Novel Dual AChE and ROCK2 Inhibitor Induces Neurogenesis via PTEN/AKT Pathway in Alzheimer's Disease Model.

Alzheimer's disease (AD) is a progressive and complex neurodegenerative disease. Acetylcholinesterase inhibitors (AChEIs) are a major class of drugs used in AD therapy. ROCK2, another promising target for AD, has been associated with the induction of neurogenesis via PTEN/AKT. This study aimed to characterize the therapeutic potential of a novel donepezil-tacrine hybrid compound (TA8Amino) to inhibit AChE and ROCK2 protein, leading to the induction of neurogenesis in SH-SY5Y cells. Experiments were carried out with undifferentiated and neuron-differentiated SH-SY5Y cells submitted to treatments with AChEIs (TA8Amino, donepezil, and tacrine) for 24 h or 7 days. TA8Amino was capable of inhibiting AChE at non-cytotoxic concentrations after 24 h. Following neuronal differentiation for 7 days, TA8Amino and donepezil increased the percentage of neurodifferentiated cells and the length of neurites, as confirmed by ß-III-tubulin and MAP2 protein expression. TA8Amino was found to participate in the activation of PTEN/AKT signaling. In silico analysis showed that TA8Amino can stably bind to the active site of ROCK2, and in vitro experiments in SH-SY5Y cells demonstrate that TA8Amino significantly reduced the expression of ROCK2 protein, contrasting with donepezil and tacrine. Therefore, these results provide important information on the mechanism underlying the action of TA8Amino with regard to multi-target activities.

A closer look at the synthesis of 2-[18F]fluoroethyl tosylate to minimize the formation of volatile side-products.

BACKGROUND: 2-[18F]Fluoroethyltosylate ([18F]FEtOTs) is a well-known 18F-fluoroalkylating agent widely used to synthesize radiotracers for positron emission tomography. The widespread use of [18F]FEtOTs is due in part to its low volatility when compared to other halide and sulfonate building blocks. In this work, the radioactive volatile side-products formed during the synthesis of [18F]FEtOTs were identified and characterized for the first time, and an optimization of the reaction conditions to minimize their formation was proposed. RESULTS: In order to characterize the volatiles produced during [18F]FEtOTs synthesis, the reaction mixtures of both cold FEtOTs and [18F]FEtOTs were co-injected onto the HPLC system. The radioactive peaks corresponding to the volatile compounds were collected, analyzed through headspace gas chromatography mass spectrometry sampler (HS-GC-MS) and identified as vinyl fluoride ([19F]VF) and 2-fluoroethanol ([19F]FEOH). By using a rotatable central composite design with a two-level full factorial core of two factors (22), it was determined that temperature and time are independent variables which affect the generation of [18F]VF and [18F]FEOH during the radiosynthesis of [18F]FEtOTs. In addition, in order to reduce the formation of the volatiles ([18F]VF and [18F]FEOH) and increase the yield of [18F]FEtOTs, it was demonstrated that the molar ratio of base to precursor must also be considered. CONCLUSION: [18F]VF and [18F]FEOH are volatile side-products formed during the radiosynthesis of [18F]FEtOTs, whose yields depend on the reaction time, temperature, and the molar ratio of base to precursor. Therefore, special care should be taken during the radiosynthesis and subsequent reactions using [18F]FEOTs in order to avoid environmental contamination and to improve the yield of the desired products.

Neuroprotective Effects of Cholinesterase Inhibitors: Current Scenario in Therapies for Alzheimer's Disease and Future Perspectives.

Alzheimer's disease (AD) is a slowly progressive neurodegenerative disease conceptualized as a continuous process, ranging from mild cognitive impairment (MCI), to the mild, moderate, and severe clinical stages of AD dementia. AD is considered a complex multifactorial disease. Currently, the use of cholinesterase inhibitors (ChEI), such as tacrine, donepezil, rivastigmine, and galantamine, has been the main treatment for AD patients. Interestingly, there is evidence that ChEI also promotes neuroprotective effects, bringing some benefits to AD patients. The mechanisms by which the ChEI act have been investigated in AD. ChEI can modulate the PI3K/AKT pathway, which is an important signaling cascade that is capable of causing a significant functional impact on neurons by activating cell survival pathways to promote neuroprotective effects. However, there is still a huge challenge in the field of neuroprotection, but in the context of unravelling the details of the PI3K/AKT pathway, a new scenario has emerged for the development of more efficient drugs that act on multiple protein targets. Thus, the mechanisms by which ChEI can promote neuroprotective effects and prospects for the development of new drug candidates for the treatment of AD are discussed in this review.

