Nitrogen heterocycles are among the most significant structural components of pharmaceuticals. Analysis of our database of U.S. FDA approved drugs reveals that 59% of unique small-molecule drugs contain a nitrogen heterocycle. In this review we report on the top 25 most commonly utilized nitrogen heterocycles found in pharmaceuticals. The main part of our analysis is divided into seven sections: (1) three- and four-membered heterocycles, (2) five-, (3) six-, and (4) seven- and eight-membered heterocycles, as well as (5) fused, (6) bridged bicyclic, and (7) macrocyclic nitrogen heterocycles. Each section reveals the top nitrogen heterocyclic structures and their relative impact for that ring type. For the most commonly used nitrogen heterocycles, we report detailed substitution patterns, highlight common architectural cores, and discuss unusual or rare structures.

Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals

Evolution of secondary metabolites from an ecological and molecular phylogenetic perspective.

Despite the tremendous importance of secondary metabolites for humans as for the plant itself, plant secondary metabolism remains poorly characterized. Here, we present an experimental approach, based on functional genomics, to facilitate gene discovery in plant secondary metabolism. Targeted metabolite analysis was combined with cDNA-amplified fragment length polymorphism-based transcript profiling of jasmonate-elicited tobacco Bright yellow 2 cells. Transcriptome analysis suggested an extensive jasmonate-mediated genetic reprogramming of metabolism, which correlated well with the observed shifts in the biosynthesis of the metabolites investigated. This method, which in addition to transcriptome data also generates gene tags, in the future might lead to the creation of novel tools for metabolic engineering of medicinal plant systems in general.

https://www.pnas.org/content/pnas/100/14/8595.full.pdf

A functional genomics approach toward the understanding of secondary metabolism in plant cells

Plant cell and tissue cultures can be established routinely under sterile conditions from explants, such as plant leaves, stems, roots, meristems etc for both the ways for multiplication and extraction of secondary metabolites. Strain improvement, methods for the selection of high-producing cell lines, and medium optimizations can lead to an enhancement in secondary metabolite production. However, most often trials with plant cell cultures fail to produce the desired products. In such cases, strategies to improve the production of secondary metabolites must be considered. One of the main problems encountered is the lack of basic knowledge of the biosynthetic routes, and mechanisms responsible for the production of plant metabolites. Where the productivity of the desired metabolites is limited by the lack of particular precursors, biotransformation using an exogenous supply of biosynthetic precursors, genetic manipulation and metabolic engineering may improve the accumulation of compounds. Feedback inhibition of metabolic enzymes as well as inhibition of membrane transport can be eliminated by the accumulation of synthesized products in a second phase introduced into the aqueous medium. Organ cultures and in vitro biomass production often have sites of synthesis and storage of secondary metabolites in separate compartments. Elicitors, compounds triggering the formation of secondary metabolites, can be abiotic or biotic. Natural elicitors include polysaccharides such as pectin and chitosan, which are also used in the immobilization and permeabilization of plant cells. Immobilization with suitable bioreactor system provides several advantages, such as continuous process operation, but for the development of an immobilized plant cell culture process, natural or artifically induced secretion of the accumulated product into the surrounding medium is necessary. The present review highlights the nature, applications, perspective and scale up methods for the production of valuable secondary metabolites in vitro.

	 

	Key words: Plant cell cultures, secondary metabolites, biotransformation, biosynthetic pathways, elicitation, immobilization, bioreactors.

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A review on trends in production of secondary metabolites from higher plants by in vitro tissue, organ and cell cultures.

The present review describes research on novel natural cyclobutane-containing alkaloids and synthetic compounds isolated from terrestrial and marine species. More than 210 compounds have been confirmed to show antimicrobial, antibacterial, anticancer, and other activities. Structures, origins, biosynthesis, photodimerization, and biological activities of a selection of cyclobutane-containing alkaloids and selected synthethic analogs of natural alkaloids are reviewed.

Bioactive cyclobutane-containing alkaloids

Chemotaxonomy and geographical distribution of tropane alkaloids

Alkaloids of Duboisia hopwoodii

The steroidal sapogenins obtained by hydrolysis of the saponins found in the leaves of eight species of Cordyline have been studied. With the exception of C. terminalis var. petiolaris, the extracts of all species yielded 1,3-dihydroxy sapogenins, which were usually the predominant compounds. C. terminalis var. petiolaris differed from all the other species examined, not only because of its lack of dihydroxy sapogenins, but also because it yielded the 5β-spirostanes, sarsasapogenin and smilagenin. The extracts of all seven other species contained only 5α-sapogenins. Compounds detected were 3-epf-tigogenin, 3-epf-neotigogenin, tigogenin, neotigogenin, diosgenin, yamogenin, cannigenin, cordylagenin, brisbagenin, ruscogenin and 255-ruscogenin.

William J. Griffin

Papers

Chemotaxonomy and geographical distribution of tropane alkaloids

Alkaloids of Duboisia hopwoodii

Steroidal Sapogenins From Leaves of Cordyline Species

Scopolamine content of a Duboisia hybrid in callus cultures

Alkaloids of the leaves of Erythrophleum chlorostachys