Development and characterization of a novel antiacne niosomal gel of rosmarinic acid.

The antibacterial and anti-inflammatory potential of rosemarinic acid (ROA), a naturally occurring ester of caffeic acid has been well reported. Antibacterial effect of ROA is attributed to nucleoid damage with an increase in spatial division and condensation of genetic material. ROA has been found dynamic against many human pathogenic bacterial strains but its inhibitory prospective has never been established against skin inflammations caused by Propionibacterium acne. The skin surface in acne prone areas is colonized with Staphylococcus aureus and Propionibacterium acnes which contribute to inflammation and acne. Resistance to current antimicrobial therapies suggested the need to explore new antimicrobial agents against acne. Present work included the preparation of ROA-loaded niosomes and their in vitro antimicrobial evaluation against P. acne and S. aureus. This work also included the development of niosomal gel of rosmarinic acid for sustained delivery to bacteria infected cells. Niosomes of rosmarinic acid were formulated by reverse phase evaporation method using different ratio of span 85 and cholesterol. The prepared formulations were evaluated for its vesicle size, entrapment efficiency, in vitro release study and antibacterial activity. In vivo study of developed formulation was conducted on Swiss albino mice in comparison with solution of plain drug and a marketed formulation of benzoyl peroxide. It was evident that niosomes are novel carrier for delivery of naturally occurring antimicrobial agents, in deeper tissues of skin. The results showed that drug-loaded niosomes dispersed in the gelling agent are an effective delivery system for treatment of acne vulgaris.

Chalcone based azacarboline analogues as novel antitubulin agents: design, synthesis, biological evaluation and molecular modelling studies.

The present study involves the design of a series of 3-aryl-9-acetyl-pyridazino[3,4-b]indoles as constrained chalcone analogues. A retrosynthetic route was proposed for the synthesis of target compounds. All the synthesized compounds were evaluated for in-vitro cytotoxicity against THP-1, COLO-205, HCT-116 and A-549 human cancer cell lines. The results indicated that 2a, 3a, 5a and 6a possessed significant cytotoxic potential with an IC50 value ranging from 1.13 to 5.76 µM. Structure activity relationship revealed that the nature of both Ring A and Ring B influences the activity. Substitution of methoxy groups on the phenyl ring (Ring A) and unsubstituted phenyl ring (Ring B) were found to be the preferred structural features. The most potent compound 2a was further tested for tubulin inhibition. Compound 2a was found to significantly inhibit the tubulin polymerization (IC50 value - 2.41 µM against THP-1). Compound 2a also caused disruption of microtubule assembly as evidenced by Immunoflourescence technique. The significant cytotoxicity and tubulin inhibition by 2a was rationalized by molecular modelling studies. The most potent structure was docked at colchicine binding site (PDB ID-1SA0) and was found to be stabilized in the cavity via various hydrophobic and hydrogen bonding interactions.

Anticancer hybrids--a patent survey.

The molecular hybridization (MH) is a strategy of rational design of such ligands or prototypes based on the recognition of pharmacophoric sub-units in the molecular structure of two or more known bioactive derivatives which, through the adequate fusion of these sub-units, lead to the design of new hybrid architectures that maintain pre-selected characteristics of the original templates. The concept of molecular hybridization and the promises/challenges associated with these hybrid molecules along with recent advances on anticancer hybrids and critical discussions on the future aspects of the hybrid drugs have already been presented through a number of reports. However, this article presents the structures of potent hybrids reported during the last two decades along with a detailed account of the patent literature. Significant number of patents on the molecules designed through this valuable drug design technique clearly highlight the present focus of the researchers all around the globe towards hybrid molecules capable of amplifying the effect of individual functionalities through action on another bio target or to interact with multiple targets as one single molecule lowering the risk of drug-drug interactions and minimizing the drug resistance. This review article basically emphasizes the patent literature along with an overview of potent hybrid structures, their IC50 /GI50 values against the various cell lines employed. The present compilation can be utilized as a guide for the medicinal chemists focusing on this area of drug design.

Lipoplexes versus nanoparticles: pDNA/siRNA delivery.

