- CHINONE-, HYDROCHINOME- AND NAPHTHOCHINONE-ANALOGUES OF VATIQUIONE FOR TREATMENT OF MITOCHONDRIAL DISORDER DISEASES
-
The disclosure provides therapeutic compositions (i.e., therapeutic agents) and methods of preventing or treating Friedreich's ataxia in a mammalian subject, reducing risk factors, signs and/or symptoms associated with Friedreich's ataxia (e.g. Complex I deficiency), and/or reducing the likelihood or severity of Friedreich's ataxia. The disclosure further provides novel intermediates for the production of said therapeutic compositions and related reduced versions of said therapeutic compositions, which reduce forms may also be used as therapeutic agents (or prodrugs of the therapeutic agent(s)).
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Page/Page column 187
(2021/04/10)
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- Regiospecific Synthesis of Calcium-Independent Daptomycin Antibiotics using a Chemoenzymatic Method
-
Daptomycin (DAP) is a calcium (Ca2+)-dependent FDA-approved antibiotic drug for the treatment of Gram-positive infections. It possesses a complex pharmacophore hampering derivatization and/or synthesis of analogues. To mimic the Ca2+-binding effect, we used a chemoenzymatic approach to modify the tryptophan (Trp) residue of DAP and synthesize kinetically characterized and structurally elucidated regiospecific Trp-modified DAP analogues. We demonstrated that the modified DAPs are several times more active than the parent molecule against antibiotic-susceptible and antibiotic-resistant Gram-positive bacteria. Strikingly, and in contrast to the parent molecule, the DAP derivatives do not rely on calcium or any additional elements for activity.
- Mupparapu, Nagaraju,Lin, Yu-Hsin Cindy,Kim, Tae Ho,Elshahawi, Sherif I.
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supporting information
p. 4176 - 4182
(2021/02/01)
-
- ANTIBIOTIC COMPOUNDS
-
Provided herein are lipidated glycopeptide compounds of formula (I); or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof. R1 is a lipid, R2 is -H or a lipid, and R3 and R4 are as defined herein. These compounds have antibiotic activity. Also provided are formulations comprising such compounds; as well as such compounds or formulations for use as a medicament. The compounds and formulations may also be used in the treatment of bacterial infection.
- -
-
Paragraph 00117
(2021/04/02)
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- BIOSYNTHESIS OF CHEMICALLY DIVERSIFIED NON-NATURAL TERPENE PRODUCTS
-
The disclosure relates to compounds of the formulae (l)-(IV) and their use as substrates for making terpenoids. New substrates for terpene biosynthesis and methods for making new types of terpenes are described herein. Diterpenes occupy a unique molecular
- -
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Page/Page column 116-120; 130-133; 138-139; 146-147
(2021/05/15)
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- Protein degradation targeting chimeric compound, preparation method and medical application thereof
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The invention relates to a protein degradation targeting chimeric compound, a preparation method and medical application thereof, specifically to a compound as shown in a general formula (I), a preparation method of the compound, and application of the co
- -
-
Paragraph 0218-0219; 0222-0223
(2021/03/31)
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- METHODS OF SYNTHESIZING FARNESYL DIBENZODIAZEPINONES
-
The present invention is directed to synthetic means for producing farnesyl dibenzodiazepinone compounds, including AMO-01.
- -
-
Paragraph 0045; 0070-0071
(2021/12/08)
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- Synergistic factors ensue high expediency in the synthesis of menaquinone [K2] analogue MK-6: Application to access an efficient one-pot protocol to MK-9
-
Here we report a practical and efficient method for the synthesis of menaquinone vitamin (K2) analog MK-6 in all trans forms through “1 + 5 convergent synthetic approach” of pentaprenyl chloride with monoprenyl menadione derivative. In the synergistic factors, less efficient leaving group/more efficient nucleophile (Cl) in the substrate makes it more prominent reaction by eliminating all Sn2’ side reaction products. Further, the addition of acetic acid in the last step (desulfonation) of reaction sequence removes the limitations of the reactions in terms of cyclized side product (multiple reactions of pentaprenyl alcohol with Et3B), byproduct (Et3B, incendiary compound) formations and their interruption in the tricky purification processes. The utility of this method was further extended to find an efficient one-pot synthesis to MK-9 to the gram scale synthesis. This approach is economical and efficient and avoids the awkward chromatographic separation processes.
