Galanthamine-library

Scheme 1. Natural product (galanthamine) inspired compound library that led to the identification of a small molecular probe (denoted as secramine) to study a pathway that shuttles proteins from the endorplasmatic reticulum (ER) to the plasma membrane via the Golgi apparatus (GA).

Scheme 5. Synthesis of a library of galanthamine analogues by Shair et al.

Galanthamine is a natural alkaloid and a potent acetylcholinesterase inhibitor. Recognizing the potential to access this rigid polycyclic core through a biomimetic oxidative coupling/Michael addition, Shair and coworkers developed a highly efficient diversity-oriented synthesis based on this scaffold (Scheme 21.16) [96]. A library of 2527 compounds was prepared on the aforementioned macrobeads... 

A solid-phase version of this biomimetic method has been developed in the context of diversity-oriented synthesis to generate a library of galanthamine-like molecules, which allowed the identification of compound A, a potent new blocker of protein trafficking from the Golgi apparatus to the plasma membrane. Interestingly, galanthamine (75) does not exhibit this biological activity (218) (Scheme 2). 

Based on the Amaryllidaceae alkaloid galanthamine, a biomimetic solid-phase synthesis of 2527 compounds was reported by Shair and coworkers (Figure 11.13) The core scaffold, initially prepared in several steps, was diversified by means of four successive reactions Mitsunobu reaction of the phenolic moiety with five primary alcohols, Michael addition of the a, 3-unsatnrated cyclohexenone with thiols, iV-acylation or A -alkylation of the cyclic secondary amine, and treatment of the ketone with hydrazines and hydroxylamines. Further evaluation of library constituents for their ability to block protein trafficking in the secretory pathway of mammalian cells led to the discovery of sercramine as a potent inhibitor of the VSVG-GFP protein movement from the Golgi apparatus to the plasma m brane. 

FIGURE 11.73 Diversity-oriented synthesis of a galanthamine-based library. (From Pelish, H.E. et al., Use of biomimetic diversity-oriented synthesis to discover galanthamine-like molecules with biological properties beyond those of the natural product, J. Am. Chem. Soc., 123, 6740, 2001.)... 

SCHEME 15.21 Shair synthesis of a library of galanthamine analogs on solid phase. 

Scheme 9 Synthesis of a Galanthamine-based library by Shair et al.

Finally, galanthamine is a complex alkaloid used for the treatment of mild-to-moderate Alzheimer s disease that is isolated from Galanthus woronowii. Galanthamine possesses a tetracyclic core 64 that was recently synthesized on solid phase by Shair and colleagues, along with an impressive 2527-membered DOS-type library of analogs (Scheme 3.13). Initially, a chiral tyrosine derivative was... 

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