Rhodium-catalyzed homo-coupling reaction of aryl Grignard reagents and its application for the synthesis of an integrin inhibitor

• Kazuyuki Sato,
• Satoki Teranishi,
• Atsushi Sakaue,
• Yukiko Karuo,
• Atsushi Tarui,
• Kentaro Kawai,
• Hiroyuki Takeda,
• Tatsuo Kinashi and
• Masaaki Omote

Beilstein J. Org. Chem. 2024, 20, 1341–1347, doi:10.3762/bjoc.20.118

• for integrins which is critical for several diseases. Keywords: biphenyltetracarboxylic acid; homo-coupling; integrin inhibitor; rhodium catalyst; Ullmann-type reaction; Introduction The Ullmann reaction is a coupling reaction of aryl halides using copper, traditionally using metallic copper-bronze

• Integrins are transmembrane heterodimers, each consisting of α and β subunits, that mediate cell–cell and cell–matrix adhesion involved in normal and pathological processes. Bidirectional signaling through integrins regulate cell shape, motility, and cell cycle progression [23]. The integrin complexes are

• highly important for performing various cellular functions, such as cell proliferation, migration, and morphological changes [24][25]. Consequently, integrin inhibitors have received great attention as novel candidates for the treatment of several intractable diseases [26][27][28]. In the process of

Microelectrode arrays, electrosynthesis, and the optimization of signaling on an inert, stable surface

• Kendra Drayton-White,
• Siyue Liu,
• Yu-Chia Chang,
• Sakashi Uppal and
• Kevin D. Moeller

Beilstein J. Org. Chem. 2022, 18, 1488–1498, doi:10.3762/bjoc.18.156

• interactions [5][6][7]. For example, a binding curve generated for the interaction between an RGD-peptide (C-PEG6-GGRGDGP) and its integrin (α5,β1) target is shown in Figure 4 below. A PEG-linker was added to the RGD-peptide so that the peptide would not be buried in the polymer coating the surface of the

• array, a scenario that would make it unavailable for binding to the integrin receptor in the subsequent analytical experiment. The PEG-6-linker was selected because it was effective and readily available from commercial sources. This linker was functionalized with a cysteine on the end opposite the

• used for the subsequent signaling experiment [20]. The hydroquinone/quinone redox couple has superior stability to the iron-based systems used previously [20], and its use leads to more reproducible binding curves. To generate the binding curve shown in Figure 4, the concentration of the integrin

Peptide stapling by late-stage Suzuki–Miyaura cross-coupling

• Hendrik Gruß,
• Rebecca C. Feiner,
• Ridhiwan Mseya,
• David C. Schröder,
• Michał Jewgiński,
• Kristian M. Müller,
• Rafał Latajka,
• Antoine Marion and
• Norbert Sewald

Beilstein J. Org. Chem. 2022, 18, 1–12, doi:10.3762/bjoc.18.1

• halotryptophans and boronic acids resulting in RGD peptides with high affinity towards integrin αVβ3, good selectivity and high plasma stability [72]. Results and Discussion Design and synthesis of SMC stapled peptides The intramolecular SMC was envisaged as a novel approach towards one-component peptide stapling

Synthesis and physicochemical evaluation of fluorinated lipopeptide precursors of ligands for microbubble targeting

• Masayori Hagimori,
• Estefanía E. Mendoza-Ortega and
• Marie Pierre Krafft

Beilstein J. Org. Chem. 2021, 17, 511–518, doi:10.3762/bjoc.17.45

• (lipopeptides) have been used as the amphiphilic components of drug delivery systems with anticancer properties, such as the tripeptide Arg–Gly–Asp (RGD) that binds to integrin αvβ3, which is expressed on endothelial cells of various malignant tumors [15][19][20][21][22]. Other lipopeptides display cell

• peptide ligands dramatically increased cellular association in HER2-positive cells. Other lipids grafted to the RGD peptide and SG spacer were integrated in PEGylated liposomes and were efficiently associated with integrin αvβ3-expressing Colon-26 cells [25]. One of our general objectives is to synthesize

