- Ligand-based rational design, synthesis and evaluation of novel potential chemical chaperones for opsin
-
Inherited blinding diseases retinitis pigmentosa (RP) and a subset of Leber's congenital amaurosis (LCA) are caused by the misfolding and mistrafficking of rhodopsin molecules, which aggregate and accumulate in the endoplasmic reticulum (ER), leading to photoreceptor cell death. One potential therapeutic strategy to prevent the loss of photoreceptors in these conditions is to identify opsin-binding compounds that act as chemical chaperones for opsin, aiding its proper folding and trafficking to the outer cell membrane. Aiming to identify novel compounds with such effect, a rational ligand-based approach was applied to the structure of the visual pigment chromophore, 11-cis-retinal, and its locked analogue 11-cis-6mr-retinal. Following molecular docking studies on the main chromophore binding site of rhodopsin, 49 novel compounds were synthesized according to optimized one-to seven-step synthetic routes. These agents were evaluated for their ability to compete for the chromophore binding site of opsin, and their capacity to increase the trafficking of the P23H opsin mutant from the ER to the cell membrane. Different new molecules displayed an effect in at least one assay, acting either as chemical chaperones or as stabilizers of the 9-cis-retinal-rhodopsin complex. These compounds could provide the basis to develop novel therapeutics for RP and LCA.
- Bassetto, Marcella,Brancale, Andrea,Pasqualetto, Gaia,Pileggi, Elisa,Rozanowska, Malgorzata,Schepelmann, Martin,Varricchio, Carmine
-
supporting information
(2021/09/24)
-
- BORONIC ESTER PRODRUGS AND USES THEREOF
-
Disclosed herein are compounds of Formula (I) or (II). The compounds include an agent (e.g., pharmaceutical agent, cosmetic agent, or nutraceutical agent) through a linker that includes a boronic ester moiety in the backbone of the linker. The compounds may be monomers. Also provided are polymers prepared by polymerizing the monomers. The polymers may be useful for delivering the agent to a subject, tissue, biological sample, or a cell. Also provided are methods of preparing the polymers, compositions and kits comprising the polymers, and methods of use (e.g., use in delivering the agent, treating a disease, preventing a disease, diagnosing a disease) involving the polymers or compositions. The structure of the boronic ester moiety may be fine tuned so that the properties related to delivery to a subject, biological sample, tissue, or cell may be fine tuned.
- -
-
Paragraph 0405-0406
(2020/12/07)
-
- Highly pH-Dependent Chemoselective Transfer Hydrogenation of α,β-Unsaturated Aldehydes in Water
-
The pH-dependent selective Ir-catalyzed hydrogenation of α,β-unsaturated aldehydes was realized in water. Using HCOOH as the hydride donor at low pH, the unsaturated alcohol products were obtained exclusively, while the saturated alcohol products were formed preferentially by employing HCOONa as the hydride donor at high pH. A wide range of functional groups including electron-rich as well as electron-poor substituents on the aryl group of α,β-unsaturated aldehydes can be tolerated, affording the corresponding products in excellent yields with high TOF values. High selectivity and yields were also observed for α,β-unsaturated aldehydes with aliphatic substituents. Our mechanistic investigations indicate that the pH value is critical to the chemoselectivity.
- Luo, Nianhua,Liao, Jianhua,Ouyang, Lu,Wen, Huiling,Liu, Jitian,Tang, Weiping,Luo, Renshi
-
p. 3025 - 3031
(2019/08/30)
-
- Synthesis of terpenoid oxo derivatives with antiureolytic activity
-
Urease is an important virulence factor for a variety of pathogenic bacteria strains such as Helicobacter pylori, which colonizes human gastric mucosa, and Proteus sp., responsible for urinary tract infections. Specific inhibition of urease activity could be a promising adjuvant strategy for eradication of these pathogens. Due to the interesting antiureolytic activity of carvone and the scant information regarding the inhibitory properties of corresponding monoterpenes, we decided to study selected monoterpenic ketones and their oxygen derivatives. Several monoterpenes and their terpenoid oxygen derivatives were evaluated in vitro against Sporosarcina pasteurii urease. The most effective inhibitors—derivatives of β-cyclocitral (ester 10 and bromolactone 14)—were described with Ki of 46.7?μM and 45.8?μM, respectively. Active inhibitors of native urease were tested against H. pylori and Proteus mirabilis whole cells. Here, the most active inhibitor, 14, was characterized with IC50 values of 0.32?mM and 0.61?mM for P. mirabilis and H. pylori, respectively. The antibacterial activity of a few tested inhibitors was also observed. Compound 14 limited the growth of E. coli (MIC50= 250?μg/mL). Interestingly, 10 was the only compound that was effective against both Gram-negative and Gram-positive bacteria. It had a MIC50 of 150?μg/mL against E. coli and S. aureus. In the presented study a group of novel antiureolytic compounds was characterised. Besides carvone stereoisomers, these are the only terpenoid urease inhibitors described so far.
