7013-07-2Relevant academic research and scientific papers
Design, synthesis, and biological evaluation of simplified side chain hybrids of the potent actin binding polyketides rhizopodin and bistramide
Herkommer, Daniel,Dreisigacker, Sandra,Sergeev, Galina,Sasse, Florenz,Gohlke, Holger,Menche, Dirk
, p. 470 - 489 (2015/04/21)
The natural products rhizopodin and bistramide belong to an elite class of highly potent actin binding agents. They show powerful antiproliferative activities against a range of tumor cell lines, with IC50 values in the low-nanomolar range. At the molecular level they disrupt the actin cytoskeleton by binding specifically to a few critical sites of G-actin, resulting in actin filament stabilization. The important biological properties of rhizopodin and bistramide, coupled with their unique and intriguing molecular architectures, render them attractive compounds for further development. However, this is severely hampered by the structural complexity of these metabolites. We initiated an interdisciplinary approach at the interface between molecular modeling, organic synthesis, and chemical biology to support further biological applications. We also wanted to expand structure-activity relationship studies with the goal of accessing simplified analogues with potent biological properties. We report computational analyses of actin-inhibitor interactions involving molecular docking, validated on known actin binding ligands, that show a close match between the crystal and modeled structures. Based on these results, the ligand shape was simplified, and more readily accessible rhizopodin-bistramide mimetics were designed. A flexible and modular strategy was applied for the synthesis of these compounds, enabling diverse access to dramatically simplified rhizopodin-bistramide hybrids. This novel analogue class was analyzed for its antiproliferative and actin binding properties.
Total synthesis of (+)-negamycin and its 5-epi-derivative
Nishiguchi, Shigenobu,Sydnes, Magne O.,Taguchi, Akihiro,Regnier, Thomas,Kajimoto, Tetsuya,Node, Manabu,Yamazaki, Yuri,Yakushiji, Fumika,Kiso, Yoshiaki,Hayashi, Yoshio
experimental part, p. 314 - 320 (2010/03/01)
(+)-Negamycin was prepared in 13 steps in an overall yield of 31% from commercially available ethyl (R)-(+)-4-chloro-3-hydroxybutanoate. The key step in the reaction sequence was a highly stereoselective asymmetric Michael addition of chiral amine (-)-21
An efficient transformation of cyclic ene-carbamates into ω-(N-formylamino)carboxylic acids by ruthenium tetroxide oxidation
Kaname, Mamoru,Yoshifuji, Shigeyuki,Sashida, Haruki
experimental part, p. 1310 - 1313 (2009/11/30)
The ruthenium tetroxide (RuO4) oxidation of cyclic ene-carbamates resulted in the endo-cyclic carbon-carbon double bond cleavage to afford the corresponding ω-(N-formylamino)carboxylic acids in good yields. Substituted cyclic ene-carbamates der
Asymmetric synthesis of (R)-(-)-carnitine
Jain, Rajendra P.,Williams, Robert M.
, p. 4437 - 4440 (2007/10/03)
A TiCl4-promoted Mukaiyama-type aldol reaction of the ketenesilyl acetal of ethyl acetate with the lactone carbonyl of (5R,6S)-4-(benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazin- 2-one (1) proceeds with a high degree of diastereoselectivity. The TBDMS-protected hemiketal thus obtained was efficiently converted into highly enantiomerically enriched (R)-(-)-carnitine by following an elimination-reduction protocol. This approach further demonstrates the utility of commercially available glycine template 1 as a potential substrate for the asymmetric synthesis of both enantiomers of carnitine.