Molecular basis for protein–protein interactions

• Brandon Charles Seychell and
• Tobias Beck

Beilstein J. Org. Chem. 2021, 17, 1–10, doi:10.3762/bjoc.17.1

• heterooligomeric complexes. Examples include integrin αIIb and β3 [70] as well as mammalian lipin isoforms, proteins that make up the phosphatidic acid phosphatase family [71], where lipin 1 can form stable homooligomeric complexes and heterooligomeric complexes with lipins 2 and 3. Examples of homooligomeric

Selected peptide-based fluorescent probes for biological applications

• Debabrata Maity

Beilstein J. Org. Chem. 2020, 16, 2971–2982, doi:10.3762/bjoc.16.247

• membrane-bound receptors interact strongly with short peptidic segments of a larger protein chain, for example, recognition of the RGD sequence (arginine–glycine–aspartic acid; Arg–Gly–Asp) by integrin receptors. They use noncovalent interactions including salt bridges [5]. Vancomycin, a glycopeptide

Facile synthesis of 7-alkyl-1,2,3,4-tetrahydro-1,8-naphthyridines as arginine mimetics using a Horner–Wadsworth–Emmons-based approach

• Rhys A. Lippa,
• John A. Murphy and
• Tim N. Barrett

Beilstein J. Org. Chem. 2020, 16, 1617–1626, doi:10.3762/bjoc.16.134

• Rhys A. Lippa John A. Murphy Tim N. Barrett Department of Pure & Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, Scotland, U.K. GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, U.K. 10.3762/bjoc.16.134 Abstract Integrin

• cores for these compounds in high yields (63–83% over 3 steps) with no need for chromatography. Key to this transformation is the phosphoramidate protecting group, which is stable to metalation steps. Keywords: arginine; Horner–Wadsworth–Emmons; integrin; phosphoramidate; tetrahydronaphthyridine

• ; Introduction Tetrahydronaphthyridines are prominent in peptidomimetic pharmaceuticals as arginine mimetics and they are widely used in Arg–Gly–Asp (RGD) peptide mimetics such as αv integrin inhibitors [1]. Tetrahydronaphthyridines represent less basic but more permeable alternatives to arginine (pKa ≈ 7 versus

Protein–protein interactions in bacteria: a promising and challenging avenue towards the discovery of new antibiotics

• Laura Carro

Beilstein J. Org. Chem. 2018, 14, 2881–2896, doi:10.3762/bjoc.14.267

• (bromodomain and extra terminal) molibresib (4, Figure 2), developed by GSK and currently in phase I for the treatment of several carcinomas [30]. It is also worth highlighting two PPI inhibitors that have recently been approved: lifitegrast (5, Figure 2) is an anti-inflammatory integrin antagonist that

Comparative cell biological study of in vitro antitumor and antimetastatic activity on melanoma cells of GnRH-III-containing conjugates modified with short-chain fatty acids

• Eszter Lajkó,
• Sarah Spring,
• Rózsa Hegedüs,
• Beáta Biri-Kovács,
• Sven Ingebrandt,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 2495–2509, doi:10.3762/bjoc.14.226

• (i) expression of cell adhesion molecules (e.g., α3 integrin [25], non-integrin laminin receptor [56]) and (ii) regulate the actin polymerization by interacting with small GTPases (e.g., Rac1, CdC24 [54]) or (iii) interfere with the expression/activity of matrix-degrading enzymes (e.g., MMP-2 [25

Synthesis and photophysical studies of a multivalent photoreactive Ru^II-calix[4]arene complex bearing RGD-containing cyclopentapeptides

• Sofia Kajouj,
• Lionel Marcelis,
• Alice Mattiuzzi,
• Adrien Grassin,
• Damien Dufour,
• Pierre Van Antwerpen,
• Didier Boturyn,
• Eric Defrancq,
• Mathieu Surin,
• Julien De Winter,
• Pascal Gerbaux,
• Ivan Jabin and
• Cécile Moucheron

