Anti-hyperlipidemic potential of natural product based labdane-pyrroles via inhibition of cholesterol and triglycerides synthesis

Jalaja, Renjitha; Leela, Shyni G.; Mohan, Sangeetha; Nair, Mangalam S.; Gopalan, Raghu K.; Somappa, Sasidhar B.

doi:10.1016/j.bioorg.2021.104664

Cited by 21 publications

(13 citation statements)

References 40 publications

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“…To begin with, fresh rhizomes of C. amada were procured from the CTCRI, Thiruvananthapuram, in January 2022. The marker compound, ( E )-labda-8(17),12-diene-15,16-dial ( 1 ), was isolated from the chloroform extract of the rhizomes by adopting our standard protocol, , as a colorless solid. The structure of the compound was confirmed by various spectroscopic and analytical data.…”

Section: Resultsmentioning

confidence: 99%

“…Semisynthetic modification of therapeutically proven lead natural products is one of the most successful approaches to optimizing their pharmacological properties and also to explore their vivid mode of action. − We have previously reported a series of novel labdane-appended scaffolds with very promising antiobesity and antihyperlipidemic properties. , These encouraging discoveries provided the insights for us to continue our focused efforts on medicinal chemistry, − in particular natural-product-based semisynthetic modifications for the development of therapeutically improved scaffolds. Therefore, in the present work, we have rationally designed and synthesized a series of 27 new phytochemical entities (NPCEs), by the strategic inclusion of aromatic or heteroaromatic fragments to the labdane template via a linker-based molecular hybridization (Figure ) and explored their potential toward multifaceted inflammatory targets.…”

Section: Introductionmentioning

confidence: 99%

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Linker-Based Pharmacophoric Design and Semisynthesis of Labdane Conjugates Active against Multi-Faceted Inflammatory Targets

Mohan,

Krishnan,

Madhusoodanan

et al. 2024

J. Agric. Food Chem.

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Prolonged inflammation leads to the genesis of various inflammatory diseases such as atherosclerosis, cancer, inflammatory bowel disease, Alzheimer's, etc. The uncontrolled inflammatory response is characterized by the excessive release of pro-inflammatory mediators such as nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1alpha (IL-1α), and inflammatory enzymes such as cyclooxygenase-2 (COX-2). Hence, the downregulation of these inflammatory mediators is an active therapy to control aberrant inflammation and tissue damage. To address this, herein, we present the rational design and synthesis of novel phytochemical entities (NPCEs) through strategic linker-based molecular hybridization of aromatic/ heteroaromatic fragments with the labdane dialdehyde, isolated from the medicinally and nutritionally significant rhizomes of the plant Curcuma amada. To validate the anti-inflammatory potential, we employed a comprehensive in vitro study assessing its inhibitory effect on the COX-2 enzyme and other inflammatory mediators, viz., NO, TNF-α, IL-6, and IL-1α, in bacterial lipopolysaccharide-stimulated macrophages, as well as in-silico molecular modeling studies targeting the inflammation regulator COX-2 enzyme. Among the synthesized novel compounds, 5f exhibited the highest anti-inflammatory potential by inhibiting the COX-2 enzyme (IC 50 = 17.67 ± 0.89 μM), with a 4-fold increased activity relative to the standard drug indomethacin (IC 50 = 67.16 ± 0.17 μM). 5f also significantly reduced the levels of LPS-induced NO, TNF-α, IL-6, and IL-1α, much better than the positive control. Molecular mechanistic studies revealed that 5f suppressed the expression of COX-2 and pro-inflammatory cytokine release dose-dependently, which was associated with the inhibition of the NF-κB signaling pathway. This infers that the labdane derivative 5f is a promising lead candidate as an anti-inflammatory agent to further explore its therapeutic landscape.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Linker-Based Pharmacophoric Design and Semisynthesis of Labdane Conjugates Active against Multi-Faceted Inflammatory Targets

Mohan,

Krishnan,

Madhusoodanan

et al. 2024

J. Agric. Food Chem.

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“…Effects, such as anti-inflammatory (22), inhibition of HMG-CoA reductase (23), anticancer activity (24), inhibition of 5-hydroxytryptamine transporters (25), antihypertensive effects (26), DPP inhibition (27), modulation of AMPA (28), dopaminergic antagonism (29), progesterone receptor antagonism (30), antimalarial activity (31) and cannabinoid receptor agonism have been identified. Furthermore, numerous commercially available drugs are derivatives of pyrrole.…”

Section: Pyrrole -Pharmacology Profile and Anticancer Propertiesmentioning

confidence: 99%

Pyrrole as an Important Scaffold of Anticancer Drugs: Recent Advances

Mateev

Georgieva²,

Zlatkov³

2022

J Pharm Pharm Sci

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With the significant increase of patients suffering from different types of cancer, it is evident that prompt measures in the development of novel and effective agents need to be taken. Pyrrole moiety has been found in various active compounds with anti-inflammatory, antiseptic, antibacterial, lipid-lowering and anticancer properties. Recent advances in the exploration of highly active and selective cytotoxic structures containing pyrrole motifs have shown promising data for future investigations. Accordingly, this review presents an overview of recent developments in the pyrrole derivatives as anticancer agents, with a main focus towards the key moieties required for the anti-tumor activities. Pyrrole molecules comprising prominent targeting capacities against microtubule polymerization, tyrosine kinases, cytochrome p450 family 1, histone deacetylase and bcl-2 proteins were reported. In addition, several mechanisms of action, such as apoptosis, cell cycle arrest, inhibiting kinases, angiogenesis, disruption of cell migration, modulation of nuclear receptor responsiveness and others were analyzed. Furthermore, in most of the discussed cases we provided synthesis schemes of the mentioned molecules. Overall, the utilization of pyrrole scaffold for the design and synthesis of novel anticancer drugs could be a promising approach for future investigations.

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“…Like any other N-heterocyclic scaffold, pyrrole and its derivatives are inherited with valuable biological properties. 16,17 In 2011, Li et al reported a metal-free strategy for synthesising pyrroles 3 (Scheme 1). 18 They demonstrated the pyrrole synthesis using divinyl ketone 1 and ethyl isocyanoacetate 2 as the starting materials.…”

Section: Synthesis Of Nitrogen-containing Heterocyclesmentioning

confidence: 99%

Recent advances in the transition metal-free synthesis of heterocycles from α,β-unsaturated ketones

Ashitha

Basavaraja

et al. 2022

Org. Chem. Front.

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Anti-hyperlipidemic potential of natural product based labdane-pyrroles via inhibition of cholesterol and triglycerides synthesis

Cited by 21 publications

References 40 publications

Linker-Based Pharmacophoric Design and Semisynthesis of Labdane Conjugates Active against Multi-Faceted Inflammatory Targets

Linker-Based Pharmacophoric Design and Semisynthesis of Labdane Conjugates Active against Multi-Faceted Inflammatory Targets

Pyrrole as an Important Scaffold of Anticancer Drugs: Recent Advances

Recent advances in the transition metal-free synthesis of heterocycles from α,β-unsaturated ketones

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