Withanolide A: synthesis and structural requirements for neurite outgrowth

Liffert, Raphael; Hoecker, Johannes; Jana, Chandan K.; Woods, Tom M.; Burch, Patrick A.; Jessen, Henning J.; Neuburger, Markus; Gademann, Karl

doi:10.1039/c3sc50653c

Cited by 28 publications

(27 citation statements)

References 59 publications

(20 reference statements)

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“…However, among all WA is the major active constituent, which draws the attention of several pharmacologists in recent years for its utility in neuropharmacological therapy (Ahmad et al, ; Baitharu et al, ). The potential of WA and its analogs toward neuronal differentiation and neurotic outgrowth is also confirmed by Liffert et al (Liffert et al, ). Furthermore, the involvement of WA to convalesce synaptic loss and neuritic damage has also been well demarcated by both in vitro and in vivo models (Kuboyama, Tohda, & Komatsu, ).…”

Section: Introductionmentioning

confidence: 64%

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Determination of permeability, plasma protein binding, blood partitioning, pharmacokinetics and tissue distribution of Withanolide A in rats: A neuroprotective steroidal lactone

Singh

Valicherla

Joshi

et al. 2018

Drug Development Research

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Preclinical Research & Development Withanolide A (WA), a steroidal lactone is a major bioactive constituent of Withania somnifera (L.) with remarkable neuropharmacological activity. In this study, we investigated the permeability, plasma protein binding (PPB), blood partitioning, intravenous (i.v.), and oral pharmacokinetics as well as i.v. tissue distribution (TD) of pure WA in a rat model. The PPB, RBCs partitioning, and permeability of WA were determined by Ultra Performance Liquid Chromatography (UPLC) method. However, the pharmacokinetics and TD of WA were evaluated by validated and sensitive liquid chromatography coupled mass spectrometry (LC‐ESI‐MS/MS) method. The PPB and permeability of WA were determined by equilibrium dialysis and parallel artificial membrane permeability assay method, respectively. The results demonstrated that WA has high PPB and passive permeability. Furthermore, WA was found to have fast equilibration between RBCs and plasma. Following i.v. (2 mg/kg) and per‐oral (25 mg/kg) administration of WA, the max concentration (Cmax) in plasma was found as 85.53 ± 6.54 and 48.04 ±5.78 ng/mL, respectively. The TD study results indicated that WA has a rapid and wide TD. The maximum concentration in various tissues was found in following order: Clung > Cliver > Ckidney ≈ Cspleen > Cheart > Cbrain. The preclinical in vitro, as well as pharmacokinetics and TD results, are anticipated to support the future preclinical and clinical application of WA.

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Section: Introductionmentioning

confidence: 64%

“…The potential of WA and its analogs toward neuronal differentiation and neurotic outgrowth is also confirmed by Liffert et al (Liffert et al, 2013). Furthermore, the involvement of WA to convalesce synaptic loss and neuritic damage has also been well demarcated by both in vitro and in vivo models (Kuboyama, Tohda, & Komatsu, 2005).…”

mentioning

confidence: 83%

Determination of permeability, plasma protein binding, blood partitioning, pharmacokinetics and tissue distribution of Withanolide A in rats: A neuroprotective steroidal lactone

Singh

Valicherla

Joshi

et al. 2018

Drug Development Research

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“…Withanolide A possesses a reactive enone moiety in the A ring, an epoxy alcohol in the B ring, as well as a tetrasubstituted unsaturated lactone side chain. The main synthetic challenges arise from the stereoselective construction of the side chain, the oxidation pattern of the A and B ring, and the diastereoselective instalment of a tertiary alcohol at C20 (35). Furthermore, structure-activity relationship studies have confirmed that the unsaturated ring A and epoxide play an important role in the cytotoxic activity of withanolides (32).…”

Section: Discussionmentioning

confidence: 95%

Antiproliferation potential of withaferin A on human osteosarcoma cells via the inhibition of G2/M checkpoint proteins

