Polycyclic Polyprenylated Acylphloroglucinols

Natural products have served as powerful therapeutics against pathogenic bacteria since the golden age of antibiotics of the mid-20th century. However, the increasing frequency of antibiotic-resistant infections clearly demonstrates that new antibiotics are critical for modern medicine. Because combinatorial approaches have not yielded effective drugs, we propose that the development of new antibiotics around proven natural scaffolds is the best short-term solution to the rising crisis of antibiotic resistance. We analyze herein synthetic approaches aiming to reengineer natural products into potent antibiotics. Furthermore, we discuss approaches in modulating quorum sensing and biofilm formation as a nonlethal method, as well as narrow-spectrum pathogen-specific antibiotics, which are of interest given new insights into the implications of disrupting the microbiome.

Natural Products as Platforms To Overcome Antibiotic Resistance

To better understand the relationship between the chemical structure and biological fate of dietary polyphenols, the hepatic metabolic stability and intestinal absorption of methylated polyphenols, in comparison with unmethylated polyphenols, were investigated in pooled human liver S9 fraction and human colon adenocarcinoma (Caco-2) cells. Consistent with previous in vivo studies, the two well known unmethylated polyphenols resveratrol (3,5,4'-trihydroxystilbene) and quercetin (3,5,7,3',4'-pentahydroxyflavone) were rapidly eliminated by the S9 fraction in the presence of the appropriate cofactors for conjugation and oxidation. In contrast, the methylated flavones, i.e., 7-methoxyflavone, 7,4'-dimethoxyflavone, 5,7-dimethoxyflavone, and 5,7,4'-trimethoxyflavone, were relatively stable, indicating high resistance to hepatic metabolism. The corresponding unmethylated flavones, i.e., 7-hydroxyflavone, 7,4'-dihydroxyflavone, chrysin (5,7-dihydroxyflavone), and apigenin (5,7,4'-trihydroxyflavone), were rapidly eliminated because of extensive glucuronidation and/or sulfation just as resveratrol and quercetin were. The rate of intestinal absorption was evaluated using Caco-2 cells grown in porous inserts. The methylated flavones showed approximately 5- to 8-fold higher apparent permeability (P(app), 22.6-27.6 x 10(-6) cm s(-1)) of apical to basolateral flux than the unmethylated flavones (P(app), 3.0-7.8 x 10(-6) cm s(-1)). The lower P(app) values for the unmethylated flavones correlated with their extensive metabolism in the Caco-2 cells. Thus, combined use of the hepatic S9 fraction and Caco-2 cells will be useful for predicting the oral bioavailability of dietary polyphenols. The higher hepatic metabolic stability and intestinal absorption of the methylated polyphenols make them more favorable than the unmethylated polyphenols to be developed as potential cancer chemopreventive agents.

https://dmd.aspetjournals.org/content/dmd/early/2006/07/25/dmd.106.011122.full.pdf

Methylated Flavonoids Have Greatly Improved Intestinal Absorption and Metabolic Stability

Many fungi, lichens, and bacteria produce xanthones (derivatives of 9H-xanthen-9-one, “xanthone” from the Greek “xanthos”, for “yellow”) as secondary metabolites. Xanthones are typically polysubstituted and occur as either fully aromatized, dihydro-, tetrahydro-, or, more rarely, hexahydro-derivatives. This family of compounds appeals to medicinal chemists because of their pronounced biological activity within a notably broad spectrum of disease states, a result of their interaction with a correspondingly diverse range of target biomolecules. This has led to the description of xanthones as “privileged structures”.(1) Historically, the total synthesis of the natural products has mostly been limited to fully aromatized targets. Syntheses of the more challenging partially saturated xanthones have less frequently been reported, although the development in recent times of novel and reliable methods for the construction of the (polysubstituted) unsaturated xanthone core holds promise for future endeavors. In particular, the fascinating structural and biological properties of xanthone dimers and heterodimers may excite the synthetic or natural product chemist.

Xanthones from Fungi, Lichens, and Bacteria: The Natural Products and Their Synthesis

The discovery and implementation of antibiotics in the early twentieth century transformed human health and wellbeing. Chemical synthesis enabled the development of the first antibacterial substances, organoarsenicals and sulfa drugs, but these were soon outshone by a host of more powerful and vastly more complex antibiotics from nature: penicillin, streptomycin, tetracycline, and erythromycin, among others. These primary defences are now significantly less effective as an unavoidable consequence of rapid evolution of resistance within pathogenic bacteria, made worse by widespread misuse of antibiotics. For decades medicinal chemists replenished the arsenal of antibiotics by semisynthetic and to a lesser degree fully synthetic routes, but economic factors have led to a subsidence of this effort, which places society on the precipice of a disaster. We believe that the strategic application of modern chemical synthesis to antibacterial drug discovery must play a critical role if a crisis of global proportions is to be averted.

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The Evolving Role of Chemical Synthesis in Antibacterial Drug Discovery

Antibiotic hyperforin from Hypericum perforatum L

The structure of albofungin

Synthesis of 12a-deoxy-5a,6-anhydrotetracycline. The first total synthesis of the naturally occuring tetracycline

The following flavonoids have been isolated from propolis and identified: acacetin (I), 7,4′-dimethoxyflavone (II), kaempferide (III), rhamnocitrin (IV), 5,7-dihydroxy-3,4′-dihydroxyflavone (V), 3,5-dihydroxy-7,4′-dimethoxyflavone (VI), (−)-pinostrobin (VII), and (−)-5-hydroxy-7,4′-dimethoxyflavanone (VIII).

S. A. Popravko

Papers

Antibiotic hyperforin from Hypericum perforatum L

The structure of albofungin

Synthesis of 12a-deoxy-5a,6-anhydrotetracycline. The first total synthesis of the naturally occuring tetracycline

Flavonoid components of propolis

Structure of the antibiotics albofungin and chloralbofungin