- Enantiodivergent syntheses of (+)- and (?)-1-(2,6-dimethylphenoxy)propan-2-ol: A way to access (+)- and (?)-mexiletine from D-(+)-mannitol
-
Chiron approach was used to acquire optically pure (R)- and (S)-1-(2,6-dimethylphenoxy)propan-2-ol, immediate precursors of (S)- and (R)-mexiletines, respectively. Two different routes were followed from a D-mannitol-derived optically pure common precursor to get the enantiomeric alcohols separately. Comparison of their specific rotation values with the corresponding literature values as well as exact mirror-image relationship between their CD curves proved their high enantiopurity. These alcohols were then transformed to the corresponding amine-drugs in an efficient one-step process instead of two steps described in the literature.
- Manna, Avrajit,Chatterjee, Sandip,Chakraborty, Ipsita,Bhaumik, Tanurima
-
-
- Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic
-
Itraconazole (ITZ) is an FDA-approved member of the triazole class of antifungal agents. Two recent drug repurposing screens identified ITZ as a promising anticancer chemotherapeutic that inhibits both the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized and evaluated first- and second-generation ITZ analogues for their anti-Hh and antiangiogenic activities to probe more fully the structural requirements for these anticancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochemically defined des-triazole ITZ analogues also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anticancer properties of the ITZ scaffold.
- Pace, Jennifer R.,Deberardinis, Albert M.,Sail, Vibhavari,Tacheva-Grigorova, Silvia K.,Chan, Kelly A.,Tran, Raymond,Raccuia, Daniel S.,Wechsler-Reya, Robert J.,Hadden, M. Kyle
-
supporting information
p. 3635 - 3649
(2016/05/24)
-
- SMALL MOLECULE INHIBITORS OF FIBROSIS
-
Described herein are compounds and compositions for the treatment of a fibrotic disease.
- -
-
Paragraph 00472; 00478
(2016/06/28)
-
- A Clickable and Photocleavable Lipid Analogue for Cell Membrane Delivery and Release
-
For drug delivery purposes, the ability to conveniently attach a targeting moiety that will deliver drugs to cells and then enable controlled release of the active molecule after localization is desirable. Toward this end, we designed and synthesized clickable and photocleavable lipid analogue 1 to maximize the efficiency of bioconjugation and triggered release. This compound contains a dibenzocyclooctyne group for bioorthogonal derivatization linked via a photocleavable 2-nitrobenzyl moiety at the headgroup of a synthetic lipid backbone for targeting to cell membranes. To assess delivery and release using this system, we report fluorescence-based assays for liposomal modification and photocleavage in solution as well as through surface immobilization to demonstrate successful liposome functionalization and photoinduced release. In addition, fluorophore delivery to and release from live cells was confirmed and characterized using fluorescence microscopy and flow cytometry analysis in which 1 was delivered to cells, derivatized, and photocleaved. Finally, drug delivery studies were performed using an azide-tagged analogue of camptothecin, a potent anticancer drug that is challenging to deliver due to poor solubility. In this case, the ester attachment of the azide tag acted as a caging group for release by intracellular esterases rather than through photocleavage. This resulted in a dose-dependent response in the presence of liposomes containing delivery agent 1, confirming the ability of this compound to stimulate delivery to the cytoplasm of cells.
- Alam, Shahrina,Alves, Daiane S.,Whitehead, Stuart A.,Bayer, Andrew M.,McNitt, Christopher D.,Popik, Vladimir V.,Barrera, Francisco N.,Best, Michael D.
-
p. 1021 - 1031
(2015/06/30)
-
- Asymmetric synthesis and effect of absolute stereochemistry of YCZ-2013, a brassinosteroid biosynthesis inhibitor
-
The four stereoisomers of 2RS,4RS-1-[[2-(2,4-dichlorophenyl)-4-(2-(2- propenyloxy)phenoxymethyl)-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole (YCZ-2013), a novel brassinosteroid biosynthesis inhibitor, were prepared. The diastereomers of 2RS,4R-5 and 2RS,4S-5 were prepared by using the corresponding optically pure R and S toluene-4-sulfonic acid 2,3-dihydroxypropyl ester (R-4,S-4). The enatiomerically and diastereomerically pure acetonide (5) was obtained by a method involving diastereoselective crystallisation of the tosylate salt, followed by re-equilibration with the mother liquor and chromatography. The optical purity of four target compounds (YCZ-2013) was confirmed by chiral high-performance liquid chromatography (HPLC) and NMR. The effects of these stereoisomers on Arabidopsis stem elongation indicated that the cis isomers of 2S,4R-YCZ-2013 and 2R,4S-YCZ-2013 exhibited potent inhibitory activity with IC50 values of approximately 24 ± 3 and 24 ± 2 nM, respectively. The IC50 values of the trans isomers of 2S,4S-YCZ-2013 and 2R,4R-YCZ-2013 are approximately 1510 ± 50 and 3900 ± 332 nM, respectively. Co-application of brassinolide (10 nM), the most potent BR, and GA3 (1 μM) to Arabidopsis seedlings grown in the dark with 2R,4S-YCZ-2013 and 2S,4R-YCZ-2013 revealed that brassinolide recovered the induced dwarfism of Arabidopsis seedlings, whereas GA3 showed no effect.