Stereospecific synthesis of functionalized ether phospholipids
Kazi, Abul B.,Shidmand, Sean,Hajdu, Joseph
, p. 9337 - 9347 (2007/10/03)
A new stereospecific synthesis of functionalized alkyl ether phospholipids is reported. The synthesis is based upon the following: (1) the use of (R)-glycidyl tosylate as a chiral glycerol precursor; (2) the opening of a boron trifluoride catalyzed epoxide ring to introduce the functionalized sn-1-alkyl substituents; (3) the role of tetrahydropyranyl in protecting the sn-2-glycerol position; and (4) the elaboration of the sn-3-carbinol function, via the base hydrolysis of the acetoxy intermediate, obtained from the displacement of the toluenesulfonyl group of the substrate in dipolar aprotic media. Phosphorylation, using two different methods, has led to the development of two major classes of alkyllysophospholipids. For preparation of 'modulator-phospholipid' analogues, the substituted glycerol is coupled with 2,2,2-trichloro-tert-butyl phosphodichloridite and an N-protected amino acid ester, while elaboration of the phosphocholine headgroup of the target platelet-activating factor (PAF) analogues is achieved via the 2-chloro-2- oxo-1,3,2-dioxaphospholane/trimethylamine sequence. The synthesis provides rapid and efficient access to both types of phospholipids: (1) construction of the functionalized/substituted glycerol skeleton is achieved in a straightforward four-step sequence in better than 50% overall yield, and (2) phosphitylation or phosphorylation of the respective glycerol intermediates relies on reagents that require minimal use of protecting groups. The phospholipid compounds prepared include (1) the first synthetic analogue exhibiting modulator activity in conjunction with the glucocorticoid-receptor complex and (2) an sn-1-(ωamino)alkyl derivative of PAF, suitable for introduction of chain-terminal spectroscopic labels for biological and physicochemical studies to elucidate the mechanism of action of this highly potent alkyl ether phospholipid. The synthetic methods described herein have a great deal of flexibility, thus providing convenient general routes to a wide range of alkyl ether phospholipids.
A Facile Synthesis of (R)-4-Amino-3-hydroxybutanoic Acid (GABOB) from 3-Hydroxypyridine
Sakagami, Hideki,Kamikubo, Takashi,Ogasawara, Kunio
, p. 221 - 222 (2007/10/03)
(R)-4-Amino-3-hydroxybutanoic acid (GABOB) has been synthesized facilely from 3-hydroxypyridine via 1-carbobenzoxy-1,2,3,4-tetrahydro-3-hydroxypyridine employing lipase-mediated kinetic resolution.
Short and Practical Syntheses of (R)-(-)-Carnitine and (R)-(-)-γ-Amino-β-hydroxybutyric Acid (GABOB)
Kolb, Hartmuth C.,Bennani, Youssef L.,Sharpless, K. Barry
, p. 133 - 141 (2007/10/02)
Short and practical syntheses of (R)-(-)-carnitine and (R)-(-)-γ-amino-β-hydroxybutyric acid have been developed, both commencing with the catalytic asymmetric dihydroxylation of allyl bromide.
Baker's yeast reduction of N-protected methyl 4-amino-3-oxobutanoates and 3-oxopentanoates
Hashiguchi,Kawada,Natsugari
, p. 403 - 408 (2007/10/02)
Baker's yeast reduction of N-tert-butoxycarbonyl (Boc) or N-benzyloxycarbonyl (Cbz) protected methyl 4-amino-3-oxopentanoates 4b-e and 4-amino-3-oxobutanoates 7a,b stereoselectively afforded the erythro-hydroxy esters 5b-e and (R)-hydroxy esters 8a,b, res
Oxaziridine-mediated ring expansions of substituted cyclobutanones: Synthesis of (-)-γ-amino-β-hydroxybutyric acid (GABOB)
Aube,Wang,Ghosh,Langhans
, p. 693 - 701 (2007/10/02)
The synthesis and photochemical rearrangement chemistry of oxaziridines derived from 3-benzyloxy- and 3-phenylcyclobutanone were examined. The oxaziridines were prepared by condensation of the ketones with α-methylbenzylamine followed by oxidation. Photolysis at 254 nm afforded good yields of readily separable lactams; 4-benzyloxy-pyrrolidin-2-one obtained in this way was converted to 4-amino-3-hydroxybutanoic acid (GABOB) by catalytic hydrogenolysis followed by acid hydrolysis.
