Total Synthesis of (-)-Anaferine: A Further Ramification in a Diversity-Oriented Approach.

The piperidine ring is a widespread motif in several natural bioactive alkaloids of both vegetal and marine origin. In the last years, a diversity-oriented synthetic (DOS) approach, aimed at the generation of a library of piperidine-based derivatives, was developed in our research group, employing commercially available 2-piperidine ethanol as a versatile precursor. Here, we report the exploration of another ramification of our DOS approach, that led us to the stereoselective total synthesis of (-)-anaferine, a bis-piperidine alkaloid present in Withania somnifera extract. This natural product was obtained in 9% overall yield over 13 steps, starting from a key homoallylic alcohol previously synthesised in our laboratory. Therefore, the collection of piperidine-derivatives accessible from 2-piperidine ethanol was enriched with a new, diverse scaffold.

An acyl-CoA thioesterase is essential for the biosynthesis of a key dauer pheromone in C. elegans.

Methyl ketone (MK)-ascarosides represent essential components of several pheromones in Caenorhabditis elegans, including the dauer pheromone, which triggers the stress-resistant dauer larval stage, and the male-attracting sex pheromone. Here, we identify an acyl-CoA thioesterase, ACOT-15, that is required for the biosynthesis of MK-ascarosides. We propose a model in which ACOT-15 hydrolyzes the ß-keto acyl-CoA side chain of an ascaroside intermediate during ß-oxidation, leading to decarboxylation and formation of the MK. Using comparative metabolomics, we identify additional ACOT-15-dependent metabolites, including an unusual piperidyl-modified ascaroside, reminiscent of the alkaloid pelletierine. The ß-keto acid generated by ACOT-15 likely couples to 1-piperideine to produce the piperidyl ascaroside, which is much less dauer-inducing than the dauer pheromone, asc-C6-MK (ascr#2, 1). The bacterial food provided influences production of the piperidyl ascaroside by the worm. Our work shows how the biosynthesis of MK- and piperidyl ascarosides intersect and how bacterial food may impact chemical signaling in the worm.

Exploring the potential and identifying Withania somnifera alkaloids as novel dihydrofolate reductase (DHFR) inhibitors by the AlteQ method.

There is an urgent need to discover and develop novel drugs to combat Mycobacterium tuberculosis, the causative agent of tuberculosis (TB) in humans. Alkaloids have been shown to have wide-ranging therapeutic application and could be ideal candidates for drug development, and research is underway to develop new anti-tubercular drugs from natural sources. In this regard, the current research deals with finding novel lead compounds from the Withania somnifera (WS) plant. Broad health benefits of WS are due to the presence of diverse chemical constituents which include anaferine and anahygrine and which belong to the alkaloid family. In the present study, these two compounds have been theoretically studied to understand their electronic properties using the density functional theory (DFT) at the B3LYP/6-311 + G (d,p) level. HOMO and LUMO properties and molecular electrostatic potential (MEP) surface were calculated. Further, to understand the mechanism of action of these compounds and to identify their putative drug target, molecular docking and dynamics studies were employed against Mycobacterium tuberculosis dihydrofolate reductase (DHFR). It was determined that NADP+ affects stability of the complexes by reducing fluctuations of residues 14-23 and 117-126. It was also found that Ile5 and Gln28 play an important role in complexation. Electron density analysis (using the AlteQ method) of the intermolecular region, analyzing both the anaferin-NADP+ and anahygrin-NADP+ complexes showed that anaferin and anahygrin complexes are more stable in the presence of NADP+. It has been established that in most intermolecular contacts the contribution of the ligand to the electron density is greater than that of NADP+. The present study thus provides an excellent way to analyze the effect of anaferine and anahygrine in essential processes of M. tuberculosis.Communicated by Ramaswamy H. Sarma.

Beyond tribulus (Tribulus terrestris L.): The effects of phytotherapics on testosterone, sperm and prostate parameters.

ETHNO-PHARMACOLOGICAL RELEVANCE: Phytotherapeutic approaches have been widely proposed to improve male health. Despite the well-touted effects of tribulus (Tribulus terrestris L) on men's health, an optimal phytotherapy remains an elusive challenge. AIM OF THE REVIEW: We sought to critically analyze the evidence in the phytotherapic literature beyond the effects of tribulus on testosterone (T) concentration and sperm analysis to also include indications for prostate health. MATERIALS AND METHODS: A focused literature search was conducted to include studies published in Cochrane, Pubmed, and Web of Science databases between the years 2002 and 2018. RESULTS: The use of tribulus and maca (Lepidium meyenii Walp, Brassicaceae) were not scientifically supported to improve serum T levels in men. Moderate evidence supports the use of long Jack (Eurycoma longifolia Jack, Simaroubaceae), mucuna (Mucuna pruriens (L.) DC., Fabaceae), ashwagandha (Withania somnifera (L.) Dunal, Solanaceae), fenugreek (Trigonella foenum-graceum L., Fabaceae), and black seeds (Nigella sativa L., Ranunculaceae) to increase total T and improve seminal parameters. Data suggests an increase in total T with the use of 5000 mg/d of powdered mucuna seed and ashwagandha root (151 and 143 ng/dL, respectively) over a 12-week period in patients with oligozoospermia. The use of mucuna was supported for patients with oligozoospermia to improve sperm parameters, with an increase of 83.3 million/mL observed after use of 5000 mg/d of powdered mucuna seed over a 12-week period. Evidence supporting the use of saw palmetto (Serenoa repens, (W.Bartram) Small, Arecaceae) to improve prostate health remains equivocal; whereas, evidence supporting the use of Pygeum africanum Hook.f., Rosaceae, Urtica dioica L., Urticaceae, beta-sitosterols, pollen extract, onion, garlic, and tomato, appears favorable and promising. CONCLUSION: Scientific evidence supports the use of mucuna and ashwagandha as phytotherapics for improving serum T concentrations and semen parameters. Despite inconclusive evidence for use of tribulus as a T booster, it may provide advantageous effects on sperm parameters in men with idiopathic infertility. Nutraceutical strategies and some phytotherapics may also be effective to promote prostate health. Popular foodstuffs (onion, garlic, and tomato), nutraceutical agents (pollen extract and beta-sitosterols), and herbal medicines (Pygeum africanum and Urtica dioica) are rational approaches.