- Oh, Keimei,Yamada, Kazuhiro,Yoshizawa, Yuko
-
p. 6915 - 6919
(2014/01/06)
-
- A new synthesis of lysophosphatidylcholines and related derivatives. Use of p-toluenesulfonate for hydroxyl group protection
-
A new stereoselective synthesis of lysophosphatidylcholines is reported. The synthesis is based upon (1) the use of 3-p-toluenesulfonyl-sn-glycerol to provide the stereocenter for construction of the optically active lysophospholipid molecule, (2) tetrahydropyranylation of the secondary alcohol function to achieve orthogonal protection of the sn-2- and sn-3-glycerol positions, and (3) elaboration of the phosphodiester headgroup using a 2-chloro-1,3,2-dioxaphospholane/trimethylamine sequence. In the course of developing the synthesis it has been discovered that methoxyacetate displacement of the sn-3-p-toluenesulfonate yields a reactive methoxyacetyl ester, which in turn can be selectively cleaved with methanol/tertbutylamine, while the ester group at the sn-1-position remains unaffected. The sequence has been shown to be suitable for preparation of spectroscopically labeled lysophosphatidylcholines. One of these compounds was readily converted to a double-labeled mixed-chain phosphatidylcholine applicable for real-time fluorescence resonance energy transfer (FRET) assay of lipolytic enzymes. In addition, the work led to new synthetic strategies based on chemoselective manipulation of the tosyl group in the presence of other base-labile groups such as FMOC derivatives that are often used for the protection of amino and hydroxyl groups in syntheses.
- Rosseto, Renato,Bibak, Niloufar,DeOcampo, Rosemarie,Shah, Trishul,Gabrielian, Ara,Hajdu, Joseph
-
p. 1691 - 1698
(2007/10/03)
-
- Nucleophilic reaction of glycidol tosylate and the corresponding cyclic sulfate with various nucleophiles: A comparative study
-
The nucleophilic reaction of glycidol tosylate and the corresponding cyclic sulfate tosylate have been carried out with a number of nucleophiles to study the possible attack of nucleophiles at C1, C2 or C3 positions. The regioselectivity and reactivity of both the substrates i.e. epoxide tosylate 1 and the corresponding cyclic sulfate 2 have been compared and established that under similar conditions cyclic sulfate counterpart shows better regioselectivity and better reactivity than the corresponding epoxide.
- Lohray,Rajesh,Bhushan
-
p. 586 - 592
(2007/10/03)
-
- Polymer-aided stereodivergent synthesis (PASS): A new concept for the discrete preparation of optical antipodes
-
A new concept to the discrete prepartion of optical antipodes is reported. The approach makes use of a cyclization/cleavage procedure that has been applied to polymer-supported quasi-meso compound 1, containing a polymeric leaving group and a regular leaving group. Two-directional cyclization leads to the formation and separation of quasi-enantiomers 2 and 3 simultaneously, with one being immobilized and on free in solution. Treatment of 2 and 3 with appropriate nucleophiles gives discrete enantiomers 4 and 5.
- Ten Holte, Peter,Thijs, Lambertus,Zwanenburg, Binne
-
p. 1093 - 1095
(2007/10/03)
-
- Assignment of the stereochemistry of spiroxamine by two-dimensional NMR spectroscopy and stereoselective chemical synthesis
-
Spiroxamine is a new powdery mildew fungicide in cereals consisting of four biologically active isomers (two diastereomers, four enantiomers). The four isomers were separated by preparative high-performance liquid chromatography (HPLC) on a chiral stationary phase. At this stage it was not possible to assign their stereochemistry. Using stereoselective synthesis starting with the corresponding chirally pure glycerol derivates, the configuration at the asymmetric center, could be fixed. The resulting diastereomers were separated by preparative HPLC. Using COSY, HSQC and NOESY NMR spectroscopy it was possible to assign the configuration of the amino residue relative to the cyclohexyl ring. The 600 MHz 1H NMR spectra permitted a complete assignment of all proton signals. The stereochemical assignment is based on NOEs observed in the NOESY spectrum.
