Synthesis of an 11-unsubstituted analogue of (±)-huperzine A

Camps, Pelayo; Contreras, Joan Picas; Morral, Jordi; Muñoz‐Torrero, Diego; Font-Bardı́a, Mercè; Soláns, Xavier

doi:10.1016/s0040-4020(99)00434-2

Cited by 10 publications

(2 citation statements)

References 51 publications

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“…Figure 7 shows that the Cl atom of huprine X lies in a small hydrophobic pocket in the active site of TcAChE. Participation of Leu333 in this binding pocket, as suggested by theoretical studies (29), is not supported by the X-ray data, since its closest atom (L333Cδ2) is >5 Å away from the Cl atom. Since the binding affinity decreases upon replacement of chlorine by a methyl or fluorine (31), it is plausible that close contact dispersion forces are responsible for the higher affinity of the former due to its optimal fit in the binding pocket.…”

Section: Species Specificity the K I Values Displayed In Tablementioning

confidence: 92%

“…Indeed, in the case of AChE, determination of the 3D structures of the appropriate ligand-AChE complexes was a prerequisite for making correct structural assignments for (-)-huperzine A (9), donepezil (16), and galanthamine (11), as well as for the snake venom toxin, fasciculin-II (27,28). Thus, the experimental determination of the 3D structure of huprine X complexed with TcAChE seemed desirable for comparison with the theoretical predictions obtained by docking protocols (29,30). This structure, taken together with data obtained from recent synthetic modifications (26,31), could provide the basis for structure-based drug design aimed at generating a second generation of huprine X analogues.…”

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confidence: 99%

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3D Structure of Torpedo californica Acetylcholinesterase Complexed with Huprine X at 2.1 Å Resolution: Kinetic and Molecular Dynamic Correlates^,

et al. 2002

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Huprine X is a novel acetylcholinesterase (AChE) inhibitor, with one of the highest affinities reported for a reversible inhibitor. It is a synthetic hybrid that contains the 4-aminoquinoline substructure of one anti-Alzheimer drug, tacrine, and a carbobicyclic moiety resembling that of another AChE inhibitor, (-)-huperzine A. Cocrystallization of huprine X with Torpedo californica AChE yielded crystals whose 3D structure was determined to 2.1 A resolution. The inhibitor binds to the anionic site and also hinders access to the esteratic site. Its aromatic portion occupies the same binding site as tacrine, stacking between the aromatic rings of Trp84 and Phe330, whereas the carbobicyclic unit occupies the same binding pocket as (-)-huperzine A. Its chlorine substituent was found to lie in a hydrophobic pocket interacting with rings of the aromatic residues Trp432 and Phe330 and with the methyl groups of Met436 and Ile439. Steady-state inhibition data show that huprine X binds to human AChE and Torpedo AChE 28- and 54-fold, respectively, more tightly than tacrine. This difference stems from the fact that the aminoquinoline moiety of huprine X makes interactions similar to those made by tacrine, but additional bonds to the enzyme are made by the huperzine-like substructure and the chlorine atom. Furthermore, both tacrine and huprine X bind more tightly to Torpedo than to human AChE, suggesting that their quinoline substructures interact better with Phe330 than with Tyr337, the corresponding residue in the human AChE structure. Both (-)-huperzine A and huprine X display slow binding properties, but only binding of the former causes a peptide flip of Gly117.

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Section: Species Specificity the K I Values Displayed In Tablementioning

confidence: 92%

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confidence: 99%

3D Structure of Torpedo californica Acetylcholinesterase Complexed with Huprine X at 2.1 Å Resolution: Kinetic and Molecular Dynamic Correlates^,

et al. 2002

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The Barton‐McCombie Reaction

2012

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Deoxygenations of alcohols, i.e., processes that replace a hydroxyl group with hydrogen at a saturated carbon, find applications in both total synthesis and the systematic modifications of natural products. They may also be employed to introduce deuterium or tritium in a site‐specific manner. Reductive methods that involve ionic or highly polarized reagents or intermediates can be limited in their applicability: for example, competing reaction pathways including cationic rearrangements and anionic eliminations may be encountered in sterically hindered systems with substrates bearing heteroatoms close to the center undergoing reduction. As evidenced by developments over the last few decades, methods that involve the generation and direct quenching via hydrogen atom abstraction of the derived, carbon‐centered radical typically show the greatest tolerance for the presence of other functional groups and for variations in both the steric acid and the electronic environment in the vicinity of the center undergoing deoxygenation. Derivatization of the hydroxyl is a prerequisite, the determinant factors for efficient formation of the deoxygenated product lies in the ability of the combination of the substrate and reagents to induce homolysis of the C‐O bond coupled with the induction of homolysis to rapidly reduce a free radical by hydrogen donation, thereby propagating an efficient chain process. A high‐yielding way to realize this sequence was first described by Barton McCombie using the free‐radical chain reaction of O ‐thioacyl derivatives of secondary alcohols with tri‐ n ‐butylstannane. This chapter provides a detailed description and comparison of the combinations of substrates and reagents that will bring about these processes and provides a summary and evaluation of alternative deoxygenation methods. Mechanistic and stereochemical issues set out the scope and limitations of these processes with respect to both the thioacylation and reduction steps and exemplify some applications to both total synthesis and the modification of natural products.

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Synthetic Uses ofR₃MH(M = Ge,Sn,Pb)

Carland

Schiesser

2009

Patai's Chemistry of Functional Groups

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Introduction The Preparation of Novel Trialkylgermanes and Stannanes Trialkyltin Hydrides as Reagents in Radical Chain Reactions Trialkyltin Hydrides in Non‐Radical Chemistry Trialkylgermanium and Lead Hydrides in Synthesis Acknowledgement

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Synthesis of an 11-unsubstituted analogue of (±)-huperzine A

Cited by 10 publications

References 51 publications

3D Structure of Torpedo californica Acetylcholinesterase Complexed with Huprine X at 2.1 Å Resolution: Kinetic and Molecular Dynamic Correlates^,

3D Structure of Torpedo californica Acetylcholinesterase Complexed with Huprine X at 2.1 Å Resolution: Kinetic and Molecular Dynamic Correlates^,

The Barton‐McCombie Reaction

Synthetic Uses ofR₃MH(M = Ge,Sn,Pb)

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Synthesis of an 11-unsubstituted analogue of (±)-huperzine A

Cited by 10 publications

References 51 publications

3D Structure of Torpedo californica Acetylcholinesterase Complexed with Huprine X at 2.1 Å Resolution: Kinetic and Molecular Dynamic Correlates,

3D Structure of Torpedo californica Acetylcholinesterase Complexed with Huprine X at 2.1 Å Resolution: Kinetic and Molecular Dynamic Correlates,

The Barton‐McCombie Reaction

Synthetic Uses ofR3MH(M = Ge,Sn,Pb)

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Product

Resources

About

3D Structure of Torpedo californica Acetylcholinesterase Complexed with Huprine X at 2.1 Å Resolution: Kinetic and Molecular Dynamic Correlates^,

3D Structure of Torpedo californica Acetylcholinesterase Complexed with Huprine X at 2.1 Å Resolution: Kinetic and Molecular Dynamic Correlates^,

Synthetic Uses ofR₃MH(M = Ge,Sn,Pb)