Copper-Catalyzed Dual Cyclization for the Synthesis of Quinindolines.

A synthetic approach to quinindoline derivatives by the Cu-catalyzed dual cyclization has been developed. This catalytic reaction is a practical method for the systematic synthesis of quinindoline core structure, which contains a limited-step synthetic strategy and can tolerant a wide variety of substituents. In addition, the mechanistic study reveals that the reaction initiates from a Lewis acid accelerated addition of aniline to nitrile and provides the indole substructure, and then the subsequent Cu-catalyzed C-N coupling reaction furnishes the quinoline subunit and affords the quinindoline structure.

Capillary-HPLC with tandem mass spectrometry in analysis of alkaloid dyestuffs - a new approach.

Development of the identification method of alkaloid compounds in Amur cork tree as well as not examined so far Oregon grape and European Barberry shrubs are presented. The novel approach to separation of alkaloids was applied and the capillary-high-performance liquid chromatography (capillary-HPLC) system was used, which has never previously been reported for alkaloid-based dyestuffs analysis. Its optimization was conducted with three different stationary phases (unmodified octadecylsilane-bonded silica, octadecylsilane modified with polar groups and silica-bonded pentaflourophenyls) as well as with different solvent buffers. Detection of the isolated compounds was carried out using diode-array detector (DAD) and tandem mass spectrometer with electrospray ionization (ESI MS/MS). The working parameters of ESI were optimized, whereas the multiple reactions monitoring (MRM) parameters of MS/MS detection were chosen based on the product ion spectra of the quasi-molecular ions. Calibration curve of berberine has been estimated (y = 1712091x + 4785.03 with the correlation coefficient 0.9999). Limit of detection and limit of quantification were calculated to be 3.2 and 9.7 ng/mL, respectively. Numerous alkaloids (i.e., berberine, jatrorrhizine and magnoflorine, as well as phellodendrine, menisperine and berbamine) were identified in the extracts from alkaloid plants and silk and wool fibers dyed with these dyestuffs, among them their markers.

A mini review on human serum albumin - natural alkaloids interaction and its role as drug carrier.

Human serum albumin (HSA) is one of the main protein components of the circulatory system. It's well characterized physiological role is to carry numerous ligands to their target site. Overall pharmacokinetic profile of a drug is deliberately influenced by its affinity towards plasma proteins, especially with albumins. Alkaloids as small molecules are natural nitrogenous organic compounds that have significant medicinal properties that bind to HSA. There are three sites viz., I, II and III, on HSA molecule where the drug/small molecule binds based on their molecular size, structure and hydrophobicity. The major driving forces for the interaction of alkaloids-HSA are non-covalent interactions. Drug-HSA interaction is an admired area of research since it has been lately employed for both therapeutic and investigative reasons and is one of the main elements determining the pharmacokinetic and pharmacodynamic profiles of the therapeutic molecules. Displacement and drug-drug interactions, clinical alteration of drug-albumin affinity in diseases affecting the therapeutic role of the drugs, use of HSA nanoparticles for the delivery of drug in cancer are the major significant issues that have been discussed in this review. This article provides an overview of the multifunctional properties of HSA as a drug carrier, as well as how knowledge of these properties is currently being used to improve the bioavailability of drugs with the ability to bind to albumin for future pharmaceutical, clinical, and commercial applications of the albumin protein.Communicated by Ramaswamy H. Sarma.

Harnessing the power of natural alkaloids: the emergent role in epilepsy therapy.

The quest for effective epilepsy treatments has spotlighted natural alkaloids due to their broad neuropharmacological effects. This review provides a comprehensive analysis of the antiseizure properties of various natural compounds, with an emphasis on their mechanisms of action and potential therapeutic benefits. Our findings reveal that bioactive substances such as indole, quinoline, terpenoid, and pyridine alkaloids confer medicinal benefits by modulating synaptic interactions, restoring neuronal balance, and mitigating neuroinflammation-key factors in managing epileptic seizures. Notably, these compounds enhance GABAergic neurotransmission, diminish excitatory glutamatergic activities, particularly at NMDA receptors, and suppress proinflammatory pathways. A significant focus is placed on the strategic use of nanoparticle delivery systems to improve the solubility, stability, and bioavailability of these alkaloids, which helps overcome the challenges associated with crossing the blood-brain barrier (BBB). The review concludes with a prospective outlook on integrating these bioactive substances into epilepsy treatment regimes, advocating for extensive research to confirm their efficacy and safety. Advancing the bioavailability of alkaloids and rigorously assessing their toxicological profiles are essential to fully leverage the therapeutic potential of these compounds in clinical settings.

A tetramethylpyrazine-loaded hyaluronic acid-based hydrogel modulates macrophage polarization for promoting wound recovery in diabetic mice.