- Kozio?, Agata,Macegoniuk, Katarzyna,Grela, Ewa,Grabowiecka, Agnieszka,Biernat, Monika,Lochyński, Stanis?aw
-
-
- A general strategy for the stereoselective synthesis of the furanosesquiterpenes structurally related to pallescensins 1-2
-
Here, we describe a general stereoselective synthesis of the marine furanosesquiterpenes structurally related to pallescensins 1-2. The stereoisomeric forms of the pallescensin 1, pallescensin 2, and dihydropallescensin 2 were obtained in high chemical and isomeric purity, whereas isomicrocionin-3 was synthesized for the first time. The sesquiterpene framework was built up by means of the coupling of the C10 cyclogeranyl moiety with the C5 3-(methylene)furan moiety. The key steps of our synthetic procedure are the stereoselective synthesis of four cyclogeraniol isomers, their conversion into the corresponding cyclogeranylsulfonylbenzene derivatives, their alkylation with 3-(chloromethyl)furan, and the final reductive cleavage of the phenylsulfonyl functional group to afford the whole sesquiterpene framework. The enantioselective synthesis of the α-, 3,4-dehydro-γ- and γ-cyclogeraniol isomers was performed using both a lipase-mediated resolution procedure and different regioselective chemical transformations.
- Serra, Stefano
-
-
- STABILIZED MUTANT OPSIN PROTEINS
-
Methods and compositions for stabilizing opsin protein, such as a Pro23His mutant opsin protein, in a vertebrate visual system, by administration of opsin-binding synthetic retinoids, are provided. The mutant opsin protein binds to the synthetic retinoid, which stabilizes the mutant opsin protein and/or ameliorates the effects of the mutant opsin protein on the vertebrate visual system.
- -
-
Paragraph 0064
(2016/03/13)
-
- SUBSTITUTED QUINOLIZINE DERIVATIVES USEFUL AS HIV INTEGRASE INHIBITORS
-
The present invention relates to Substituted Quinolizine Derivatives of Formula (I): and pharmaceutically acceptable salts or prodrug thereof, wherein X, Y, R1, R2, R3, R4, R5, R9 and R10 are as defined herein. The present invention also relates to compositions comprising at least one Substituted Quinolizine Derivative, and methods of using the Substituted Quinolizine Derivatives for treating or preventing HIV infection in a subject.
- -
-
Page/Page column 106
(2015/04/15)
-
- OPSIN-BINDING LIGANDS, COMPOSITIONS AND METHODS OF USE
-
Compounds and compositions are disclosed that are useful for treating ophthalmic conditions caused by or related to production of toxic visual cycle products that accumulate in the eye, such as dry adult macular degeneration, as well as conditions caused by or related to the misfolding of mutant opsin proteins and/or the mis-localization of opsin proteins. Compositions of these compounds alone or in combination with other therapeutic agents are also described, along with therapeutic methods of using such compounds and/or compositions. Methods of synthesizing such agents are also disclosed.
- -
-
Page/Page column 76
(2013/06/27)
-
- Discrete iron complexes for the selective catalytic reduction of aromatic, aliphatic, and α,β-unsaturated aldehydes under water-gas shift conditions
-
Iron-catalyzed reductions: Selective iron-catalyzed reduction of aldehydes with hydrogen generated in situ by the water-gas shift reaction is presented (see scheme). The generality and selectivity of this mild procedure are demonstrated by the efficient reduction of various aromatic, aliphatic and α,β-unsaturated aldehydes.
