Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• –melatonin hybrids (LATMHs), deciding to incorporate melatonin as a new target for the MTDL [39]. Melatonin has the ability to combat OS, which is a crucial factor in the pathogenesis of AD. Moreover, it plays a neuroprotective role against Aβ-peptides and easily crosses the blood–brain barrier (BBB

O,S,Se-containing Biginelli products based on cyclic β-ketosulfone and their postfunctionalization

• Kateryna V. Dil and
• Vitalii A. Palchykov

Beilstein J. Org. Chem. 2024, 20, 2143–2151, doi:10.3762/bjoc.20.184

• , was found to be 67–129 Å2 for all compounds except products 4 and 2e. None of the compounds penetrate the BBB (blood–brain barrier) except for seleno-2p and desulfurized product 7. Regarding water solubility, we can conclude that all compounds are either soluble or moderately soluble. For more details

2-Heteroarylethylamines in medicinal chemistry: a review of 2-phenethylamine satellite chemical space

• Carlos Nieto,
• Alejandro Manchado,
• Ángel García-González,
• David Díez and
• Narciso M. Garrido

Beilstein J. Org. Chem. 2024, 20, 1880–1893, doi:10.3762/bjoc.20.163

• solute carrier protein which is used as strategic target for blood–brain-barrier drug delivery. In general, the authors found the compounds less potent than the natural substrate ʟ-tryptophan, with exception of derivative 112 (Scheme 17). Tetrazoles: Taking advantage of using tetrazoles not as a phenyl

Research progress on the pharmacological activity, biosynthetic pathways, and biosynthesis of crocins

• Zhongwei Hua,
• Nan Liu and
• Xiaohui Yan

Beilstein J. Org. Chem. 2024, 20, 741–752, doi:10.3762/bjoc.20.68

• Pharmacokinetic investigations have shown that crocins can be hydrolyzed to crocetin (1) in the gastrointestinal tract of mice. Crocetin derivatives can penetrate the blood–brain barrier to exert therapeutic effects on neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, retinal diseases

Chemical approaches to discover the full potential of peptide nucleic acids in biomedical applications

• Nikita Brodyagin,
• Martins Katkevics,
• Venubabu Kotikam,
• Christopher A. Ryan and
• Eriks Rozners

Beilstein J. Org. Chem. 2021, 17, 1641–1688, doi:10.3762/bjoc.17.116

• covalent conjugation of PNA to delivery enhancing compounds. Cell-penetrating peptides derived from natural proteins: The initial success of PNA delivery involved PNA conjugates taken up by receptor-mediated endocytosis. Pardridge and co-workers successfully demonstrated in vivo delivery and blood-brain

• barrier crossing of PNAs by intravenous administration of PNA conjugated to OX26 murine monoclonal antibody to the rat transferrin receptor [165]. The limitation of this strategy was complexity of the construct and lack of clear evidence for the cellular uptake. The first report of using the PNA–peptide

Enhanced target cell specificity and uptake of lipid nanoparticles using RNA aptamers and peptides

• Roslyn M. Ray,
• Anders Højgaard Hansen,
• Maria Taskova,
• Bernhard Jandl,
• Jonas Hansen,
• Citra Soemardy,
• Kevin V. Morris and
• Kira Astakhova

Beilstein J. Org. Chem. 2021, 17, 891–907, doi:10.3762/bjoc.17.75

• Lipid nanoparticles (LNPs) constitute a facile and scalable approach for delivery of payloads to human cells. LNPs are relatively immunologically inert and can be produced in a cost effective and scalable manner. However, targeting and delivery of LNPs across the blood–brain barrier (BBB) has proven

• the usefulness of aptamer-loaded LNPs to increase target cell specificity and potentially deliverability of central-nervous-system-active RNAi therapeutics across the BBB. Keywords: aptamer; blood–brain barrier; gene therapy; HIV-1; lipid nanoparticle; Introduction Lipid nanoparticles (LNPs

• across the blood–brain barrier (BBB) is critical. For example, despite successful implementation of antiretroviral drugs for the treatment of human immunodeficiency virus 1 (HIV-1), HIV-1-associated neurological disorders persist due to the poor uptake of antiretroviral drugs across the BBB [12][13][14

Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups

• Xiaowei Li,
• Xiaolin Shi,
• Xiangqian Li and
• Dayong Shi

Beilstein J. Org. Chem. 2019, 15, 2213–2270, doi:10.3762/bjoc.15.218

• their metabolic stability, lipophilicity, and the ability to penetrate the blood–brain barrier. Similar to fluorination, trifluoromethylation can also be achieved by three reaction types: nucleophilic, electrophilic and radical trifluoromethylation. In recent years, many novel trifluoromethylation

A chemically contiguous hapten approach for a heroin–fentanyl vaccine

• Yoshihiro Natori,
• Candy S. Hwang,
• Lucy Lin,
• Lauren C. Smith,
• Bin Zhou and
• Kim D. Janda

Beilstein J. Org. Chem. 2019, 15, 1020–1031, doi:10.3762/bjoc.15.100

• circulating in the blood stream can block the “high” by forming a drug–antibody complex incapable of passing through the blood brain barrier. Ancillary, the vaccine’s immune response can alleviate the potential for overdose by reducing the total amount of drug exposed to µ-opioid receptors that induce

Synthesis of a tubugi-1-toxin conjugate by a modulizable disulfide linker system with a neuropeptide Y analogue showing selectivity for hY1R-overexpressing tumor cells

• Rainer Kufka,
• Robert Rennert,
• Goran N. Kaluđerović,
• Lutz Weber,
• Wolfgang Richter and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2019, 15, 96–105, doi:10.3762/bjoc.15.11

• -overexpressing breast cancers in a patients pilot study (n = 5) by using a PET tracer based on the hY1R-specific NPY analogue [F7,P34]-pNPY [35]. This study demonstrated that it is not to be expected that NPY-based diagnostic or therapeutic PDCs will pass the blood-brain barrier and therefore could induce

Pd-Catalyzed microwave-assisted synthesis of phosphonated 13α-estrones as potential OATP2B1, 17β-HSD1 and/or STS inhibitors

• Rebeka Jójárt,
• Szabolcs Pécsy,
• György Keglevich,
• Mihály Szécsi,
• Réka Rigó,
• Csilla Özvegy-Laczka,
• Gábor Kecskeméti and
• Erzsébet Mernyák

Beilstein J. Org. Chem. 2018, 14, 2838–2845, doi:10.3762/bjoc.14.262

• organic anion transporting polypeptides (OATP) protein family [3][4]. Human OATP2B1 is one of the OATPs transporting estrone 3-sulfate, expressed in the intestine, blood–brain barrier, liver and placenta [5][6][7][8][9]. Moreover, OATP2B1 is overexpressed in certain malignancies, including breast cancer

On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

• Eirinaios I. Vrettos,
• Gábor Mező and
• Andreas G. Tzakos

Beilstein J. Org. Chem. 2018, 14, 930–954, doi:10.3762/bjoc.14.80

• peptide named angiopep-2 (TFFYGGSRGKRNNFKTEEY), due to its ability to cross the blood-brain barrier (BBB). The BBB is formed by the endothelial cells of the brain, restricting and controlling the exchange of molecules between the central nervous system and the rest body. Angiopep-2 is able to cross the

• pending for clinical trials. An interesting example of a PDC able to cross the blood-brain barrier (BBB), is ANG1005 [136], composed of three molecules of paclitaxel linked by a cleavable succinyl ester linkage to the angiopep-2 peptide (Figure 8). BBB is formed by the brain capillary endothelium with

Membrane properties of hydroxycholesterols related to the brain cholesterol metabolism

• Malte Hilsch,
• Ivan Haralampiev,
• Peter Müller,
• Daniel Huster and
• Holger A. Scheidt

Beilstein J. Org. Chem. 2017, 13, 720–727, doi:10.3762/bjoc.13.71

• of a human being [4][6]. Insoluble cholesterol is transported in the blood in small lipoprotein particles of varying density and the rate, at which cholesterol crosses the lipid membrane, is extremely low [7]. To overcome the blood–brain barrier, nature has developed efficient mechanisms to convert