Wang

2015

Experimental and Therapeutic Medicine

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Abstract. Withaferin A (WA) is a well-known steroidal lactone of the medicinally important plant, Withania somnifera. This secondary metabolite has been noted for its anticancer effects against a number of human cancer cell lines. However, there are a limited number of studies investigating the growth inhibitory potential of WA against human osteosarcoma cells and the underlying molecular mechanisms. Thus, in the present study, the antiproliferative activities of WA, along with the underlying mechanisms of action, were investigated using flow cytometry for cell cycle distribution and western blot analysis for the assessment of various checkpoint proteins. In addition, the antiproliferative activity was evaluated using a sulforhodamine B assay, where MG-63 and U2OS human osteosarcoma cell lines were treated with different concentrations of WA. Furthermore, the mRNA expression levels of the checkpoint proteins in the WA-treated MG-63 and U2OS cells were examined. The results obtained corresponded with the western blot analysis results. Furthermore, WA was shown to significantly inhibit the proliferation of the two types of treated cell lines (MG-63 and U2OS). Flow cytometric analysis revealed that WA induced cell cycle arrest at the G2/M phase, which was associated with the inhibition of cyclin B1, cyclin A, Cdk2 and p-Cdc2 (Tyr15) expression and an increase in the levels of p-Chk1 (Ser345) and p-Chk2 (Thr68). In conclusion, the present study found that the antiproliferative potential of WA was associated with the induction of cell cycle arrest at the G2/M phase, which was a result of the attenuation of the expression levels of G2/M checkpoint proteins.

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“…[196] The Gademann research group designed a synthesis of (+)- 218 starting from pregnenolone ( 224 ; Scheme 36). [197] Crucial steps of this approach include: a) a vinylogous aldol reaction between aldehyde 225 and the lithium enolate of 226 to afford lactone 227 ; and b) an elegant singlet oxygenene reaction [198] to produce the C5 tertiary alcohol of 228 . The singlet oxygen was generated in situ from oxygen under irradiation with a Na lamp in the presence of mesotetraphenylporphyrin (TPP) as the sensitizer.…”

Section: Neurotrophic Natural Productsmentioning

confidence: 99%

“…[196b] However, conflicting results precluded a clearer view of the mechanism of action of 218 . [197a,199] …”

Section: Neurotrophic Natural Productsmentioning

confidence: 99%

Neurotrophic Natural Products: Chemistry and Biology

2013

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Neurodegenerative diseases and spinal cord injury affect approximately 50 million people worldwide, bringing the total healthcare cost to over 600 billion dollars per year. Nervous system growth factors, that is, neurotrophins, are a potential solution to these disorders, since they could promote nerve regeneration. An average of 500 publications per year attests to the significance of neurotrophins in biomedical sciences and underlines their potential for therapeutic applications. Nonetheless, the poor pharmacokinetic profile of neurotrophins severely restricts their clinical use. On the other hand, small molecules that modulate neurotrophic activity offer a promising therapeutic approach against neurological disorders. Nature has provided an impressive array of natural products that have potent neurotrophic activities. This Review highlights the current synthetic strategies toward these compounds and summarizes their ability to induce neuronal growth and rehabilitation. It is anticipated that neurotrophic natural products could be used not only as starting points in drug design but also as tools to study the next frontier in biomedical sciences: the brain activity map project.

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Withanolide A: synthesis and structural requirements for neurite outgrowth

Cited by 28 publications

References 59 publications

Determination of permeability, plasma protein binding, blood partitioning, pharmacokinetics and tissue distribution of Withanolide A in rats: A neuroprotective steroidal lactone

Determination of permeability, plasma protein binding, blood partitioning, pharmacokinetics and tissue distribution of Withanolide A in rats: A neuroprotective steroidal lactone

Antiproliferation potential of withaferin A on human osteosarcoma cells via the inhibition of G2/M checkpoint proteins

Neurotrophic Natural Products: Chemistry and Biology

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