A Coarse-Grained Molecular Dynamics Perspective on the Release of 5-Fluorouracil from Liposomes.

Liposomes, small bilayer phospholipid-containing vesicles, are frequently used to ensure slow drug release for a prolonged and improved therapeutic effect. Nevertheless, current findings on the membrane affinity and permeability of the anticancer agent 5-fluorouracil (5-FU) are confounding, which leads to a lack of a clear understanding of how lipid composition impacts the distribution of 5-FU within liposomal structures and its delivery. In the current work, we report a comprehensive coarse-grained molecular dynamics (CGMD) investigation on the influence of cholesterol (CHOL) and the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) on the partitioning of 5-FU in 1,2-dipalmitoyl--glycero-3-phosphocholine (DPPC) double-bilayer systems, as well as its in vitro release from liposomes with identical lipid compositions.

Impact of Lipid Composition on Vesicle Protein Adsorption: A BSA Case Study.

Investigating the interaction between liposomes and proteins is of paramount importance in the development of liposomal formulations with real potential for bench-to-bedside transfer. Upon entering the body, proteins are immediately adsorbed on the liposomal surface, changing the nanovehicles' biological identity, which has a significant impact on their biodistribution and pharmacokinetics and ultimately on their therapeutic effect. Albumin is the most abundant plasma protein and thus usually adsorbs immediately on the liposomal surface.

Exploring Pyrrolo-Fused Heterocycles as Promising Anticancer Agents: An Integrated Synthetic, Biological, and Computational Approach.

Five new series of pyrrolo-fused heterocycles were designed through a scaffold hybridization strategy as analogs of the well-known microtubule inhibitor phenstatin. Compounds were synthesized using the 1,3-dipolar cycloaddition of cycloimmonium N-ylides to ethyl propiolate as a key step. Selected compounds were then evaluated for anticancer activity and ability to inhibit tubulin polymerization in vitro.

Synthesis and Biological Screening of New Cyano-Substituted Pyrrole Fused (Iso)Quinoline Derivatives.

Several new cyano-substituted derivatives with pyrrolo[1,2-]quinoline and pyrrolo[2,1-]isoquinoline scaffolds were synthesized by the [3 + 2] cycloaddition of (iso)quinolinium ylides to fumaronitrile. The cycloimmonium ylides reacted in situ as 1,3-dipoles with fumaronitrile to selectively form distinct final compounds, depending on the structure of the (iso)quinolinium salt. Eleven compounds were evaluated for their anticancer activity against a panel of 60 human cancer cell lines.

Cytotoxic substituted indolizines as new colchicine site tubulin polymerisation inhibitors.

A potential microtubule destabilising series of new indolizine derivatives was synthesised and tested for their anticancer activity against a panel of 60 human cancer cell lines. Compounds , , , and showed a broad spectrum of growth inhibitory activity against cancer cell lines representing leukaemia, melanoma and cancer of lung, colon, central nervous system, ovary, kidney, breast, and prostate. Among them, compound was distinguishable by its excellent cytostatic activity, showing GI values in the range of 10-100 nM on 43 cell lines.

Design, Synthesis, Molecular Modelling and Anticancer Activities of New Fused Phenanthrolines.

Three series of fused pyrrolophenanthroline derivatives were designed as analogues of phenstatin and synthesized in two steps starting with 1,7-phenanthroline, 4,7-phenanthroline and 1,10-phenanthroline, respectively. Two (Compounds and ) of the four compounds tested against a panel of sixty human cancer cell lines of the National Cancer Institute (NCI) exhibited significant growth inhibition activity on several cell lines. Compound showed a broad spectrum in terms of antiproliferative efficacy with GI values in the range of 0.

Synthesis, molecular modelling and anticancer evaluation of new pyrrolo[1,2-b]pyridazine and pyrrolo[2,1-a]phthalazine derivatives.

Two new series of heterocyclic derivatives with potential anticancer activity, in which a pyrrolo[1,2-b]pyridazine or a pyrrolo[2,1-a]phthalazine moiety was introduced in place of the 3'-hydroxy-4'-methoxyphenyl ring of phenstatin have been synthesised and their structure-activity relationship (SAR) was studied. Fourteen of the new compounds were evaluated for their in vitro cytotoxic activity by National Cancer Institute (NCI) against 60 human tumour cell lines panel. The best five compounds in terms of in vitro growth inhibition were screened in the second stage five dose-response studies, three of them showing a very good antiproliferative activity with GI<100 nM on several cell lines including colon, ovarian, renal, prostate, brain and breast cancer, melanoma and leukemia.

Advantages of Graphene Biosensors for Human Stem Cell Therapy Potency Assays.

Regenerative medicine is challenged by the need to conform to rigorous guidelines for establishing safe and effective development and translation of stem cell-based therapies. Counteracting widespread concerns regarding unproven cell therapies, stringent cell-based assays seek not only to avoid harm but also to enhance quality and efficacy. Potency indicates that the cells are functionally fit for purpose before they are administered to the patient.

Versatile graphene biosensors for enhancing human cell therapy.

Technological advances in engineering and cell biology stimulate novel approaches for medical treatment, in particular cell-based therapy. The first cell-based gene therapy against cancer was recently approved by the US Food and Drug Administration. Progress in cancer diagnosis includes a blood test detecting five cancer types.

Ligand-selective small molecule modulators of the constitutively active vGPCR US28.

US28 is a broad-spectrum constitutively active G protein-coupled receptor encoded by the human cytomegalovirus (HCMV). It binds and scavenges multiple CC-chemokines as well as CXCL1 (fractalkine) by constitutive receptor endocytosis to escape immune surveillance. We herein report the design and characterization of a novel library of US28-acting commercially available ligands based on the molecular descriptors of two previously reported US28-acting structures.

Molecular Mechanism of Action for Allosteric Modulators and Agonists in CC-chemokine Receptor 5 (CCR5).

The small molecule metal ion chelators bipyridine and terpyridine complexed with Zn (ZnBip and ZnTerp) act as CCR5 agonists and strong positive allosteric modulators of CCL3 binding to CCR5, weak modulators of CCL4 binding, and competitors for CCL5 binding. Here we describe their binding site using computational modeling, binding, and functional studies on WT and mutated CCR5. The metal ion Zn is anchored to the chemokine receptor-conserved Glu-283 Both chelators interact with aromatic residues in the transmembrane receptor domain.

Structure-based discovery of novel US28 small molecule ligands with different modes of action.

The human cytomegalovirus-encoded G protein-coupled receptor US28 is a constitutively active receptor, which can recognize various chemokines. Despite the recent determination of its 2.9 Å crystal structure, potent and US28-specific tool compounds are still scarce.

Probing Biased Signaling in Chemokine Receptors.

The chemokine system mediates leukocyte migration during homeostatic and inflammatory processes. Traditionally, it is described as redundant and promiscuous, with a single chemokine ligand binding to different receptors and a single receptor having several ligands. Signaling of chemokine receptors occurs via two major routes, G protein- and β-arrestin-dependent, which can be preferentially modulated depending on the ligands or receptors involved, as well as the cell types or tissues in which the signaling event occurs.