- Yerramsetti, Nanaji,Dampanaboina, Lavanya,Mendu, Venugopal,Battula, Satyanarayana
-
-
- Ferulin C triggers potent PAK1 and p21-mediated anti-tumor effects in breast cancer by inhibiting Tubulin polymerization in vitro and in vivo
-
Ferulin C, a natural sesquiterpene coumarin, isolated from the roots of Ferula ferulaeoides (Steud.) Korov, displaying potent antiproliferatory activity against breast cancer cells. This study aimed to elucidate the underlying molecular mechanisms of Ferulin C-induced breast cancer cells death in vitro and in vivo. Ferulin C presented potent antiproliferatory activity against MCF-7 and MDA-MB-231 cells and remarkable tubulin polymerization inhibitory activity (IC50 = 9.2 μM). Meanwhile, we predicted Ferulin C bind to the Colchicine site of tubulin through CETSA assay, molecular docking and molecular dynamics (MD) simulations. In immunofluorescence assay, Ferulin C disturbed the microtubule integrity and structure. Furthermore, Ferulin C stimulated significant cell cycle arrest in the G1/S period via p21Cip1/Waf1 - CDK2 signaling, induced classic cell apoptosis, impaired metastasis via down-regulating Ras-Raf-ERK and AKT-mTOR signaling. Intriguingly, Ferulin C treatment induced autophagy by ULK1 signaling to synergize with the inhibition of proliferation and metastasis. Based upon the RNAseq analysis, PAK1, as a novel essential modulator, was involved in the signaling regulated by Ferulin C -induced α/β-tubulin depolymerization. Additionally, Ferulin C displayed an acceptable antiproliferatory activity in an MCF-7 xenograft model without inducing obvious weight loss in the Ferulin C treated mice. Summarily, our findings substantiated that Ferulin C was a potent, colchicine site binding microtubule-destabilizing agent with anti-proliferation and anti-metastasis activity via PAK1 and p21-mediated signaling in breast cancer cells.
- He, Zhendan,Huang, Jian,Pan, Dabo,Wang, Jinhui,Yao, Dahong,Zhang, Jin,Zhen, Yongqi
-
-
- On the mechanism of ophiobolin F synthase and the absolute configuration of its product by isotopic labelling experiments
-
An ophiobolin F synthase homolog was discovered from Aspergillus calidoustus CBS121601. The cyclisation mechanism of this terpene synthase was investigated by extensive isotopic labelling experiments and the absolute configuration of its product ophioboli
- Dickschat, Jeroen S.,Quan, Zhiyang
-
supporting information
p. 6072 - 6076
(2020/10/27)
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- A Branched Diterpene Cascade: The Mechanism of Spinodiene Synthase from Saccharopolyspora spinosa
-
A diterpene synthase from Saccharopolyspora spinosa was found to convert geranylgeranyl diphosphate into the new natural products spinodiene A and B, accompanied by 2,7,18-dolabellatriene. The structures and the formation mechanism of the enzyme products were investigated by extensive isotopic labelling experiments, which revealed an unusual branched isomerisation mechanism towards the neutral intermediate 2,7,18-dolabellatriene. A Diels–Alder reaction was used to convert the main diterpene product with its rare conjugated diene moiety into formal sesterterpene alcohols.
- Rinkel, Jan,Lauterbach, Lukas,Dickschat, Jeroen S.
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supporting information
p. 452 - 455
(2018/12/13)
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- Potentiation of the activity of β-lactam antibiotics by farnesol and its derivatives
-
Farnesol, a sesquiterpene alcohol, potentiates the activity of β-lactam antibiotics against antibiotic-resistant bacteria. We document that farnesol and two synthetic derivatives (compounds 2 and 6) have poor antibacterial activities of their own, but they potentiate the activities of ampicillin and oxacillin against Staphylococcus aureus strains (including methicillin-resistant S. aureus). These compounds attenuate the rate of growth of bacteria, which has to be taken into account in assessment of the potentiation effect.
- Kim, Choon,Hesek, Dusan,Lee, Mijoon,Mobashery, Shahriar
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p. 642 - 645
(2018/02/09)
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- Mechanistic Investigations of Two Bacterial Diterpene Cyclases: Spiroviolene Synthase and Tsukubadiene Synthase
-
The mechanisms of two diterpene cyclases from streptomycetes—one with an unknown product that was identified as the spirocyclic hydrocarbon spiroviolene and one with the known product tsukubadiene—were investigated in detail by isotope labeling experiment
- Rabe, Patrick,Rinkel, Jan,Dolja, Etilia,Schmitz, Thomas,Nubbemeyer, Britta,Luu, T. Hoang,Dickschat, Jeroen S.
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supporting information
p. 2776 - 2779
(2017/02/26)
-
- Characterization of the single-subunit oligosaccharyltransferase STT3A from Trypanosoma brucei using synthetic peptides and lipid-linked oligosaccharide analogs
-
The initial transfer of a complex glycan in protein N-glycosylation is catalyzed by oligosaccharyltransferase (OST), which is generally a multisubunit membrane protein complex in the endoplasmic reticulum but a single-subunit enzyme (ssOST) in some protists. To investigate the reaction mechanism of ssOST, we recombinantly expressed, purified and characterized the STT3A protein from Trypanosoma brucei (TbSTT3A). We analyzed the in vitro activity of TbSTT3A by synthesizing fluorescently labeled acceptor peptides as well as lipid-linked oligosaccharide (LLO) analogs containing a chitobiose moiety coupled to oligoprenyl carriers of distinct lengths (C10, C15, C20 and C25) and with different double bond stereochemistry. We found that in addition to proline, charged residues at the +1 position of the sequon inhibited glycan transfer. An acidic residue at the -2 position significantly increased catalytic turnover but was not essential, in contrast to the bacterial OST. While all synthetic LLO analogs were processed by TbSTT3A, the length of the polyprenyl tail, but not the stereochemistry of the double bonds, determined their apparent affinity. We also synthesized phosphonate analogs of the LLOs, which were found to be competitive inhibitors of the reaction, although with lower apparent affinity to TbSTT3A than the active pyrophosphate analogs.