Synthesis, biological evaluation and molecular docking studies of novel 1,2,3-triazole-quinazolines as antiproliferative agents displaying ERK inhibitory activity.

ERK1/2 inhibitors have attracted special attention concerning the ability of circumventing cases of innate or log-term acquired resistance to RAF and MEK kinase inhibitors. Based on the 4-aminoquinazoline pharmacophore of kinases, herein we describe the synthesis of 4-aminoquinazoline derivatives bearing a 1,2,3-triazole stable core to bridge different aromatic and heterocyclic rings using copper-catalysed azide-alkyne cycloaddition reaction (CuAAC) as a Click Chemistry strategy. The initial screening of twelve derivatives in tumoral cells (CAL-27, HN13, HGC-27, and BT-20) revealed that the most active in BT-20 cells (25a, IC50 24.6 µM and a SI of 3.25) contains a more polar side chain (sulfone). Furthermore, compound 25a promoted a significant release of lactate dehydrogenase (LDH), suggesting the induction of cell death by necrosis. In addition, this compound induced G0/G1 stalling in BT-20 cells, which was accompanied by a decrease in the S phase. Western blot analysis of the levels of p-STAT3, p-ERK, PARP, p53 and cleaved caspase-3 revealed p-ERK1/2 and p-STA3 were drastically decreased in BT-20 cells under 25a incubation, suggesting the involvement of these two kinases in the mechanisms underlying 25a-induced cell cycle arrest, besides loss of proliferation and viability of the breast cancer cell. Molecular docking simulations using the ERK-ulixertinib crystallographic complex showed compound 25a could potentially compete with ATP for binding to ERK in a slightly higher affinity than the reference ERK1/2 inhibitor. Further in silico analyses showed comparable toxicity and pharmacokinetic profiles for compound 25a in relation to ulixertinib.

Improving Cytotoxicity against Breast Cancer Cells by Using Mixed-Ligand Ruthenium(II) Complexes of 2,2'-Bipyridine, Amino Acid, and Nitric Oxide Derivatives as Potential Anticancer Agents.

BACKGROUND: Several metal-based molecules that display cytotoxicity against multiple cell lines have been pursued in an attempt to fight against cancer and to overcome the typical side effects of drugs like cisplatin. In this scenario, ruthenium complexes have been extensively studied due to their activity in both in vitro and in vivo biological systems, including various cancer cell strains. OBJECTIVE: We aimed to develop a method to synthesize novel [Ru(NO)(bpy)2L2]2+ complexes containing amino acid ligands by using an alternative Click Chemistry approach, namely the copper azide-alkyne cycloaddition reaction (CuAAC reaction), to construct nitrosyl/nitrite complexes bearing a modified lysine residue. METHODS: We synthesized a new ligand by Click Chemistry approach and new compounds bearing the unprecedented ligand. Cytotoxicity was assessed by the classical MTT colorimetric assay. MCF-7 and MDAMB- 231 cells were used as breast cancer cell models. MCF-10 was used as a model of healthy cells. RESULTS: Amino acid ligands related to N3-Lys(Fmoc) and the new pyLys were successfully synthesized by the diazotransfer reaction and the CuAAC reaction, respectively. The latter reaction involves coupling between N3-Lys(Fmoc) and 3ethynylpyridine. Both N3-Lys(Fmoc) and the new pyLys were introduced into the ruthenium bipyridine complex I, or cis-[RuII(NO)(NO2)(bpy)2]2+, to generate the common nitro-based complex III, which was further converted to the final complex IV. Results of the MTT assay proved the cytotoxic effect of cis- [RuII(NO)(pyLysO-)(bpy)2](PF6)2 against the mammalian breast cancer cells MCF-7 and MDA-MB231. CONCLUSION: The viability assays revealed that complex IV, bearing a NO group and a modified lysine residue, was able to release NO and cross tumor cell membranes. In this work, Complex IV was observed to be the most active ruthenium bipyridine complex against the mammalian breast cancer cells MCF-7 and MDA-MB231: it was approximately twice as active as cisplatin, whilst complexes I-III proved to be less cytotoxic than complex IV. Additional tests using healthy MCF 10A cells showed that complexes II-IV were three- to sixfold less toxic than cisplatin, which suggested that complex IV was selective against cancer cells.