Beilstein J. Org. Chem. 2018, 14, 1758–1768, doi:10.3762/bjoc.14.150

• healthy ones. The next step in the development of phototherapeutic agents based on polyazaaromatic RuII complexes is thus the specific targeting of cancerous cells. In this regard, αvβ3 integrin represents an interesting target as this membrane receptor is overexpressed in the endothelial cells of

• neoangiogenic vessels and in several human tumor cells [39][40]. It is well known that RGD-containing oligopeptides (RGD = Arg-Gly-Asp tripeptide pattern) bind selectively to αvβ3 integrin with a high affinity and a very high selectivity [41][42][43]. As multivalency enhances the binding strength of a ligand to

One hundred years of benzotropone chemistry

• Arif Dastan,
• Haydar Kilic and
• Nurullah Saracoglu

Beilstein J. Org. Chem. 2018, 14, 1120–1180, doi:10.3762/bjoc.14.98

• ]annulenes as a novel series of potent and specific αv integrin antagonists starting from 4,5-benzotropone (11) (Figure 4 and Scheme 13) [73]. TBS-enol ether intermediate 68 was first formed by the Mukaiyama–Michael reaction of O-silyl ketene acetal to 4,5-benzotropone (11) at low temperature in the presence

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

• -glycine-aspartic acid (RGD): A widely applied peptide carrier is the tripeptide arginine-glycine-aspartic acid (RGD) motif, which was first identified by Ruoslahti and Pierschbacher in the early 1980s [40] within fibronectin that mediates cell attachment and was known to target integrin α5β1 [41]. In

• general, the ‘integrin’ nomenclature was first used in 1987 to describe a family of receptors, appearing as heterodimers of noncovalently associated α and β subunits, able to link the extracellular matrix (ECM) with the intracellular cytoskeleton to mediate cell adhesion, migration and proliferation [42

• carcinogenesis is highly dependent on migration, invasion and angiogenesis renders integrins important anticancer targets. Integrin αvβ3 is an important factor in tumor angiogenesis and metastasis [45], two common characteristics of cancer that discriminates it from other diseases. Notably, integrin αvβ3 (also

Development of novel cyclic NGR peptide–daunomycin conjugates with dual targeting property

• Andrea Angelo Pierluigi Tripodi,
• Szilárd Tóth,
• Kata Nóra Enyedi,
• Gitta Schlosser,
• Gergely Szakács and
• Gábor Mező

Beilstein J. Org. Chem. 2018, 14, 911–918, doi:10.3762/bjoc.14.78

• CD13+ HT-1080 human fibrosarcoma and CD13− but integrin positive HT-29 human colon adenocarcinoma cells. However, it seems that the free ε-amino group of Lys in the cycle is not necessary for the biological activity. Therefore, we developed novel cyclic NGR peptide–daunomycin conjugates in which Lys

• ratio of 3:1 after hydrolysis [5][6][7][8][9][10][11]. IsoDGR peptides are bound to RGD-integrin receptors with high affinity [12][13][14]. Due to their function in tumor proliferation, metastasis and angiogenesis, integrin receptors are also promising targets for cancer therapy. Thus, NGR-peptide

• conjugates revealed substantial in vitro cytostatic/cytotoxic effects. Our results indicated that the conjugates had an antitumor effect against both CD13+ HT-1080 cells and CD13− (but integrin receptor positive) HT-29 human colon cancer cells. Moreover, we showed that the toxicity and the selectivity of the

Synthesis and biological evaluation of RGD and isoDGR peptidomimetic-α-amanitin conjugates for tumor-targeting

• Lizeth Bodero,
• Paula López Rivas,
• Barbara Korsak,
• Torsten Hechler,
• Andreas Pahl,
• Christoph Müller,
• Daniela Arosio,
• Luca Pignataro,
• Cesare Gennari and
• Umberto Piarulli