- Ramírez, Ana S.,Boilevin, Jérémy,Biswas, Rasomoy,Gan, Bee Ha,Janser, Daniel,Aebi, Markus,Darbre, Tamis,Reymond, Jean-Louis,Locher, Kaspar P.
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p. 525 - 535
(2017/06/09)
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- Convergent synthesis of menaquinone-7 (MK-7)
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A practical synthesis of menaquinone-7 (MK-7, vitamin K2) in the all-Trans form was designed. Stereoselective synthesis of MK-7 was achieved through a "1 + 6" convergent strategy by condensation of two building blocks, menadione monoprenyl derivative (fragment "1") with hexaprenyl bromide (fragment "6", 82%). Pd-catalyzed desulfonation with LiEt3BH (78%) was followed by oxidation of the hydroquinone moiety using ammonium cerium(IV) nitrate (72%). The major challenge in our methodology was the preparation of all-Trans hexaprenyl bromide by coupling of two triprenyl units derived from trans,trans-farnesol. Manufacturing on a pilot scale was accomplished through our approach. The scalable method was designed especially for a large, kilogram-scale production from easily available intermediates. Furthermore, the proposed methodology avoids many chromatographic purifications and allows for a relatively cost-effective manufacturing. Moreover, our synthesis yielded high-purity (99.9%) final product MK-7, which can be used as a dietary supplement as well as an active pharmaceutical ingredient.
- Baj, Aneta,Wa?ejko, Piotr,Kutner, Andrzej,Kaczmarek, L?ukasz,Morzycki, Jacek W,Witkowski, Stanisl?aw
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p. 1026 - 1033
(2017/01/16)
-
- Mimicking the Main Events of the Biosynthesis of Drimentines: Synthesis of Δ8′-Isodrimentine A and Related Compounds
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Drimentines are a family of tetracyclic alkaloids biosynthetically originating from the condensation of sesquiterpene units onto cyclic dipeptides. A straightforward assembly of the fused “pyrroloindoline–diketopiperazine” core of drimentines is described herein and used for the synthesis of Δ8′-isodrimentine A. The strategy involves a bio-inspired indole dearomatization of a tryptophan-containing cyclodipeptide by a drimane-type decaline followed by the intramolecular trapping of the resulting indolenine intermediate in an uninterrupted reactive sequence. The starting diketopiperazine was prepared by classical peptidic coupling and the drimane-type decaline from (+)-sclareolide. A fully biomimetic approach with a linear sesquiterpene unit is also reported and led to farnesylated pyrroloindoline–diketopiperazines, which correspond to the proposed biosynthetic precursors of both drimentines A and D. The end product Δ8′-isodrimentine A and its congeners were evaluated in vitro for their cytotoxic activities against three human tumor cell lines.
- Skiredj, Adam,Beniddir, Mehdi A.,Evanno, Laurent,Poupon, Erwan
-
supporting information
p. 2954 - 2958
(2016/07/11)
-
- Organic Photocatalytic Cyclization of Polyenes: A Visible-Light-Mediated Radical Cascade Approach
-
A visible-light-mediated, organic photocatalytic stereoselective radical cascade cyclization of polyprenoids is described. The desired cascade cyclization products are achieved in good yields and high stereoselectivities with eosinY as photocatalyst in hexafluoro-2-propanol. The catalyst system is also suitable for 1,3-dicarbonyl compounds, which require only catalytic amounts of LiBr to promote the formation of the corresponding enols.
- Yang, Zhongbo,Li, Han,Zhang, Long,Zhang, Ming-Tian,Cheng, Jin-Pei,Luo, Sanzhong
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p. 14723 - 14727
(2015/10/19)
-
- Biphilic organophosphorus catalysis: Regioselective reductive transposition of allylic bromides via PIII/PV redox cycling
-
We report that a regioselective reductive transposition of primary allylic bromides is catalyzed by a biphilic organophosphorus (phosphetane) catalyst. Spectroscopic evidence supports the formation of a pentacoordinate (σ5-P) hydridophosphorane as a key reactive intermediate. Kinetics experiments and computational modeling are consistent with a unimolecular decomposition of the σ5-P hydridophosphorane via a concerted cyclic transition structure that delivers the observed allylic transposition and completes a novel PIII/PV redox catalytic cycle. These results broaden the growing repertoire of reactions catalyzed within the PIII/PV redox couple and suggest additional opportunities for organophosphorus catalysis in a biphilic mode.