Synthesis of MUC1-derived glycopeptide bearing a novel triazole STn analog.

The synthesis of MUC1 glycopeptides bearing modified tumor-associated carbohydrate antigens (TACAs) represents an effective strategy to develop potential antitumor vaccines that trigger strong immune response. In this context, we present herein the multistep synthesis of the triazole glycosyl amino acid Neu5Ac-α/ß2-triazole-6-ßGalNAc-ThrOH 1 as STn antigen analog, along with its assembly on the corresponding MUC1 peptide to give NAcProAsp [Neu5Acα/ß2-triazole-6-ßGalNAc]ThrArgProGlyOH 2. Despite interacting differently with SM3 monoclonal antibody, as shown by molecular dynamic simulations, this unnatural triazole glycopeptide may represent a promising candidate for cancer immunotherapy.

Novel Hybrid Acetylcholinesterase Inhibitors Induce Differentiation and Neuritogenesis in Neuronal Cells in vitro Through Activation of the AKT Pathway.

BACKGROUND: Alzheimer's disease (AD) is characterized by a progressive loss of episodic memory associated with amyloid-ß peptide aggregation and the abnormal phosphorylation of the tau protein, leading to the loss of cholinergic function. Acetylcholinesterase (AChE) inhibitors are the main class of drugs used in AD therapy. OBJECTIVE: The aim of the current study was to evaluate the potential of two tacrine-donepezil hybrid molecules (TA8Amino and TAHB3), which are AChE inhibitors, to induce neurodifferentiation and neuritogenesis in SH-SY5Y cells. METHODS: The experiments were carried out to characterize neurodifferentiation, cellular changes related to responses to oxidative stress and pathways of cell survival in response to drug treatments. RESULTS: The results indicated that the compounds did not present cytotoxic effects in SH-SY5Y or HepG2 cells. TA8Amino and TAHB3 induced neurodifferentiation and neuritogenesis in SH-SY5Y cells. These cells showed increased levels of intracellular and mitochondrial reactive oxygen species; the induction of oxidative stress was also demonstrated by an increase in SOD1 expression in TA8Amino and TAHB3-treated cells. Cells treated with the compounds showed an increase in PTEN(Ser380/Thr382/383) and AKT(Ser473) expression, suggesting the involvement of the AKT pathway. CONCLUSION: Our results demonstrated that TA8Amino and TAHB3 present advantages as potential drugs for AD therapy and that they are capable of inducing neurodifferentiation and neuritogenesis.

Synthesis and Evaluation of [18F]FEtLos and [18F]AMBF3Los as Novel 18F-Labelled Losartan Derivatives for Molecular Imaging of Angiotensin II Type 1 Receptors.

Losartan is widely used in clinics to treat cardiovascular related diseases by selectively blocking the angiotensin II type 1 receptors (AT1Rs), which regulate the renin-angiotensin system (RAS). Therefore, monitoring the physiological and pathological biodistribution of AT1R using positron emission tomography (PET) might be a valuable tool to assess the functionality of RAS. Herein, we describe the synthesis and characterization of two novel losartan derivatives PET tracers, [18F]fluoroethyl-losartan ([18F]FEtLos) and [18F]ammoniomethyltrifluoroborate-losartan ([18F]AMBF3Los). [18F]FEtLos was radiolabeled by 18F-fluoroalkylation of losartan potassium using the prosthetic group 2-[18F]fluoroethyl tosylate; whereas [18F]AMBF3Los was prepared following an one-step 18F-19F isotopic exchange reaction, in an overall yield of 2.7 ± 0.9% and 11 ± 4%, respectively, with high radiochemical purity (>95%). Binding competition assays in AT1R-expressing membranes showed that AMBF3Los presented an almost equivalent binding affinity (Ki 7.9 nM) as the cold reference Losartan (Ki 1.5 nM), unlike FEtLos (Ki 2000 nM). In vitro and in vivo assays showed that [18F]AMBF3Los displayed a good binding affinity for AT1R-overexpressing CHO cells and was able to specifically bind to renal AT1R. Hence, our data demonstrate [18F]AMBF3Los as a new tool for PET imaging of AT1R with possible applications for the diagnosis of cardiovascular, inflammatory and cancer diseases.

Antitumour Anthracyclines: Progress and Perspectives.