The failure of wound healing often causes lower limb disability and amputation of diabetic patients. Current strategies for diabetic wound management often fail to achieve the expected outcomes, and emerging alternatives are urgently needed. Recent advances in the identification of active compounds from traditional herbal medicines provide promising therapeutics for tissue repair and regeneration. In this study, the pro-healing effects of tetramethylpyrazine (TMP, a natural alkaloid found in Ligusticum chuanxiong Hort) for diabetic wounds were for the first time demonstrated. The cutaneous healing was mainly achieved by TMP-mediated macrophage polarization from pro-inflammatory to pro-healing phenotype. In addition, the topical administration of TMP was facilitated by the hyaluronic acid (HA) hydrogel for promoting the full-thickness wounds in the experimental diabetic mice. Consequently, TMP-loaded HA hydrogel (TMP-HA) profoundly accelerated the wound closure in comparison with TMP-loaded INTRASITE Gel (it is a commercial hydrogel), which was evident with the inflammation mitigation, the angiogenesis enhancement, and the collagen deposition. Our work reveals the macrophage-modulatory function of TMP for diabetic wound healing and demonstrates great potential of TMP-HA for clinical application.

Modulation of GABAA receptors and of GABAergic synapses by the natural alkaloid gelsemine.

The Gelsemium elegans plant preparations have shown beneficial activity against common diseases, including chronic pain and anxiety. Nevertheless, their clinical uses are limited by their toxicity. Gelsemine, one of the most abundant alkaloids in the Gelsemium plants, have replicated these therapeutic and toxic actions in experimental behavioral models. However, the molecular targets underlying these biological effects remain unclear. The behavioral activity profile of gelsemine suggests the involvement of GABAA receptors (GABAARs), which are the main biological targets of benzodiazepines (BDZs), a group of drugs with anxiolytic, hypnotic, and analgesic properties. Here, we aim to define the modulation of GABAARs by gelsemine, with a special focus on the subtypes involved in the BDZ actions. The gelsemine actions were determined by electrophysiological recordings of recombinant GABAARs expressed in HEK293 cells, and of native receptors in cortical neurons. Gelsemine inhibited the agonist-evoked currents of recombinant and native receptors. The functional inhibition was not associated with the BDZ binding site. We determined in addition that gelsemine diminished the frequency of GABAergic synaptic events, likely through a presynaptic modulation. Our findings establish gelsemine as a negative modulator of GABAARs and of GABAergic synaptic function. These pharmacological features discard direct anxiolytic or analgesic actions of gelsemine through GABAARs but support a role of GABAARs on the alkaloid induced toxicity. On the other hand, the presynaptic effects of the alkaloid provide an additional mechanism to explain their beneficial effects. Collectively, our results contribute novel information to improve understanding of gelsemine actions in the mammalian nervous system.

Improved delivery of natural alkaloids into lung cancer through woody oil-based emulsive nanosystems.

Most antitumor ingredients found in nature have poor solubility. These ingredients are expected to have much better absorption and higher bioavailability than synthetic antitumor agents. Woody oil emulsive nanosystems carrying poorly soluble natural alkaloids were fabricated (evodiamine (EA) carried by fructus bruceae oil-based emulsive nanosystems, or EFEN). Fructus bruceae oil has two excipient-like properties (oil phase and stabilizer) that contribute to the formulation and one drug-like property (antitumor effects) that synergizes with the antitumor effect of EA. The properties of EFEN were compared with free EA, a blank nanoemulsion, an EA-loaded emulsive nanosystem, and a fructus bruceae oil-loaded emulsive nanosystem. For the first time, this suggests that increases in the sensitivity of lung cancer cells to poorly soluble natural alkaloids can be achieved by delivering drugs using woody oil-based emulsive nanosystems. In this study, woody oil-based emulsive nanosystems efficiently deliver poorly soluble natural alkaloids.

Probing the G­quadruplex from hsa-miR-3620-5p and inhibition of its interaction with the target sequence.

G-quadruplexes have been reported to exist both in human genome and transcriptome and are of great interests due to their important biological functions. Up to now, the formation and property of G-quadruplex in human mature microRNAs has not been explored yet. In this study, we discovered that hsa-miR-3620-5p, a guanine rich human mature microRNA, could fold into a stable parallel G-quadruplex in near physiological condition for the first time. We explored the formation, folding pattern and binding affinity of the miR-3620-5p G-quadruplex by ESI-MS, CD, NMR and SPR. The results indicated that its high-order structure was comprised of three G-quartets with two bases in each parallel loop stretching outward and two bases flanking at each end. In addition, sanguinarine, a natural alkaloid screened from traditional Chinese medicine was characterized to have high binding affinity and thermodynamic stabilization effects through π-π stacking interaction with the external G-quartets. Furthermore, the potent interaction of sanguinarine with miR-3620-5p G-quadruplex could block the base pairing between miR-3620-5p and its target sequence. Therefore, our study revealed the possibility of regulating microRNA functions using potent G-quadruplex binders, and could provide a new approach to affect the microRNA:mRNA interactions.