- Reichl, Kyle D.,Dunn, Nicole L.,Fastuca, Nicholas J.,Radosevich, Alexander T.
-
supporting information
p. 5292 - 5295
(2015/05/13)
-
- Hybrid molecule from Farnesylthiosalicylic acid-diamine and phenylpropenoic acid as Ras-related signaling inhibitor with potent antitumor activities
-
Novel series of Farnesylthiosalicylic acid-diamine/phenylpropenoic acid hybrids were designed and synthesized. Their in vitro growth inhibitory assays showed that most compounds displayed strong antiproliferation activity against seven cancer cells. Especially, the new hybrid 12f, by the conjugation of 10a with ferulic acid, could selectively suppress the proliferation of tumor cells and display significantly lower toxicities to normal cells than its intermediate 10a. Furthermore, 12f dose-dependently induced SMMC-7721 cell apoptosis. Additionally, our observations demonstrated that 12f inhibited both Ras-related signaling and phosphorylated NF-κB synergistically, which may be advantageous to the strong antitumor activities of 12f. Our findings suggest that these novel hybrids may hold a great promise as therapeutic agents for the intervention of human cancers.
- Ling, Yong,Wang, Zhiqiang,Wang, Xuemin,Li, Xianghua,Wang, Xinyang,Zhang, Wei,Dai, Hong,Chen, Li,Zhang, Yihua
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p. 145 - 152
(2015/01/30)
-
- Hybrids from farnesylthiosalicylic acid and hydroxamic acid as dual ras-related signaling and histone deacetylase (HDAC) inhibitors: Design, synthesis and biological evaluation
-
Abstract A novel series of hybrids was designed and synthesized by combining key elements from farnesylthiosalicylic acid (FTS) and hydroxamic acid. Several 3,7,11-trimethyldodeca-2,6, 10-trien-1-yl) thio)benzamide derivatives, particularly those with bra
- Ling, Yong,Wang, Xuemin,Wang, Chenniu,Xu, Chenjun,Zhang, Wei,Zhang, Yihua,Zhang, Yanan
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p. 971 - 976
(2015/06/08)
-
- GGA DERIVATIVES
-
This invention relates to geranylgeranyl acetone (GGA) derivatives, pharmaceutical compositions comprising GGA derivatives and the use of GGA derivatives.
- -
-
Paragraph 0340; 0341
(2015/05/26)
-
- Synthesis and biological evaluation of farnesylthiosalicylamides as potential anti-tumor agents
-
Fourteen hybrids of farnesylthiosalicylic acid (FTS) with various diamines were synthesized and biologically evaluated. It was found that FTS-monoamide molecules (10a-g) displayed strong anti-proliferative activity against seven human cancer cell lines, superior to FTS and FTS-bisamide compounds (11a-g). The mono-amide 10f was the most active, with IC50s of 3.78-7.63 μM against all tested cancer cells, even more potent than sorafenib (9.12-22.9 μM). In addition, 10f induced SMMC-7721 cell apoptosis, down-regulated the expression of Bcl-2 and up-regulated Bax and caspase-3. Furthermore, 10f had the improved aqueous solubility relative to FTS. Finally, treatment with 10f dose-dependently inhibited the Ras-related signaling pathways in SMMC-7721 cells. Collectively, 10f could be a promising candidate for the intervention of human cancers.
- Ling, Yong,Wang, Zhiqiang,Zhu, Hongyan,Wang, Xuemin,Zhang, Wei,Wang, Xinyang,Chen, Li,Huang, Zhangjian,Zhang, Yihua
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p. 374 - 380
(2014/01/17)
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- Polyisoprenylated methylated protein methyl esterase: A putative biomarker and therapeutic target for pancreatic cancer
-
Pancreatic cancer is the most deadly neoplasm with a 5-year survival rate of less than 6%. Over 90% of cases harbor K-Ras mutations, which are the most challenging to treat due to lack of effective therapies. Here, we reveal that polyisoprenylated methyla
- Aguilar, Byron J.,Nkembo, Augustine T.,Duverna, Randolph,Poku, Rosemary A.,Amissah, Felix,Ablordeppey, Seth Y.,Lamango, Nazarius S.
