SmC * mesophases and enable the first comparative structure-activity study on metal-containing ferroelectric liquid crystals to be made

α-Melanocyte stimulating hormone message and inhibitory sequences: Comparative structure-activity studies on melanocytes

We investigated the structure-activity relationships of α-MSH (α-melanocyte stimulating hormone) fragment derivatives of the generic formulae Ac-α-MSH(x−13)-NH 2 and Ac-α-MSH(6−x)-NH 2. The minimal C-terminal sequences required for melanotropic activity were 8–13 and 7–13, respectively, in the frog and lizard skin bioassays. The Arg 8-Trp 9 sequence appears to be a fundamental component of the minimal message sequences found to date such as α-MSH(6–9), α-MSH(8–13) and α-MSH(7–13). We discovered that Ac-α-MSH(7–10)-NH 2 was a weak and selective α-MSH antagonist on the lizard skin bioassay. Analysis of α-MSH(7–10) analogues of the generic formula Ac-Xaa-Arg-Trp-Yaa-NH 2 led to Ac-[D- Trp 7,D- Phe 10]α- MSH(7–10)- NH 2 , a moderately potent, specific and competitive inhibitor of α-MSH in both the frog and the lizard skin bioassays.

Comparative structure-activity studies on mammalian [Arg 8] LH-RH and chicken [Gln 8] LH-RH by fluorimetric titration

Fluorimetric titrations of mammalian [Arg 8] LH-RH, chicken [Gln 8] LH-RH and an analogue [Lys 8] LH-RH revealed pK values of 5.80, 6.22 and 6.01 for His 2, and 9.65, 9.88 and 9.88 for Tyr 5. The titration ranges for His 2 were 1.72, 2.03 and 1.71 while the range for Tyr 5 was rather similar ( ∼ 1.7) for all three peptides. Biological activity and receptor binding in the mammalian system for chicken LH-RH was 1% relative to mammalian LH-RH while [Lys 8] LH-RH had a relative activity of approximately 10%. In contrast, mammalian and chicken LH-RH were equipotent in stimulating LH release from chicken pituitary cells. The results indicate differences in the receptors related to the conformations of LH-RH and position 8-substituted analogues.

ChemInform Abstract: STRUCTURE‐ACTIVITY RELATIONSHIP STUDY OF ANTHRAQUINONES: 1,4‐DIHYDROXY‐5,8‐BIS((2‐(2‐HYDROXYETHOXY)ETHYL)AMINO)‐9,10‐ANTHRACENEDIONE, AN ANALOG OF AN ESTABLISHED ANTINEOPLASTIC AGENT

AbstractDurch Umsetzung des Tetrahydroxy‐dihydro‐anthrachinons (I) mit Aminoethoxyethanol (II) und anschließende Oxidation mit Luftsauerstoff erhäIt man das Anthrachinonderivat ‐( III), das keine antineoplastische Wirkung zeigt.

Structure—Activity Relationship Study of Anthraquinones: 1 ,4-Dihydroxy-5,8-bis[[2-(2-hydroxyethoxy)ethyl]amino]-9,10-anthracenedione, an Analog of an Established Antineoplastic Agent

An oxygen analog of the antineoplastic anthraquinone, 1,4-dihydroxy-5,8-bis[[2-(2-hydroxyethyl)amino]ethyl]arnino - 9,10 -an-thracenedione, was synthesized. This compound, 1,4-dihydroxy-5,8-bis[[2-(2-hydroxyethoxy)ethyl]amino]-9,10-anthracenedione, was found to be inactive against P-388 lymphocytic leukemia. A comparative structure-activity study of these two anthraquinones in terms of previously postulated N—O—O triangulation hypothesis was discussed.

Synthesis of ethyl 6-substituted-chroman- and -chromone-2-carboxylates. A comparative structure-activity study employing the 6-phenyl and phenoxy analogs in the triton hyperlipidemic rat model.

To explore the effect of lipophilicity on antilipidemic activity in the Triton WR-1339 induced hyperlipidemic rat model we synthesized the 6-cyclohexyl, phenyl, and phenoxy analogs of ethyl chroman-2-carboxylate. Results obtained were analyzed in light of the biological activity observed for the 6-chloro-substituted and unsubstituted chromans, the 6-chlorochroman-4-one ester, and the 6-chloro-, phenyl-, and phenoxychromone esters. The suggestion is made that chromones likely exert their antilipidemic effects by a somewhat different set of mechanisms than do the chromans and clofibrate. Whereas the 6-chlorochromanone ester is inactive, the 6-chlorochromone ester is active in both normal and hyperlipidemic Sprague-Dawley rats. The major differential effect was observed for ethyl 6-cyclohexylchroman-2-carboxylate which did not lower cholesterol levels but returned triglyceride levels to normal in hyperlipidemic rats.