Beilstein J. Org. Chem. 2018, 14, 407–415, doi:10.3762/bjoc.14.29

• synthesized by joining integrin ligands to α-amanitin via various linkers and spacers. The conjugates were evaluated for their ability to inhibit biotinylated vitronectin binding to the purified αVβ3 receptor, retaining good binding affinity, in the same nanomolar range as the free ligands. The

• antiproliferative activity of the conjugates was evaluated in three cell lines possessing different levels of αVβ3 integrin expression: human glioblastoma U87 (αVβ3+), human lung carcinoma A549 (αVβ3−) and breast adenocarcinoma MDA-MB-468 (αVβ3−). In the U87, in the MDA-MB-468, and partly in the A549 cancer cell

• lines, the cyclo[DKP-isoDGR]-α-amanitin conjugates bearing the lysosomally cleavable Val-Ala linker were found to be slightly more potent than α-amanitin. Apparently, for all these α-amanitin conjugates there is no correlation between the cytotoxicity and the expression of αVβ3 integrin. To determine

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

• of pentapeptides to α- and β-CD [88]. The two peptides used in this study were: Tyr-Ile-Gly-Ser-Arg (YIGSR) and Tyr-Gly-Gly-Phe-Leu (YGGFL). The former interacts specifically with the integrin receptors on specific neuronal cells whereas the latter is known to bind to brain receptor sites. From

Is conformation a fundamental descriptor in QSAR? A case for halogenated anesthetics

• Maria C. Guimarães,
• Mariene H. Duarte,
• Josué M. Silla and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2016, 12, 760–768, doi:10.3762/bjoc.12.76

• high level calculations (in a receptor-free environment) in QSAR modelling was evaluated using a comparative study of the optimized and bioactive conformations of the fluorinated anesthetic isoflurane, which binds to a 4-helix bundle protein (apoferritin) [12] and to the integrin LFA1 enzyme [13

• conformational isomerism. However, is there an environment capable of overcoming intramolecular interactions and then changing the conformational preference of isoflurane? While comparison of 1 with the bioconformation of isoflurane bound to the integrin LFA1 enzyme (PDB code: 3F78 [13]) reveals small

• the small hydrogen atom) at R1 tend to strongly favor the increase in pMAC of anesthetic derivatives. Because the absence of intermolecular hydrogen bonds between enflurane (a similar anesthetic haloether) and the integrin LFA1 enzyme [16], the structural requirements mentioned above should be

Regulation of integrin and growth factor signaling in biomaterials for osteodifferentiation

• Qiang Wei,
• Theresa L. M. Pohl,
• Anja Seckinger,
• Joachim P. Spatz and
• Elisabetta A. Cavalcanti-Adam

Beilstein J. Org. Chem. 2015, 11, 773–783, doi:10.3762/bjoc.11.87

• extracellular matrix (ECM) is the essential component the in stem cell niche, in which both integrin ligands and growth factors are important regulators to directly or indirectly modulate the cell behavior. In this review, we summarize the current knowledge about the potential of integrin ligands and growth

• factors to induce osteogenic differentiation of stem cells, and discuss the signaling pathways that are initiated by both individual and cooperative parameters. The joint effect of integrin ligands and growth factors is highlighted as the multivalent interactions for bone therapy. Keywords: biomaterials

• ; growth factor; integrin; osteodifferentiation; stem cells; Review Introduction Current bone grafting therapeutics do not provide satisfying solutions to the problems of non-healing bone defects. The gold-standard therapy is the grafting of autologous bone; however, it is limited by low availability as

Human dendritic cell activation induced by a permannosylated dendron containing an antigenic GM₃-lactone mimetic

• Renato Ribeiro-Viana,
• Elena Bonechi,
• Javier Rojo,
• Clara Ballerini,
• Giuseppina Comito,
• Barbara Richichi and
• Cristina Nativi

Beilstein J. Org. Chem. 2014, 10, 1317–1324, doi:10.3762/bjoc.10.133

• , dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN), which belongs to the class of CLRs, is expressed mainly on the surface of immature DCs and plays a crucial role in the uptake of specific pathogens. DC-SIGN is able to bind in a Ca2+-dependent manner mannose and fucose residues on highly