- Etzel,Gau,Kraemer,Stelzer,Weissmueller
-
-
- Eine neue Ligandenklasse fuer die asymmetrische Dihydroxylierung von Olefinen
-
Keywords: Asymmetrische Dihydroxylierungen; Chirale Liganden; Chinchonaalkaloide; Katalyse; Osmiumverbindungen
- Becker, Heinrich,Sharpless, K. Barry
-
p. 447 - 449
(2007/10/03)
-
- GENERAL METHOD OF PREPARATION OF N- DERIVATIVES OF HETEROCYCLIC BASES
-
Reaction of (R)-1-O-p-toluenesulfonyl-1,2,3-propanetriol (IV) with N-trimethylacetylimidazole (II) afforded (R)-1-O-p-toluenesulfonyl-3-O-trimethylacetyl-1,2,3-propanetriol (V) which was reacted with dimethoxymethane in the presence of phosphorus pentoxide to give (R)-2-O-methoxymethyl-1-O-p-toluenesulfonyl-3-O-trimethylacetyl-1,2,3-propanetriol (VI).Compound VI was treated with acetic anhydride and boron trifluoride etherate and the obtained 2-acetoxy derivative VII reacted with bromotrimethylsilane to give the intermediary bromomethyl ether VIII.Compound VIII on reaction with tris(2-propyl) phosphite afforded (R)-2-O-bis(2-propyl)phosphonomethyl-1-O-p-toluenesulfonyl-3-O-trimethylacetyl-1,2,3-propanetriol (IX).Condensation of synthon IX with sodium salts of adenine, 2,6-diaminopurine, or with cytosine, 6-azacytozine or 2-chloroadenine in the presence of cesium carbonate, afforded fully protected diesters X and XIIIb which on methanolysis and reaction with bromotrimethylsilane gave N- derivatives of adenine (XIa), 2-chloroadenine (XIb), 2,6-diaminopurine (XIc), cytosine (XIVa) and 6-azacytosine (XIVb).In an analogous reaction, sodium salt of 4-methoxy-2-pyrimidone reacted with compound IX to give an intermediate XIIIa which on treatment with methanolic ammonia and subsequent deblocking under the same conditions also afforded the cytosine derivative XIVa.Sodium salt of 2-amino-6-chloropurine was in this way converted into the corresponding 2-aminopurine derivative XVIII.Deprotection of this compound gave 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)-2-aminopurine (XIX).
- Alexander, Petr,Holy, Antonin
-
p. 1151 - 1163
(2007/10/02)
-
- Enzymatic Resolution of 1,2-Diols: Comparison between Hydrolysis and Transesterification Reactions
-
A new practical procedure for the enzymatic resolution of 1,2-diols 1a-e has been developed by lipase-catalysed regio- and enantio-selective esterification using anhydrides as acylating agents in organic solvents.
- Bosetti, Aldo,Bianchi, Daniele,Cesti, Pietro,Golini, Paolo,Spezia, Sandro
-
p. 2395 - 2398
(2007/10/02)
-
- Synthesis of optically active lipopeptide analogs from the outer membrane of Escherichia coli
-
The synthesis of optically active lipopeptide derivatives has been accomplished by the use of chiral glycerol derivatives. Lipopeptide derivatives with (R)-glycerol moieties showed higher mitogenic activities than those with the (S)-configuration. N-2,2,2-Trichloroethoxycarbonyl lipopeptide derivatives increased mitogenic activity.
- Kurimura,Takemoto,Achiwa
-
p. 2590 - 2596
(2007/10/02)
-
- Synthesis of biologically active acycloazt derivatives and related compounds
-
The synthesis of optically active acyclic analogues of 3'-azido-3'-deoxythymidine, which lack only the 2'-CH2 of the sugar, is described. The synthesis of some nucleoside analogues that contain the N-acetyl-D-neuraminic acid moiety is also described.
- Murata,Achiwa
-
p. 836 - 838
(2007/10/02)
-
- Synthesis and pharmacological screening of new phenylpiperazinepropane derivatives and their enantiomers
-
Enantiomers of phenylpiperazine-1,2-diol derivatives were synthesized with the purpose to obtain a better antitussive activity/sedative effect ratio. (S)-isomers showed better pharmacological profiles than (R)-isomers and corresponding racemates. Among the (S)-isomers, the unsubstituted compound, levodropropizine (S(-)-3-(4-phenylpiperazin-1-yl)propane-1,2-diol, DF 526), has the most favourable antitussive activity/sedative effect ratio and was selected for pharmacotoxicological evaluation.
- Giani,Marinone,Melillo,Borsa,Tonon
-
p. 1139 - 1141
(2007/10/02)
-
- Process for the preparation of optically-active carbazole derivatives, new R- and S-carbazole derivatives and pharmaceutical compositions containing these compounds
-
A process for the preparation of S- or R-carbazole derivatives of the general formula: STR1 in which R is an unsubstituted or substituted amino radical and pharmacologically acceptable salts, by either reacting R-(-)-epichlorohydrin (for the S-carbazole derivative); or reacting an S-epoxide derivative of the general formula: STR2 in which R1 is the residue of a substituted sulphonic acid derivative (for the R-carbazole derivative); with 4-hydroxycarbazole and then with ammonia or a substituted amine of the general formula RH, and recovering the compound or converting it to a pharmacologically acceptable salt. The new R-(+)- and S(-)-carbazole derivatives provided by the inventive process have unexpected beta blocking and vasodilatory properties and are useful in pharmaceutical compositions. R-(+)-carbazole derivatives are also useful for the treatment of glaucoma.
- -
-
-
- Preparation of epihalohydrin enantiomers
-
Processes for preparing (S) or (R) epihalohydrin and an (S) substituted glycerol intermediate are disclosed.
- -
-
-
- Preparation of epihalohydrin enantiomers
-
Processes for preparing (S) or (R) epihalohydrin and an (S) substituted glycerol intermediate are disclosed.
- -
-
-