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p. 323 - 333
(2014/06/09)
-
- Synthetic endeavors toward 2-nitro-4-alkylpyrroles in the context of the total synthesis of heronapyrrole C and preparation of a carboxylate natural product analogue
-
The synthesis of 2-nitro-4-oligoprenyl-substituted pyrrole derivatives relevant to the heronapyrroles and related natural products was investigated. Among numerous approaches, nitration of a 3-farnesyl-substituted unprotected pyrrole using AcONO2 gave the best results, albeit still with unsatisfactory yield and regioselectivity. Therefore, the synthesis of (-)-heronapyrrole C acid, an analogue of the naturally occurring antibiotic heronapyrrole C carrying a bioisosteric carboxylate in place of the nitro group, was examined. In lieu of the unsatisfactory nitration, a regioselective acylation with Cl3CCOCl was carried out (>8:1 regioselectivity, in contrast to the 1:1.3 ratio for the nitration). The trichloromethyl ketone was converted to the desired acid in a haloform reaction at the final stage of the synthesis. Further key steps of the analogue synthesis involved a position- and stereoselective Corey-Noe-Lin dihydroxylation and an organocatalytic double Shi epoxidation. A biomimetic polyepoxide cyclization cascade established the bis-THF backbone. Thus, (-)-heronapyrrole C acid was synthesized in eight steps (14.5% overall yield) from commercially available starting materials.
- Schmidt, Jens,Stark, Christian B. W.
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p. 1920 - 1928
(2014/04/03)
-
- Synthesis and biological evaluation of novel farnesylthiosalicylic acid derivatives for cancer treatment
-
Novel farnesylthiosalicylic acid (FTS) derivatives were synthesized by coupling with different substituted diamines. Their in vitro growth inhibitory activities against seven human cancer cell lines were evaluated. The results revealed that the synthetic farnesylthiosalicylamides displayed significant antitumor activities compared to the positive control FTS. Especially, compound 8f exhibited the strongest antitumor activities with IC50 values of 6.20-7.83 μM, which were one- to threefold less than those of sorafenib and six- to tenfold less than that of FTS against each cell line in vitro. Furthermore, 8f could inhibit the Ras-related signaling pathway and induce SMMC-7721 cell apoptosis superior to FTS in a dose-dependent manner. These data indicate that 8f may hold greater promise as therapeutic agent for the intervention of human cancers.
- Ling, Yong,Wang, Xuemin,Zhu, Hongyan,Wang, Zhiqiang,Xu, Chenjun,Wang, Xinyang,Chen, Li,Zhang, Wei
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p. 327 - 333
(2014/05/20)
-
- PROCESS FOR PREPARATION OF MK-7 TYPE OF VITAMIN K2
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Process for preparation of MK-7 type of vitamin K2 is characterized by attaching hexaprenyl chain of ?all-trans" configuration to monoprenyl derivative of menadiol following ?1 + 6" synthetic strategy. According to the invention, a-sulfonyl carbanion generated in situ from the protected monoprenyl menadiol of the formula (II), wherein R1 represents C1-3-alkyl group, is reacted with hexaprenyl halide of the formula (VII), wherein X represents halogen atom, preferably bromine, both Z' and Z' represent H or one of Z' and Z" represents H and the other represents phenylsulfonyl group -SO2Ph in the alkylation reaction. The hexaprenyl halide of formula (VII) is obtained by coupling two triprenyl units in alkylation reaction, with or without separation of the intermediates.
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-
Page/Page column 26; 27
(2014/05/07)
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- METHODS FOR TREATING NEURON DAMAGE
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This invention relates to the use of geranylgeranyl acetone (GGA), its isomers, and GGA derivatives in a method for for treating a disease in a subject mediated in part by miRNA-378 or miRNA-711 increased activity comprising administering to the subject a therapeutically effective amount of 5-trans-GGA or a derivative thereof.
- -
-
Paragraph 0292
(2014/07/22)
-
- Identification of CDP-archaeol synthase, a missing link of ether lipid biosynthesis in Archaea
-
Archaeal membrane lipid composition is distinct from Bacteria and Eukarya, consisting of isoprenoid chains etherified to the glycerol carbons. Biosynthesis of these lipids is poorly understood. Here we identify and characterize the archaeal membrane prote
- Jain, Samta,Caforio, Antonella,Fodran, Peter,Lolkema, Juke S.,Minnaard, Adriaan J.,Driessen, Arnold J.M.
-
supporting information
p. 1392 - 1401
(2014/12/11)
-
- Total synthesis of the proposed structure of astakolactin
-
The first total synthesis of the proposed structure of astakolactin, a sesterterpene metabolite isolated from the marine sponge Cacospongia scalaris, has been achieved, mainly featuring Johnson-Claisen rearrangement, asymmetric Mukaiyama aldol reaction an
- Tonoi, Takayuki,Mameda, Keisuke,Fujishiro, Moe,Yoshinaga, Yutaka,Shiina, Isamu
-
supporting information
p. 2421 - 2427
(2014/12/12)
-
- GGA AND GGA DERIVATIVES COMPOSITIONS THEREOF AND METHODS FOR TREATING NEURODEGENERATIVE DISEASES INCLUDING PARALYSIS INCLUDING THEM
-
This invention relates to geranylgeranyl acetone (GGA) derivatives and the use of GGA, its isomers, and GGA derivatives in methods for inhibiting neural death, increasing neural activity, increasing axon growth and cell viability, and increasing the survival rate of subjects administered the GGA or GGA derivatives.