Small interfering RNA (siRNA) has been widely used as potential therapeutic for treatment of various genetic disorders. However, rapid degradation, poor cellular uptake and limited stability in blood limit the effectiveness of the systemic delivery of siRNA. Therefore, an efficient delivery system is required to enhance its transfection and duration of therapeutics. In the present study, plasmid DNA (pEGFPN3) expressing green fluorescent protein (GFP) was used as a reporter gene. Chitosan nanoparticles/polyplexes and cationic liposomes/lipoplexes were developed and compared for their transfectivity and therapeutic activity in mammalian cell line (HEK 293). The nanoparticulates were first characterized by assessing the surface charge (zeta potential), size (dynamic light scattering) and morphology (transmission electron microscope) followed by evaluation for their DNA retardation ability, transfection efficiency and cytotoxicity on HEK 293 cell line. The chitosan nanoparticles/plasmid DNA (pDNA) complex and liposomes/pDNA complex were co-transfected with GFP-specific siRNA into HEK 293 cells and it was found that both are efficient delivery vehicles for siRNA transfection, resulting in ~57% and ~70% suppression of the targeted gene (GFP), respectively, as compared with the mock control (cells transfected with nanocarrier/pDNA complexes alone). This strong inhibition of GFP expression indicated that cationic liposomes are better than chitosan nanoparticles and can be used as an effective carrier of siRNA in mammalian cells.

Synthesis and evaluation of novel 3a,9a-dihydro-1-ethoxycarbonyl-1-cyclopenteno[5,4-b]benzopyran-4-ones as antifungal agents.

An efficient synthesis of novel antifungal 3a,9a-dihydro-1-ethoxycarbonyl-1-cyclopenteno[5,4-b]benzopyran-4-ones (10a-j) through 1,3-dipolar cycloaddition of all carbon 1,3-dipole (7) with substituted 3-formylchromones (8a-j) has been developed. The synthesized compounds were characterized spectroscopically and evaluated in vitro for antifungal activity against various strains. Some of the compounds 10b, 10d and 10i exhibit significant inhibitory potential against Aspergillus niger, Saccahromyces cerevisiae and Candida albicans.

Intracellular delivery of redox cycler-doxorubicin to the mitochondria of cancer cell by folate receptor targeted mitocancerotropic liposomes.

Cancer cells reflect higher level of ROS in comparison to the normal cell, so they become more vulnerable to further oxidative stress induced by exogenous ROS-generating agents. Through this a novel therapeutic strategy has evolved, which involves the delivery of redox cycler-doxorubicin (DOX) to the mitochondria of cancer cell where it acts as a source of exogenous ROS production. The purpose of this study is to develop a liposomal preparation which exhibits a propensity to selectively target cancer cell along with the potential of delivering drug to mitochondria of cell. We have rendered liposomes mitocancerotropic (FA-MTLs) by their surface modification with dual ligands, folic acid (FA) for cancer cell targeting and triphenylphosphonium (TPP) cations for mitochondria targeting. The cytotoxicity, ROS production and cell uptake of doxorubicin loaded liposomes were evaluated in FR (+) KB cells and found to be increased considerably with FA-MTLs in comparison to folic acid appended, mitochondria targeted and non-targeted liposomes. As confirmed by confocal microscopy, the STPP appended liposomes delivered DOX to mitochondria of cancer cell and also showed higher ROS production and cytotoxicity in comparison to folic acid appended and non-targeted liposomes. Most importantly, mitocancerotropic liposomes showed superior activity over mitochondria targeted liposomes which confirm the synergistic effect imparted by the presence of dual ligands - folic acid and TPP on the enhancement of cellular and mitochondrial delivery of doxorubicin in KB cells.

siRNA delivery using nanocarriers - an efficient tool for gene silencing.

Small interfering RNAs (siRNA) are one of the most recent additions used to silence gene expression. At present siRNA is the most extensively used gene-silencing technique over other nucleic-acid based approaches to treat disease including cancer, hepatitis, respiratory disease, cardiovascular diseases, neuronal disease and autoimmune disease. However, systemic delivery of siRNA in vivo, remains to be the biggest challenge to be overcome. Various strategies have been developed to deliver siRNA efficiently into target cell such as chemical modification of siRNA, physical strategies, viral and non viral-vectors mediated delivery. Among all the approaches non viral vectors including lipoplexes and polyplexes were found to be most successful which have been reviewed in this article. Further therapeutic applications of RNAi have also been briefly reviewed.