Synthesis and characterization of novel bioactive 1,2,4-oxadiazole natural product analogs bearing the N-phenylmaleimide and N-phenylsuccinimide moieties

• Catalin V. Maftei,
• Elena Fodor,
• Peter G. Jones,
• M. Heiko Franz,
• Gerhard Kelter,
• Heiner Fiebig and
• Ion Neda

Beilstein J. Org. Chem. 2013, 9, 2202–2215, doi:10.3762/bjoc.9.259

• glycogen synthase kinase 3 (GSK-3), a key regulator of both differentiation and cellular proliferation [9]. An alternative antitumor strategy involves the inhibition of processes involved in tumor growth, e.g., angiogenesis. Integrin αvβ3 is a receptor that has been found on the surface of many tumor cells

Towards a biocompatible artificial lung: Covalent functionalization of poly(4-methylpent-1-ene) (TPX) with cRGD pentapeptide

• Lena Möller,
• Christian Hess,
• Jiří Paleček,
• Yi Su,
• Axel Haverich,
• Andreas Kirschning and
• Gerald Dräger

Beilstein J. Org. Chem. 2013, 9, 270–277, doi:10.3762/bjoc.9.33

• -acid sequence. We chose cRGD pentapeptide 1b derived from lysine precursor 1a, as cRGD’s intensively studied by the Kessler group [6][7][8][9] are well-established cell-recognition motifs that can trigger integrin-mediated cell adhesion [9]. Because of the high potential to stimulate this, these RGD

• TPX materials 8a and 8b functionalized with cRGD. Particularly, we investigated the growth of endothelial cells (ECs) through integrin-mediated binding. ECs were seeded at a density of 1 × 104 cells/cm2 on TPX membranes 8a and 8b [5]. Adherence, growth and viability of cells were monitored and

An easily accessible sulfated saccharide mimetic inhibits in vitro human tumor cell adhesion and angiogenesis of vascular endothelial cells

• Grazia Marano,
• Claas Gronewold,
• Martin Frank,
• Anette Merling,
• Christian Kliem,
• Sandra Sauer,
• Manfred Wiessler,
• Eva Frei and
• Reinhard Schwartz-Albiez

Beilstein J. Org. Chem. 2012, 8, 787–803, doi:10.3762/bjoc.8.89

• {[(β-D-galactopyranosyl)oxy]methyl}furan (BGF) nor methyl β-D-galactopyranoside nor 3,4-bis(hydroxymethyl)furan, which were used as controls, eliciting comparable biological activity. In silico modeling experiments, in which binding of GSF to the extracellular domain of the integrin αvβ3 was determined

• , revealed specific docking of GSF to the same binding site as the natural peptidic ligands of this integrin. The sulfate in the molecule coordinated with one manganese ion in the binding site. These studies show that this chemically easily accessible molecule GSF, synthesized in three steps from 3,4-bis

• inhibitory capacity of the lead compound GSF to block adhesion and migration both of tumor cells and vascular endothelial cells and endothelial-cell-mediated angiogenesis. Surprisingly, GSF may not only block carbohydrate–protein interactions but also integrin-mediated protein–protein interactions, and thus

Synthesis of glycoconjugate fragments of mycobacterial phosphatidylinositol mannosides and lipomannan

• Benjamin Cao,
• Jonathan M. White and
• Spencer J. Williams

Beilstein J. Org. Chem. 2011, 7, 369–377, doi:10.3762/bjoc.7.47

• dendritic cell specific intercellular adhesion molecule-grabbing non-integrin (DC-SIGN) [8]. Thus, while total syntheses of many PIM structures have now been reported, the synthesis of substructures remains a worthwhile endeavor as these are useful to clarify fine details of enzymatic substrate recognition

Molecular recognition of organic ammonium ions in solution using synthetic receptors

• Andreas Späth and
• Burkhard König

Beilstein J. Org. Chem. 2010, 6, No. 32, doi:10.3762/bjoc.6.32