- -
-
Paragraph 0279; 0280; 0283; 0291
(2014/10/18)
-
- Design, synthesis and anticancer activity evaluation of diazepinomicin derivatives
-
A series of diazepinomicin derivatives were synthesized and evaluated in vitro for their growth inhibitory activity against the human carcinoma cell lines. The results indicated the anticancer selectivity of this kind of compounds. Based on the results, preliminary structure-activity relationships were discussed.
- Yu, Yongguo,Wu, Jianbo,Lei, Fan,Chen, Lei,Wan, Weili,Hai, Li,Guan, Mei,Wu, Yong
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p. 369 - 373
(2013/07/26)
-
- A convergent stereocontrolled synthesis of [3-14C]solanesol
-
In this communication, we report the synthesis of 5 mCi of [3- 14C]solanesol (1) prepared from ethyl [3-14C]acetoacetate and (all-E)-octaprenyl bromide (2) in four steps, with a specific radioactivity of 19.83 mCi/mmol and with a chemical/ stereochemical and radiochemical purity of ≥ 95%. (Figure 1). Position 3 of the chain was selected for 14C labelling because of the metabolic stability of this position. Unlabelled (all-E)-octaprenyl (18) (Scheme 4) necessary for this work was prepared via a convergent iterative 'allyl-allyl' coupling approach of precursors easily derived from readily available inexpensive starting materials. Copyright
- Roe, Stephen J.,Oldfield, Mark F.,Geach, Neil,Baxter, Andrew
-
p. 485 - 491
(2014/03/21)
-
- GERANYLGERANYLACETONE DERIVATIVES
-
Provided herein are geranylgeranylacetone derivatives and methods of using them.
- -
-
Paragraph 0173
(2013/04/13)
-
- Membrane anchoring γ-secretase modulators with terpene-derived moieties
-
Modulation of γ-secretase activity is a promising therapeutic strategy for the treatment of Alzheimer's disease. Herein we report on the synthesis of carprofen- and tocopherol-derived small-molecule modulators carrying terpene moieties as lipophilic membrane anchors. Additionally, these modulators are equipped with an acidic moiety, which contributes to the desired modulatory effect on the γ-secretase with decreased formation of Aβ42 and increased Aβ38 production.
- Naumann, Eva Christine,G?ring, Stefan,Ogorek, Isabella,Weggen, Sascha,Schmidt, Boris
-
supporting information
p. 3852 - 3856
(2013/07/27)
-
- GGA AND GGA DERIVATIVES, COMPOSITIONS THEREOF AND METHODS FOR TREATING NEURODEGENERATIVE DISEASES INCLUDING PARALYSIS INCLUDING THEM
-
This invention relates to geranylgeranyl acetone (GGA) derivatives and the use of GGA, its isomers, and GGA derivatives in methods for inhibiting neural death, increasing neural activity, increasing axon growth and cell viability, and increasing the survival rate of subjects administered the GGA or GGA derivatives.
- -
-
Paragraph 0267; 0268; 0271
(2013/09/12)
-
- Synthesis of isoprenoid chain-contained chemical probes for an investigation of molecular interactions by using quartz crystal microbalance
-
Five probes including four that contained isoprenoid chain were synthesized. These probes were assembled onto the gold-coated quartz crystal chips for analysis of their interactions with four yeast proteins by using the quartz crystal microbalance technology. Results showed that 3-phosphoglycerate phosphokinase and triosephosphate isomerase had clear interactions with certain probes, while glutathione reductase and phosphoglucose isomerase gave much lower interaction signals. It also suggested that 3-phosphoglycerate phosphokinase had two sites interacting with the probe attached with a geranyl moiety. Further molecule simulation experiments provided supportive information on these intermolecular interactions. Together, our data suggested that there are hydrophobic interactions, with relatively good selectivity, between isoprenoid chain and proteins.
- Liu, Wujun,Zhang, Yixin,Hou, Shuhua,Zhao, Zongbao Kent
-
supporting information
p. 6208 - 6210
(2013/10/22)
-
- Synthesis of aurachin D and isoprenoid analogues from the myxobacterium Stigmatella aurantiaca
-
Aurachins, a family of isoprenoid quinoline alkaloids isolated from the myxobacterium Stigmatella aurantiaca, possess multiple interesting bioactivities and were subject of intensive studies of biosynthesis. In this Letter, we describe the efficient few step total synthesis of the parent compound aurachin D and two isoprenoid analogues via Conrad-Limpach cyclization. The main antimicrobial and cytotoxic profiles of these derivatives were explored.