Anthracyclines are ranked among the most effective chemotherapeutics against cancer. They are glycoside drugs comprising the amino sugar daunosamine linked to a hydroxy anthraquinone aglycone, and act by DNA intercalation, oxidative stress generation and topoisomerase II poisoning. Regardless of their therapeutic value, multidrug resistance and severe cardiotoxicity are important limitations of anthracycline treatment that have prompted the discovery of novel analogues. This review covers the most clinically relevant anthracyclines and their development over decades, since the first discovered natural prototypes to recent semisynthetic and synthetic derivatives. These include registered drugs, drug candidates undergoing clinical trials, and compounds under pre-clinical investigation. The impact of the structural modifications on antitumour activity, toxicity and resistance profile is addressed.

1,2,3-Triazole tethered 2-mercaptobenzimidazole derivatives: design, synthesis and molecular assessment toward C6 glioma cell line.

Aim: Glioblastoma multiforme (GBM) is an aggressive cancer with very limited clinical therapies. Herein, we have designed novel mercaptobenzimidazole derivatives (1-7) as multitarget antineoplastic drugs and assessed their antiproliferative profiles on an experimental model for GBM, the C6 glioma line. Results: The target compounds were synthesized in few steps with reasonable yields (33-90%). Compounds 1 (∼18 µM) and 4 (∼20 µM) showed dose-dependent antiproliferative effects on C6 glioma and significantly increased early apoptosis, but only 4 disrupted the cell cycle progression and did not induce autophagy. Docking simulations suggested these compounds as dual kinase and colchicine binding site inhibitors. Conclusion: In spite of the limited selective toxicity, 4 hold the potential to be further optimized for the treatment of GBM.

Iminosugars: Effects of Stereochemistry, Ring Size, and N-Substituents on Glucosidase Activities.

N-substituted iminosugar analogues are potent inhibitors of glucosidases and glycosyltransferases with broad therapeutic applications, such as treatment of diabetes and Gaucher disease, immunosuppressive activities, and antibacterial and antiviral effects against HIV, HPV, hepatitis C, bovine diarrhea (BVDV), Ebola (EBOV) and Marburg viruses (MARV), influenza, Zika, and dengue virus. Based on our previous work on functionalized isomeric 1,5-dideoxy-1,5-imino-D-gulitol (L-gulo-piperidines, with inverted configuration at C-2 and C-5 in respect to glucose or deoxynojirimycin (DNJ)) and 1,6-dideoxy-1,6-imino-D-mannitol (D-manno-azepane derivatives) cores N-linked to different sites of glucopyranose units, we continue our studies on these alternative iminosugars bearing simple N-alkyl chains instead of glucose to understand if these easily accessed scaffolds could preserve the inhibition profile of the corresponding glucose-based N-alkyl derivatives as DNJ cores found in miglustat and miglitol drugs. Thus, a small library of iminosugars (14 compounds) displaying different stereochemistry, ring size, and N-substitutions was successfully synthesized from a common precursor, D-mannitol, by utilizing an SN2 aminocyclization reaction via two isomeric bis-epoxides. The evaluation of the prospective inhibitors on glucosidases revealed that merely D-gluco-piperidine (miglitol, 41a) and L-ido-azepane (41b) DNJ-derivatives bearing the N-hydroxylethyl group showed inhibition towards α-glucosidase with IC50 41 µM and 138 µM, respectively, using DNJ as reference (IC50 134 µM). On the other hand, ß-glucosidase inhibition was achieved for glucose-inverted configuration (C-2 and C-5) derivatives, as novel L-gulo-piperidine (27a) and D-manno-azepane (27b), preserving the N-butyl chain, with IC50 109 and 184 µM, respectively, comparable to miglustat with the same N-butyl substituent (40a, IC50 172 µM). Interestingly, the seven-membered ring L-ido-azepane (40b) displayed near twice the activity (IC50 80 µM) of the corresponding D-gluco-piperidine miglustat drug (40a). Furthermore, besides α-glucosidase inhibition, both miglitol (41a) and L-ido-azepane (41b) proved to be the strongest ß-glucosidase inhibitors of the series with IC50 of 4 µM.

Highly potent and selective aryl-1,2,3-triazolyl benzylpiperidine inhibitors toward butyrylcholinesterase in Alzheimer's disease.