- Tlili, Anis,Schranck, Johannes,Neumann, Helfried,Beller, Matthias
-
p. 15935 - 15939
(2013/02/21)
-
- OPSIN-BINDING LIGANDS, COMPOSITIONS AND METHODS OF USE
-
Compounds and compositions of said compounds along with methods of use of compounds are disclosed for treating ophthalmic conditions related to mislocalization of opsin proteins, the misfolding of mutant opsin proteins and the production of toxic visual cycle products that accumulate in the eye. Compounds and compositions useful in the these methods, either alone or in combination with other therapeutic agents, are also described.
- -
-
Page/Page column 155-156
(2010/12/31)
-
- Design and synthesis of potential new apoptosis agents: hybrid compounds containing perillyl alcohol and new constrained retinoids
-
Novel retinoids 1-3 containing perillyl alcohol were synthesized through the addition of perillyl alcohol to the activated carboxylic acids (retinoids) promoted by DCC (N,N′-dicyclohexyl carbodiimide). A set of structurally and functionally diverse perillyl alcohol derivatives of retinoids were obtained in good yields (78-82%). Biological evaluation of these novel hybrid compounds (containing retinoids and perillyl alcohol) is currently underway in our laboratory.
- Das, Bhaskar C.,Mahalingam, Sakkarapalayam M.,Panda, Lipsa,Wang, Bo,Campbell, Phillp D.,Evans, Todd
-
scheme or table
p. 1462 - 1466
(2010/04/29)
-
- STYRENYL DERIVATIVE COMPOUNDS FOR TREATING OPHTHALMIC DISEASES AND DISORDERS
-
The present invention relates generally to compositions and methods for treating neurodegenerative diseases and disorders, particularly ophthalmic diseases and disorders. Provided herein are styrenyl derivative compounds, including but not limited to stilbene derivative compounds, and compositions comprising these compounds, that are useful for treating and preventing ophthalmic diseases and disorders, including age-related macular degeneration (AMD) and Stargardt's Disease.
- -
-
Page/Page column 134; 136
(2008/12/08)
-
- Synthesis, antimicrobial and antineoplastic activities for agelasine and agelasimine analogs with a β-cyclocitral derived substituent
-
Agelasines and agelasimines are antimicrobial and cytotoxic purine derivatives isolated from marine sponges (Agelas sp.). We have synthesized structurally simplified analogs of these natural products starting from β-cyclocitral. The novel compounds were found to be strong inhibitors of a wide variety of pathogenic microorganisms (incl. Mycobacterium tuberculosis) as well as cancer cell lines. The biological activities were generally in the same range as those previously found for the structurally more complex agelasines and agelasimines isolated in small amounts from natural sources. We also report for the first time that agelasine and agelasimine analogs inhibit growth of protozoa (Acanthamoeba castellanii and Acanthamoeba polyphaga). Acanthamoeba keratitis is an increasingly common and severe corneal infection, closely associated with contact lens wear.
- Proszenyak, Agnes,Charnock, Colin,Hedner, Erik,Larsson, Rolf,Bohlin, Lars,Gundersen, Lise-Lotte
-
p. 625 - 634
(2008/12/21)
-
- Novel strategy for the synthesis of the butenolide moiety of peridinin
-
Tartaric acid is the starting point for the stereoselective synthesis of the butenolide unit (see scheme)in peridinin, a marine carotenoid. Key steps were the desymmetrization of tartaric acid bis(Weinreb amide), an E-selective olefination by Ando-type bromophosphonates, and an anti-selective Mitsunobu elimination (for establishing the C1′=Cγ bond).
- Olpp, Thomas,Brueckner, Reinhard
-
p. 1553 - 1557
(2007/10/03)
-
- Synthesis of iodinated analogues of all trans retinoic acid (ATRA) for SPECT imaging
-
Two derivatives of all trans retinoic acid in which one of the methyl groups has been replaced by iodine have been prepared.