- Dejon, Lisa,Speicher, Andreas
-
supporting information
p. 6700 - 6702
(2013/11/19)
-
- METHODS FOR TREATING NEURODEGENERATIVE DISEASES
-
This invention relates to the 5-cis and 5-trans isomers of geranylgeranyl acetone, preferably such synthetic isomers, and pharmaceutical compositions containing such isomers. Other aspects of this invention relate to the use of geranylgeranyl acetone and its isomers in methods for inhibiting neural death, increasing neural activity, and increasing axon growth and cell viability. Geranylgeranyl acetone is a known anti-ulcer drug used commercially and in clinical situations. GGA has also been shown to exert cytoprotective effects on a variety of organs, such as the eye, brain, and heart.
- -
-
Page/Page column 33
(2012/03/26)
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- A stereoselective hydroamination transform to access polysubstituted indolizidines
-
Stereoselective, intramolecular, formal hydroamination of dienamines via directed hydroboration is reported. Four stereocenters are set in the process. Natural and unnatural indolizidine alkaloids can be synthesized from simple unsaturated amines using the title process.
- Pronin, Sergey V.,Tabor, M. Greg,Jansen, Daniel J.,Shenvi, Ryan A.
-
supporting information; experimental part
p. 2012 - 2015
(2012/03/12)
-
- Modular synthesis of diphospholipid oligosaccharide fragments of the bacterial cell wall and their use to study the mechanism of moenomycin and other antibiotics
-
We present a flexible, modular route to GlcNAc-MurNAc-oligosaccharides that can be readily converted into peptidoglycan (PG) fragments to serve as reagents for the study of bacterial enzymes that are targets for antibiotics. Demonstrating the utility of these synthetic PG substrates, we show that the tetrasaccharide substrate lipid IV (3), but not the disaccharide substrate lipid II (2), significantly increases the concentration of moenomycin A required to inhibit a prototypical PG-glycosyltransferase (PGT). These results imply that lipid IV and moenomycin A bind to the same site on the enzyme. We also show the moenomycin A inhibits the formation of elongated polysaccharide product but does not affect length distribution. We conclude that moenomycin A blocks PG-strand initiation rather than elongation or chain termination. Synthetic access to diphospholipid oligosaccharides will enable further studies of bacterial cell wall synthesis with the long-term goal of identifying novel antibiotics.
- Gampe, Christian M.,Tsukamoto, Hirokazu,Wang, Tsung-Shing Andrew,Walker, Suzanne,Kahne, Daniel
-
experimental part
p. 9771 - 9778
(2012/02/15)
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- Transpeptidase-mediated incorporation of d-amino acids into bacterial peptidoglycan
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The β-lactams are the most important class of antibiotics in clinical use. Their lethal targets are the transpeptidase domains of penicillin binding proteins (PBPs), which catalyze the cross-linking of bacterial peptidoglycan (PG) during cell wall synthesis. The transpeptidation reaction occurs in two steps, the first being formation of a covalent enzyme intermediate and the second involving attack of an amine on this intermediate. Here we use defined PG substrates to dissect the individual steps catalyzed by a purified E. coli transpeptidase. We demonstrate that this transpeptidase accepts a set of structurally diverse d-amino acid substrates and incorporates them into PG fragments. These results provide new information on donor and acceptor requirements as well as a mechanistic basis for previous observations that noncanonical d-amino acids can be introduced into the bacterial cell wall.
- Lupoli, Tania J.,Tsukamoto, Hirokazu,Doud, Emma H.,Wang, Tsung-Shing Andrew,Walker, Suzanne,Kahne, Daniel
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supporting information; experimental part
p. 10748 - 10751
(2011/09/13)
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- N-Methylimidazolium chloride-catalyzed pyrophosphate formation: Application to the synthesis of Lipid i and NDP-sugar donors
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N-Methylimidazolium chloride is found to catalyze a coupling reaction between monophosphates and activated phosphorous-nitrogen intermediates such as a phosphorimidazolide and phosphoromorpholidate to form biologically important unsymmetrical pyrophosphat
- Tsukamoto, Hirokazu,Kahne, Daniel
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supporting information; experimental part
p. 5050 - 5053
(2011/10/09)
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- PROCESS FOR THE PREPARATION OF VITAMIN K2
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A new process for making polyprenols is described as well as the use of these building blocks in the synthesis of Vitamin K2. The process involves reaction of a compound of formula (X) with a compound of formula (XI) in the presence of a base so as to form a compound of formula (XII) and conversion of that compound into a compound of formula (XIII).
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Page/Page column 31
(2011/10/13)
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- Carbenium ion trapping using sulfonamides: an acid-catalysed synthesis of pyrrolidines by intramolecular hydroamination
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Cyclisations of homoallylic sulfonamides proceed smoothly via carbenium ion generation using trifluoromethanesulfonic (triflic) acid, the ease of cyclisation being directly related to the ion stability to give good to excellent yields of the corresponding pyrrolidines. Both toluene- and nitrophenyl-sulfonyl groups are suitable for all substrates tested whereas the corresponding carbamates are only useful in cases of tertiary and highly stabilised carbenium ions. Polyene-derived sulfonamides can also be cyclised to the corresponding polycyclic systems in remarkably high yields, in reactions reminiscent of related cascades encountered in terpene biosynthesis.