Acetylcholinesterase (AChE) is the key enzyme targeted in Alzheimer's disease (AD) therapy, nevertheless butyrylcholinesterase (BuChE) has been drawing attention due to its role in the disease progression. Thus, we aimed to synthesize novel cholinesterases inhibitors considering structural differences in their peripheral site, exploiting a moiety replacement approach based on the potent and selective hAChE drug donepezil. Hence, two small series of N-benzylpiperidine based compounds have successfully been synthesized as novel potent and selective hBuChE inhibitors. The most promising compounds (9 and 11) were not cytotoxic and their kinetic study accounted for dual binding site mode of interaction, which is in agreement with further docking and molecular dynamics studies. Therefore, this study demonstrates how our strategy enabled the discovery of novel promising and privileged structures. Remarkably, compound 11 proved to be one of the most potent (0.17 nM) and selective (>58,000-fold) hBuChE inhibitor ever reported.

Potential Triazole-based Molecules for the Treatment of Neglected Diseases.

Neglected Diseases (NDs) affect million of people, especially the poorest population around the world. Several efforts to an effective treatment have proved insufficient at the moment. In this context, triazole derivatives have shown great relevance in medicinal chemistry due to a wide range of biological activities. This review aims to describe some of the most relevant and recent research focused on 1,2,3- and 1,2,4-triazolebased molecules targeting four expressive NDs: Chagas disease, Malaria, Tuberculosis and Leishmaniasis.

Protozoan Parasites Glycosylphosphatidylinositol Anchors: Structures, Functions and Trends for Drug Discovery.

BACKGROUND: Glycosylphosphatidylinositol (GPI) anchors are molecules located on cell membranes of all eukaryotic organisms. Proteins, enzymes, and other macromolecules which are anchored by GPIs are essential elements for interaction between cells, and are widely used by protozoan parasites when compared to higher eukaryotes. METHODS: More than one hundred references were collected to obtain broad information about mammalian and protozoan parasites' GPI structures, biosynthetic pathways, functions and attempts to use these molecules as drug targets against parasitic diseases. Differences between GPI among species were compared and highlighted. Strategies for drug discovery and development against protozoan GPI anchors were discussed based on what has been reported on literature. RESULTS: There are many evidences that GPI anchors are crucial for parasite's survival and interaction with hosts' cells. Despite all GPI anchors contain a conserved glycan core, they present variations regarding structural features and biosynthetic pathways between organisms, which could offer adequate selectivity to validate GPI anchors as drug targets. Discussion was developed with focus on the following parasites: Trypanosoma brucei, Trypanosoma cruzi, Leishmania, Plasmodium falciparum and Toxoplasma gondii, causative agents of tropical neglected diseases. CONCLUSION: This review debates the main variances between parasitic and mammalian GPI anchor biosynthesis and structures, as well as clues for strategic development for new anti-parasitic therapies based on GPI anchors.

Novel glucopyranoside C2-derived 1,2,3-triazoles displaying selective inhibition of O-GlcNAcase (OGA).

O-GlcNAcylation or O-GlcNAc modification is a post-translational modification of several proteins responsible for fundamental cellular processes. Dysregulation of the O-GlcNAc pathway has been linked to the etiology of several diseases such as neurodegenerative and cardiovascular diseases, type 2 diabetes and cancer. O-GlcNAcase (OGA) catalyzes the removal of O-GlcNAc from the modified proteins and several carbohydrate-based OGA inhibitors have been synthesized to understand the role of O-GlcNAc-modified proteins in physiological and pathological conditions. However, many of the inhibitors lack selectivity for OGA over lysosomal hexosaminidases A and B. Aiming the selectively inhibition of OGA, we propose herein the synthesis of twelve novel glucopyranoside derivatives exploring the bioisosteric replacement of the GlcNAc 2-acetamide group by 1,4-disubstituted 1,2,3-triazole ring, bearing a variety of central chains with different shapes. Compounds were readily prepared through "Copper(I) Catalyzed Azide/Alkyne Cycloaddition" (CuAAC) reaction between a sugar azide and different terminal alkynes. Initial Western Blot analyses and further inhibitory assays proved that compounds 6a (IC50 = 0.50 ± 0.02 µM, OGA), 6k (IC50 = 0.52 ± 0.01 µM, OGA) and 6l (IC50 = 0.72 ± 0.02 µM, OGA) were the most potent and selective compounds of the series. Structure-activity relationship analyses and molecular docking simulations demonstrated that the bridge of two-carbon atoms between the C-4 position of the triazole and the phenyl ring (6a), which may be replaced by heteroatoms such as N (6k) or O (6l), is fundamental for accommodation and inhibition within OGA catalytic pocket.