• influencing important membrane functions. A special situation is encountered in the human brain, which contains a large amount of the body cholesterol. Almost all brain cholesterol is produced by local synthesis. It is the blood–brain barrier, which effectively protects the brain from the exchange with

• cholesterol provided from lipoproteins in the circulation, the cholesterol homeostasis in the brain is as far as possible self-contained. Regardless, a certain amount of cholesterol has to cross the blood–brain barrier in both directions. This transport function is fulfilled by hydroxycholesterols, which

Computational methods in drug discovery

• Sumudu P. Leelananda and
• Steffen Lindert

Beilstein J. Org. Chem. 2016, 12, 2694–2718, doi:10.3762/bjoc.12.267

Interactions between cyclodextrins and cellular components: Towards greener medical applications?

• Loïc Leclercq

Beilstein J. Org. Chem. 2016, 12, 2644–2662, doi:10.3762/bjoc.12.261

• hydroxypropylated α-, β-, and γ-CDs have been studied on an in vitro model of blood-brain barrier by Monnaert and co-workers [75]. The results prove that the native CDs are the most toxic (γ-CD < β-CD < α-CD). As expected, lipid effluxes on the brain capillary endothelial cells in the presence of native CDs reveal

• cholesterol content in blood–brain barrier cells compared to erythrocytes. Indeed, the cholesterol fraction is markedly higher in erythrocytes than in other cells. As for hemolysis, the presence of hydrophilic substituents (e.g., 2-hydroxypropyl and sulfobutyl ether) annihilates the cytotoxicity while the

Biomimetic synthesis and HPLC–ECD analysis of the isomers of dracocephins A and B

• Viktor Ilkei,
• András Spaits,
• Anita Prechl,
• Áron Szigetvári,
• Zoltán Béni,
• Miklós Dékány,
• Csaba Szántay Jr,
• Judit Müller,
• Árpád Könczöl,
• Ádám Szappanos,
• Attila Mándi,
• Sándor Antus,
• Ana Martins,
• Attila Hunyadi,
• György Tibor Balogh,
• György Kalaus (†),
• Hedvig Bölcskei,
• László Hazai and
• Tibor Kurtán

Beilstein J. Org. Chem. 2016, 12, 2523–2534, doi:10.3762/bjoc.12.247

• lowest acidic pKa values are predominant in physiological environment, which is also indicated by the difference of log D values between pH 7.4 and pH 6.5. The blood–brain barrier (BBB) specific penetration of dracocephins isomers has also been studied by the PAMPA (parallel artificial membrane

New synthetic strategies for xanthene-dye-appended cyclodextrins

• Milo Malanga,
• Andras Darcsi,
• Mihaly Balint,
• Gabor Benkovics,
• Tamas Sohajda and
• Szabolcs Beni

Beilstein J. Org. Chem. 2016, 12, 537–548, doi:10.3762/bjoc.12.53

• fluorophores for labeling in order to assess if these versatile molecules cross biological barriers (e.g., cell membrane, blood–brain barrier) and to follow their distribution in living matter [3]. Among the fluorescent dyes, the group of fluorophores based on xanthene scaffolds is one of the most popular. Two

Diastereoselective synthesis of new O-alkylated and C-branched inositols and their corresponding fluoro analogues

• Charlotte Collet,
• Françoise Chrétien,
• Yves Chapleur and
• Sandrine Lamandé-Langle

Beilstein J. Org. Chem. 2016, 12, 353–361, doi:10.3762/bjoc.12.39

• this compound crosses the blood brain barrier (BBB) with difficulty [32]. The same PET imaging studies using the diastereoisomeric compound of myo configuration (2-[18F]fluoro-2-deoxy-myo-inositol), did not get better results [33]. On the other hand, these radiotracers have shown interesting features

Terminal lipophilization of a unique DNA dodecamer by various nucleolipid headgroups: Their incorporation into artificial lipid bilayers and hydrodynamic properties