- Li, Haibing,Morin, Christophe
-
p. 5673 - 5676
(2007/10/03)
-
- Novel domino reactions for diterpene synthesis
-
New types of concerted domino acylation-cycloalkylation/alkylation- cycloacylation reactions have been described. These processes promoted by methanesulfonic acid-phosphorus pentoxide and concentrated H2SO 4, respectively, provide efficient, elegant, and expeditious routes for biologically active naturally occurring diterpenoids, namely (±)-ferruginol (1), (±)-nimbidiol (2), (±)-nimbiol (3), (±)-totarol (4), and ar-abietatriene (5).
- Bhar, Shanta S.,Ramana
-
p. 8935 - 8937
(2007/10/03)
-
- A conjugate addition-radical cyclisation approach to sesquiterpene-phenol natural products
-
A conjugate addition-radical cyclization approach to sesquiterpenephenol natural products was discussed. The first step involved the conjugate addition of an organocopper species to a chromone-3-carboxylate which resulted in 2,2-disubstituted chroman-4-ones. The second step was the generation of a β-ketoester radical. The last step involved a stereoselective manganese(III) acetate-mediated radical cyclization reaction.
- Crombie, Barry S.,Smith, Colin,Varnavas, Christalla Z.,Wallace, Timothy W.
-
p. 206 - 215
(2007/10/03)
-
- Chemistry of natural compounds and bioorganic chemistry: Enantioselectivity of enzymatic acylation of some structurally various racemic alcohols in anhydrous aprotic media
-
Partial acylation of (R,S)-3,7-dimethyloctan-l-ol (1) and (R,S)-7-methoxy-3,7-dimethyloctan-l-ol (2) with vinyl acetate catalyzed by the lipase from Candida cylindracea affords in good yields the corresponding S-configured acetates with 92-98% enantiomeric excess (ee). Under similar conditions, racemic α-cyclogeraniol (3), drim-7-en-11-ol, methyl 4-(3-hydroxy-2-methylpropyl)benzoate, and its η6-chromium(tricarbonyl) complex (6) are acylated with rather poor (and, for the two latter, opposite) enantioselectivity, whereas (R,S)-2,4:3,5-di-O-benzylidenexylitol remains unaffected. Racemic isoborneol (8) and 2-nitro-1-phenylethanol also remain almost or completely unconverted. Attempts to perform enantioselective acylation of alcohols 3 and 8 with Ac2O in the presence of porcine pancreatic lipase (PPL) proved equally unsuccessful. By contrast, the PPL-catalyzed acylation of alcohol 6 with vinyl acetate at 17% conversion affords the levorotatory acetate (S)-6a with ca. 100% ee. PPL-Mediated partial acylation of (R,S)-pantolactone with Ac2O, followed by mild deacylation of the resulting R acetate, gives (R)-(-)-pantolactone of 97% enantiomeric purity in 60% overall yield.
- Gamalevich,Serebryakov
-
p. 171 - 183
(2007/10/03)
-
- Enantioselective synthesis of cuparane sesquiterpenes. Synthesis of (-)-cuparene and (-)-δ-cuparenol
-
(-)-Cuparene and (-)-δ-cuparenol, two cuparane-type sesquiterpenoids, were synthesized from β-cyclogeraniol in 47% and 27% overall yield, respectively, using a Katsuki-Sharpless asymmetric epoxidation, a pinacollic rearrangement, and a Robinson annulation as key synthetic steps.
- Abad, Antonio,Agullo, Consuelo,Arno, Manuel,Cunat, Ana C.,Garcia, M. Teresa,Zaragoza, Ramon J.