Biological and In silico Studies on Synthetic Analogues of Tyrosine Betaine as Inhibitors of Neprilysin - A Drug Target for the Treatment of Heart Failure.

BACKGROUND: Fungal secondary metabolites are important sources for the discovery of new pharmaceuticals, as exemplified by penicillin, lovastatin and cyclosporine. Searching for secondary metabolites of the fungi Metarhizium spp., we previously identified tyrosine betaine as a major constituent. METHODS: Because of the structural similarity with other inhibitors of neprilysin (NEP), an enzyme explored for the treatment of heart failure, we devised the synthesis of tyrosine betaine and three analogues to be subjected to in vitro NEP inhibition assays and to molecular modeling studies. RESULTS: In spite of the similar binding modes with other NEP inhibitors, these compounds only displayed moderate inhibitory activities (IC50 ranging from 170.0 to 52.9 µM). However, they enclose structural features required to hinder passive blood brain barrier permeation (BBB). CONCLUSIONS: Tyrosine betaine remains as a starting point for the development of NEP inhibitors because of the low probability of BBB permeation and, consequently, of NEP inhibition at the Central Nervous System, which is associated to an increment in the Aß levels and, accordingly, with a higher risk for the onset of Alzheimer's disease.

Insights into Anti-Trypanosomal Agents Based on Synthetic Glycoconjugates.

Chagas disease is still a worldwide threat, with estimated 6 to 7 million infected people, mainly in Latin America. Current treatments still rely only on benznidazol and nifurtimox, drugs with poor efficacy in chronic infection phase and recognized toxicity. Thus, there is an urgent need for new therapeutic agents against this disease. In this review we present an updated selection over the last decade of synthetic glycoconjugates as anti-trypanosomal agents, properly addressed as monosaccharideand disaccharide-based agents, and multivalent-based derivatives, disclosing relevant methods for their synthesis, along with their activities on T. cruzi and its trans-sialidase (TcTS). In addition, synthetic glycoconjugates as potential vaccines and diagnostic antigens against T. cruzi are also reported.

Chameleon-like behavior of indolylpiperidines in complex with cholinesterases targets: Potent butyrylcholinesterase inhibitors.

Alzheimer's disease (AD) is the most common form of dementia worldwide with an increasing prevalence for the next years. The multifactorial nature of AD precludes the design of new drugs directed to a single target being probably one of the reasons for recent failures. Therefore, dual binding site acetylcholinesterase (AChE) inhibitors have been revealed as cognitive enhancers and ß-amyloid modulators offering an alternative in AD therapy field. Based on the dual ligands NP61 and donepezil, the present study reports the synthesis of a series of indolylpiperidines hybrids to optimize the NP61 structure preserving the indole nucleus, but replacing the tacrine moiety of NP61 by benzyl piperidine core found in donepezil. Surprisingly, this new family of indolylpiperidines derivatives showed very potent and selective hBuChE inhibition. Further studies of NMR and molecular dynamics have showed the capacity of these hybrid molecules to change their bioactive conformation depending on the binding site, being capable to inhibit with different shapes BuChE and residually AChE.

Beyond the "Lock and Key" Paradigm: Targeting Lipid Rafts to Induce the Selective Apoptosis of Cancer Cells.

For more than 40 years, the fluid mosaic model of cellular membranes has supported our vision of an inert lipid bilayer containing membrane protein receptors that are randomly hit by extracellular molecules to trigger intracellular signaling events. However, the notion that compartmentalized cholesterol- and sphingomyelin-rich membrane microdomains (known as lipid rafts) spatially arrange receptors and effectors to promote kinetically favorable interactions necessary for the signal transduction sounds much more realistic. Despite their assumed importance for the dynamics of ligand-receptor interactions, lipid rafts and biomembranes as a whole remain less explored than the other classes of biomolecules because of the higher variability and complexity of their membrane phases, which rarely provide the detailed atomic-level structural data in X-ray crystallography assays necessary for molecular modeling studies. The fact that some alkylphospholipids (e.g. edelfosine: 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) selectively induce the apoptotic death of cancer cells by recruiting Fas death receptors and the downstream signaling molecules into clusters of lipid rafts suggests these potential drug targets deserve a more in-depth investigation. Herein, we review the structure of lipid rafts, their role in apoptotic signaling pathways and their potential role as drug targets for the treatment of cancer.