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Synthesis and structure-activity relationships of novel cationic lipids with anti-inflammatory and antimicrobial activities.

ABSTRACT: Certain membrane-active cationic steroids are known to also possess both anti-inflammatory and antimicrobial properties. This combined functionality is particularly relevant for potential therapies of infections associated with elevated tissue damage, for example, cystic fibrosis airway disease, a condition characterized by chronic bacterial infections and ongoing inflammation. In this study, six novel cationic glucocorticoids were synthesized using beclomethasone, budesonide, and flumethasone. Products were either monosubstituted or disubstituted, containing one or two steroidal groups, respectively. In vitro evaluation of biological activities demonstrated dual anti-inflammatory and antimicrobial properties with limited cytotoxicity for all synthesized compounds. Budesonide-derived compounds showed the highest degree of both glucocorticoid and antimicrobial properties within their respective mono- and disubstituted categories. Structure-activity analyses revealed that activity was generally related to the potency of the parent glucocorticoid. Taken together, these data indicate that these types of dual acting cationic lipids can be synthesized with the appropriate starting steroid to tailor activities as desired.

SUBMITTER: Myint M

PROVIDER: S-EPMC4459899 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Synthesis and structure-activity relationships of novel cationic lipids with anti-inflammatory and antimicrobial activities.

Myint Melissa M Bucki Robert R Janmey Paul A PA Diamond Scott L SL

Bioorganic & medicinal chemistry letters 20150511 14

Certain membrane-active cationic steroids are known to also possess both anti-inflammatory and antimicrobial properties. This combined functionality is particularly relevant for potential therapies of infections associated with elevated tissue damage, for example, cystic fibrosis airway disease, a condition characterized by chronic bacterial infections and ongoing inflammation. In this study, six novel cationic glucocorticoids were synthesized using beclomethasone, budesonide, and flumethasone. ...[more]

PMID: 26004577

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Project description:BackgroundEmergence of cross-resistance to current anti-malarial drugs has led to an urgent need for identification of potential compounds with novel modes of action and anti-malarial activity against the resistant strains. One of the most promising therapeutic targets of anti-malarial agents related to food vacuole of malaria parasite is haemozoin, a product formed by the parasite through haemoglobin degradation.MethodsWith this in mind, this study developed two-dimensional-quantitative structure-activity relationships (QSAR) models of a series of 21 haemozoin inhibitors to explore the useful physicochemical parameters of the active compounds for estimation of anti-malarial activities. The 2D-QSAR model with good statistical quality using partial least square method was generated after removing the outliers.ResultsFive two-dimensional descriptors of the training set were selected: atom count (a_ICM); adjacency and distance matrix descriptor (GCUT_SLOGP_2: the third GCUT descriptor using atomic contribution to logP); average total charge sum (h_pavgQ) in pKa prediction (pH = 7); a very low negative partial charge, including aromatic carbons which have a heteroatom-substitution in "ortho" position (PEOE_VSA-0) and molecular descriptor (rsynth: estimating the synthesizability of molecules as the fraction of heavy atoms that can be traced back to starting material fragments resulting from retrosynthetic rules), respectively. The model suggests that the anti-malarial activity of haemozoin inhibitors increases with molecules that have higher average total charge sum in pKa prediction (pH = 7). QSAR model also highlights that the descriptor using atomic contribution to logP or the distance matrix descriptor (GCUT_SLOGP_2), and structural component of the molecules, including topological descriptors does make for better anti-malarial activity.ConclusionsThe model is capable of predicting the anti-malarial activities of anti-haemozoin compounds. In addition, the selected molecular descriptors in this QSAR model are helpful in designing more efficient compounds against the P. falciparum 3D7A strain.

Project description:Purpose:Preservative-free cationic emulsion-based artificial tears (ATs) or drug vehicles are innovative eye drop formulations with tear film stabilization and drug delivery properties, and valuable in vivo anti-inflammatory and wound healing properties. These ATs have recently reached the market as ATs for the management of dry eye disease (DED) symptoms (i.e., Cationorm) or as a drug vehicle for cyclosporine (Ikervis). The aim of the present study was to explore the mechanism of action underlying the intrinsic anti-inflammatory and wound-healing efficacies harbored by the cationic emulsions of cetalkonium chloride (CE-CKC). Methods:The anti-inflammatory activity of two CE-CKC (0.002% and 0.005% CKC) emulsions was evaluated by assessing the expression of proinflammatory genes and the secretion of various markers in the following human cell types stressed by different agents: peripheral blood mononuclear cells (PBMCs; stimulation with anti-CD3/anti-CD28 or lipopolysaccharide (LPS)), CD4+ T lymphocytes (TCD4; stimulation with anti-CD3/anti-CD28), and a human corneal epithelial cell line (HCE-2; stimulation with LPS). The cells were incubated for 30 min with a 10% dilution of CE-CKC emulsions and then cultured without the emulsions for 24 h or 72 h in the presence of the various challenging agents. The supernatant was collected, and the secreted markers quantitated with flow cytometry or an enzyme-linked immunosorbent assay (ELISA). Gene expression of inflammatory markers was evaluated only in the PBMCs and HCE-2 cells stimulated with LPS. The in vitro protein kinase C (PKC) binding assay for IC50 determination was performed using standard procedures. Results:The CE-CKC emulsions decreased inflammatory gene expression in LPS-stimulated PBMCs (IFN-?, IL-17A, CXCL-9, and TNF?) and LPS-stimulated HCE-2 cells (THBS1 and CCL2). Both CE-CKC emulsions inhibited the secretion of IL-17 (from anti-CD3/anti-CD28-stimulated TCD4), TNF?, IFN-?, and IL-2 (from anti-CD3-/anti-CD28-stimulated PBMCs), and IL-6 and IL-8 (from LPS-stimulated HCE-2). The in vitro PKC binding assay revealed that CKC, the cationic agent, is a specific PKC? inhibitor. In addition, tyloxapol, another excipient, showed some anti-inflammatory activity on IL-6 and IL-8 in the LPS-stimulated HCE-2 cells. Conclusions:This study indicates that the CE-CKC emulsions are able to directly modulate the secretion and expression of proinflammatory cytokines and chemokines. The results also suggest that CKC and tyloxapol are pharmacologically active excipients with potentially beneficial effects in vivo. These data shed new light on the efficacy observed on the DED signs of these CE-CKC emulsions in clinical trials.

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Synthesis and structure-activity relationships of novel cationic lipids with anti-inflammatory and antimicrobial activities.

Publications

Synthesis and structure-activity relationships of novel cationic lipids with anti-inflammatory and antimicrobial activities.

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