-
p. 5916 - 5919
(2007/10/03)
-
- Synthesis of (+/-)-Thaps-7(15)-ene and (+/-)-Thaps-6-enes
-
The synthesis of (+/-)-3a,4,4,7a-tetramethylhydrindan-2-one 8, containing three contiguous quaternary carbons as present in thapsanes, and the total synthesis of thaps-7(15)-ene 6 and thaps-6-ene 7, probable biogenetic precursors of thapsanes, have been achieved.Thus, orthoester Claisen rearrangement of cyclogeraniol 14, followed by hydrolysis of the resultant ester 16 furnished the eneacid 13.Copper sulfate-catalysed intramolecular cyclopropanation of the diazo ketone 18, derived from the acid 13, generated the cyclopropyl ketone 12.Regiospecific reductive cleavage of cyclopropyl ketone 12 furnished the hydrindanone 8, whereas the diazo ketone 26 furnished the hydrindanone 28a via the cyclopropyl ketone 27.Wittig methylenation of the hydrindanone 28a furnished thaps-7(15)-ene 6, which on isomerisation gave thaps-6-ene 7.Allylic oxidation of thaps-6-ene furnished the thapsenone 31, a degradation product of the natural thapsane 1b.
- Srikrishna, Adusumilli,Krishnan, Kathiresan
-
p. 667 - 674
(2007/10/02)
-
- STEREOSPECIFIC SYNTHESIS OF THAPS-7(15)-ENE AND THAPS-6-ENE, PROBABLE BIOGENETIC PRECURSORS OF THAPSANES
-
Stereospecific synthesis of the title compounds, containing the basic carbocyclic skeleton of thapsanes, based on intramolecular diazoketone cyclopropanation reaction, is described.
- Srikrishna, A.,Krishnan, K.
-
p. 6577 - 6580
(2007/10/02)
-
- Bacterial Carotenoids. 51. Chirality and Chiroptical Properties of (2S)-2-Isopentenyl-3,4-dehydrorhodopin (C.p. 482) and Related C45-Carotenoids
-
Dehydration of C.p. 482 (2-isopentenyl-3,4-dehydrorhodopin; 2-(3-methyl-2-butenyl)-3,4-didehydro-1,2-dihyro-ψ,ψ-caroten-1-ol) with POCl3 provided a tert chloride, a conjugated and a non-conjugated anhydro product in varying yields depending on reaction conditions.Chiroptical propeties of C.p. 482 and its trimethylsilyl ether were considered.The 2S-chrirality of C.p. 482 was demonstrated by chiroptical comparison of its non-conjugated anhydro derivative with the same (2S)-carotenoid, here prepared by total synthesis.The dehydration to the non-conjugated anhydro derivative only slightly modified the CD curve but reduced Δε values significantly.For futher chiroptical studies (2'S)-2'-(3-methyl-2-butenyl)-1',16',3',4'-tetradehydro-1',2'-dihydro-β,ψ-carotene was synthesized.The 2'-isopentenyl substituent had a similar influence on the Cotton effects of the monochiral monocyclic C45-, the monochiral aliphatic C45- and the homodichiral aliphatic C50-carotenes considered.
- Andrewes, Arthur G.,Borch, Gunner,Liaaen-Jensen, Synnoeve
-
p. 871 - 876
(2007/10/02)
-
- SYNTHESIS AND PLANT GROWTH INHIBITORY ACTIVITIES OF (+)- AND (-)-(2Z,4E)-5-(1',2'-EPOXY-2',6',6'-TRIMETHYLCYCLOHEXYL)-3-METHYL-2,4-PENTADIENOIC ACID
-
Chiral (+)- and (-)-enantiomers of (2Z,4E)-5-(1',2'-epoxy-2',6',6'-trimethylcyclohexyl)-3-methyl-2,4-pentadienoic acid have been synthesized from the chiral epoxy alcohols (+)- and (-)-1',2'-dihydro-1',2'-epoxy-β-ionone, which were prepared by Katsuki-Sharpless'asymmetric epoxidation of β-cyclogeraniol.The (+)-enantiomer showed strong inhibitory activity in a rice seedling and lettuce germination assay, whereas the (-)-enantiomer was 103 times less active. - Key Word Index - Plant growth inhibitor; absolute configuration; relationship between enantiomers and biological activity; rice seedling growth; lettuce seed germination; abscisic acid analogue; (2Z,4E)-5-(1',2'-epoxy-2',6',6'-trimethylcyclohexyl)-3-methyl-2,4-pentadienoic acid.
- Oritani, Takayuki,Yamashita, Kyohei
-
p. 1909 - 1912
(2007/10/02)
-