- Griffiths-Jones (née Haskins), Charlotte M.,Knight, David W.
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experimental part
p. 4150 - 4166
(2010/07/05)
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- Expedient access to A-ring -α Dioxygenated terpenoids: The first synthesis of (13E)- ent -labda-8(17),13-diene-3β,15,18-triol
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A simple approach to A-ring - dioxygenated terpenoids is described which involves two key steps, namely, selenium-catalyzed selective allylic chlorination of polyprenoids and titanocene-mediated radical cyclization of epoxypolyprenes. We have applied this synthetic route to the first synthesis of the diterpene, (13E)-ent-labda-8(17),13-diene-3,15,18-triol. A stereoselective approach to this synthesis is also described.
- Domingo, Victoriano,Dieguez, Horacio R.,Morales, Carmen P.,Arteaga, Jesus F.,Qulezdelmoral, Jose F.,Barrero, Alejandro F.
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experimental part
p. 67 - 72
(2010/05/02)
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- Stereo- and regioselective synthesis of squalene tetraepoxide
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(Chemical Equation Presented) Squalene tetraepoxide, a putative biosynthetic precursor to a variety of oxacyclic triterpenoid natural products, has been efficiently synthesized by anionic coupling of two farnesol-derived diepoxides, which have arisen from
- Tong, Rongbiao,Boone, Matthew A.,McDonald, Frank E.
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experimental part
p. 8407 - 8409
(2010/02/17)
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- Method for Preparing Isoprenyl Cysteine Compounds and Analogs Thereof
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Methods of preparing isoprenyl cysteine compounds by coupling a cysteine compound with an activated (i.e. halogenated) lipid are disclosed. Also disclosed, among other things, are methods of making activated (i.e. halogenated) lipids, and methods of purifying isoprenyl cysteine compounds.
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Page/Page column 12-13
(2009/08/14)
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- Reviewing the polyolefin cyclization reaction of the C35 polyprene catalyzed by squalene-hopene cyclase
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Squalene-hopene cyclase (SHC) catalyzes the polycyclization of squalene (C30) to the pentacyclic hopene with regio- and stereochemical specificity. In this study, we reviewed the polycyclization reaction of the C35 polyprenoid cataly
- Hoshino, Tsutomu,Kumai, Yuko,Sato, Tsutomu
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supporting information; experimental part
p. 2091 - 2100
(2009/09/06)
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- New efficient synthesis of ubiquinones
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A strategy for the ecofriendly and high-yielding synthesis of ubiquinones starting from simple materials and using mild conditions is reported. CoQ1, CoQ2, CoQ3, and CoQ9 were prepared. Copyright Taylor & Francis Group, LLC.
- Bovicelli, Paolo,Borioni, Giorgio,Fabbrini, Danilo,Barontini, Maurizio
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p. 391 - 400
(2008/04/01)
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- Rapid and enantioselective synthetic approaches to germanicol and other pentacyclic triterpenes
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Two exceedingly short synthetic routes to the key intermediate 2 for the synthesis of the pentacyclic triterpene germanicol 1 have been developed. In the first, the (S)-epoxide of farnesyl bromide is transformed in just three steps to the tetracyclic intermediate 7, which is converted to chiral 2 by treatment with polyphosphoric acid. The second synthetic route to 2 involves the coupling of the (S)-epoxide 8 with vinyl iodide 9 to give 10 and two-stage acid-catalyzed cyclization of 10 to form 2. During the course of this work we have also discovered a very unusual intramolecular 1,5-proton shift from a carbocation to a C-C double bond. The details of the process have been confirmed by 2H-labeling experiments.
- Surendra, Karavadhi,Corey
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supporting information; experimental part
p. 8865 - 8869
(2009/02/03)
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- Semisynthesis and antiplasmodial activity of the quinoline alkaloid aurachin E
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A one-step synthesis of the rare aurachin E (1) from the easily accessible aurachin C (2) and cyanogen bromide is described. 3-Bromocarbamoylquinoline (5) is formed in a side reaction with concomitant loss of the 3-farnesyl residue. In an alternative approach, aurachin D (3) was reacted with phosgene and sodium azide to form the imidazolone ring of 1 via n-acylation. Unexpectedly, the initial reaction occurred at the carbonyl group of 3 to give 1H-pyrrolo[3,2-c]quinoline 4. The reaction sequence represents a novel route to this type of compound. Aurachin E, contrary to other aurachins, combines a high in vitro antiplasmodial activity with low cytotoxicity and absence of mitochondrial respiratory inhibition.
- Hoefle, Gerhard,Boehlendorf, Bettina,Fecker, Thomas,Sasse, Florenz,Kunze, Brigitte
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experimental part
p. 1967 - 1969
(2009/08/14)
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