• Emma Werz and
• Helmut Rosemeyer

Beilstein J. Org. Chem. 2015, 11, 913–929, doi:10.3762/bjoc.11.103

• lipophilized oligonucleotides at water–air or water–decane boundaries [39] as well as the transdermal application of such LONs through the human Stratum corneum by iontophoresis techniques as well as the transport across the blood–brain barrier [40]. Experimental Materials. 1-Palmitoyl-2-oleyl-sn-glycero-3

Synthetic strategies for the fluorescent labeling of epichlorohydrin-branched cyclodextrin polymers

• Milo Malanga,
• Mihály Bálint,
• István Puskás,
• Kata Tuza,
• Tamás Sohajda,
• László Jicsinszky,
• Lajos Szente and
• Éva Fenyvesi

Beilstein J. Org. Chem. 2014, 10, 3007–3018, doi:10.3762/bjoc.10.319

• used for layer-by-layer film formation [12]. The synthesis and characterization of a nanosized quaternary ammonium β-CD polymer with high load capacity of the anticancer drug doxorubicin has been described as well as its application as drug delivery carriers across the blood–brain barrier [13]. The

Synthesis of uniform cyclodextrin thioethers to transport hydrophobic drugs

• Lisa F. Becker,
• Dennis H. Schwarz and
• Gerhard Wenz

Beilstein J. Org. Chem. 2014, 10, 2920–2927, doi:10.3762/bjoc.10.310

• enter a bilayer membrane to support the API to overcome cellular barriers, such as the intestinal barrier [39] or the blood-brain barrier (BBB) [40]. Long alkyl chains (C4–C12) have already been attached via thioether or sulfoxide linkages to all primary positions by Kawabata and Ling et al. to form

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• ), muscimol (2.40), THPO (2.41) or exo-THPO (2.42, Figure 5) are potent inhibitors of GABA receptors, however, their hydrophilic nature meant that they did not cross the lipophilic blood-brain barrier. Therefore additional non-polar biaryl-appendages have been attached to these motifs separated by a short

Amyloid-β probes: Review of structure–activity and brain-kinetics relationships

• Todd J. Eckroat,
• Abdelrahman S. Mayhoub and
• Sylvie Garneau-Tsodikova

Beilstein J. Org. Chem. 2013, 9, 1012–1044, doi:10.3762/bjoc.9.116

• dyes prevented them from crossing the blood brain barrier (BBB), and consequently, no in vivo benefits were obtained from these initial investigations [10][11]. During the past decade, efforts directed at developing probes that display uptake and retention that differ in healthy and AD-affected brains

Recent progress in the discovery of small molecules for the treatment of amyotrophic lateral sclerosis (ALS)

• Allison S. Limpert,
• Margrith E. Mattmann and
• Nicholas D. P. Cosford

Beilstein J. Org. Chem. 2013, 9, 717–732, doi:10.3762/bjoc.9.82

• penetration of the blood–brain barrier (BBB) and was further tested in a SOD1 G93A transgenic mouse model. Mutant mice treated with compound 13 by intraperitoneal (i.p.) injection at 20 mg/kg daily, starting at 6 weeks of age, displayed a 13.3% increase in lifespan as compared to controls [31], suggesting

Palladium- and copper-mediated N-aryl bond formation reactions for the synthesis of biological active compounds

• Carolin Fischer and
• Burkhard Koenig

Beilstein J. Org. Chem. 2011, 7, 59–74, doi:10.3762/bjoc.7.10

• modulators. The tariquidar (44) derived compounds showed log P-dependent inhibition activity of the ABCB1 transporter, which represents an important component of the blood–brain barrier and is a major limitation in cancer chemotherapy. Primary and cyclic secondary amines were coupled to 45 to give moderate

Miniemulsion polymerization as a versatile tool for the synthesis of functionalized polymers

• Daniel Crespy and
• Katharina Landfester

Beilstein J. Org. Chem. 2010, 6, 1132–1148, doi:10.3762/bjoc.6.130

• since the monomer is very reactive and the polymerization can be conducted in the presence of a large amount of water. Moreover, the polymers were shown to be able to pass the blood brain barrier, making them ideal candidates as vectors for drug delivery. Therefore it is not surprising that several