Biocatalytic approaches have yielded efficient total syntheses of the major Amaryllidaceae alkaloids, all based on the key enzymatic dioxygenation of suitable aromatic precursors. This paper discusses the logic of general synthetic design for lycoricidine, narciclasine, pancratistatin, and 7-deoxypancratistatin. Experimental details are provided for the recently accomplished syntheses of narciclasine, ent-7-deoxypancratistatin, and 10b-epi-deoxypancratistatin via a new and selective opening of a cyclic sulfate over aziridines followed by aza-Payne rearrangement. The structural core of 7-deoxypancratistatin has also been degraded to a series of intermediates in which the amino inositol unit is cleaved and deoxygenated in a homologous fashion. These truncated derivatives and the compounds from the synthesis of the unnatural derivatives have been tested against six important human cancer cell lines in an effort to further develop the understanding of the mode of action for the most active congener in this group, pancratistatin. The results of the biological activity testing as well as experimental, spectral, and analytical data are provided in this manuscript for all relevant compounds.

An efficient synthesis of C-1 derivatives of 7-deoxypancratistatin is reported. The key steps include the following: selective opening of an epoxide with aluminum acetylide in the presence of an aziridine; solid-state silica-gel-catalyzed opening of an aziridine; oxidative cleavage of a phenanthrene core and its recyclization to phenanthridone to provide the key C-1 aldehyde 22. The conversion of this aldehyde to C-1 acetoxymethyl and C-1 hydroxymethyl derivatives is described along with the evaluation of their biological activity against several cancer cell lines and in an apoptosis study. The C-1 acetoxymethyl derivative has shown promising activity comparable to that of the natural product. In addition, a total synthesis of trans-dihydrolycoricidine and a formal total synthesis of 7-deoxypancratistatin are reported from aldehyde 22. Detailed experimental and spectral data are provided for all new compounds.thudlicky@brocku.ca .

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The drug efflux pump P-glycoprotein (P-gp) has been shown to promote multidrug resistance (MDR) in tumors as well as to influence ADME properties of drug candidates. Here we synthesized and tested a series of benzophenone derivatives structurally analogous to propafenone-type inhibitors of P-gp. Some of the compounds showed ligand efficiency and lipophilic efficiency (LipE) values in the range of compounds which entered clinical trials as MDR modulators. Interestingly, although lipophilicity plays a dominant role for P-gp inhibitors, all compounds investigated showed LipE values below the threshold for promising drug candidates. Docking studies of selected analogues into a homology model of P-glycoprotein suggest that benzophenones show an interaction pattern similar to that previously identified for propafenone-type inhibitors.

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Pancratistatin (1) and narciclasine (3; Scheme 1), well-known constituents [1] of the Amaryllidaceae species, have been the subject of intense study, both in the realm of total synthesis [2] and with respect to their anticancer activities.[3] Both compounds contain a free phenolic hydroxy group that is part of the enolized b-ketoamide function. It is this functional group that accounts for the greater (10-fold or more) activity of Scheme 1. Amaryllidaceae constituents containing the enolized b-ketoamide motif and their b-carboline-1-one analogue.

This review summarizes recent developments in the total synthesis of morphine alkaloids and some of the semisynthetic derivatives. The literature is covered for the period of 5 years after the publication of the last review in 2005. The syntheses that appeared in this period are covered in detail and are placed in the context of all syntheses of opiate alkaloids since the original one published by Gates in 1952. The introduction covers the historical aspects of total synthesis of these alkaloids. The synthesis of some of the medicinally useful derivatives is reviewed in the last section along with some of the methodology required for their preparation.

In this tutorial review, which should be of general interest to synthetic organic chemists at large, recent progress in the total synthesis of the tetrahydroisoquinoline antitumor antibiotics cyanocycline A, naphthyridinomycin, bioxalomycin alpha2, and lemonomycin is highlighted in detail and some biological background information is given as well. Preparations of truncated derivatives and uncompleted synthetic approaches are also described. The literature coverage includes the newest research results through the year 2008.