Amino acid motifs in natural products: synthesis of O-acylated derivatives of (2S,3S)-3-hydroxyleucine

• Oliver Ries,
• Martin Büschleb,
• Markus Granitzka,
• Dietmar Stalke and
• Christian Ducho

Beilstein J. Org. Chem. 2014, 10, 1135–1142, doi:10.3762/bjoc.10.113

• opening up an excellent approach for the synthesis of bioactive natural products and derivatives thereof for structure activity relationship (SAR) studies. Keywords: chiral pool; cross metathesis; esterification; β-hydroxy-α-amino acids; natural products; Introduction Besides the proteinogenic β-hydroxy

• active site located on the cytosolic side of the membrane [10][11][12][13][14]. For previously reported SAR studies on muraymycins and their analogues, the fatty acid side chain was either neglegted or replaced with a structurally distinct lipophilic mimic [15][16][17]. Mansour and co-workers found a

Total synthesis and cytotoxicity of the marine natural product malevamide D and a photoreactive analog

• Werner Telle,
• Gerhard Kelter,
• Heinz-Herbert Fiebig,
• Peter G. Jones and
• Thomas Lindel

Beilstein J. Org. Chem. 2014, 10, 316–322, doi:10.3762/bjoc.10.29

• was still active, because it had been shown in several SAR studies that limited variation of the amine or alcohol component at the C-terminal amide or ester moieties of the dolastatin family members can be tolerated without much loss of cytotoxicity. This includes epimerization of the thiazole

The myxocoumarins A and B from Stigmatella aurantiaca strain MYX-030

• Tobias A. M. Gulder,
• Snežana Neff,
• Traugott Schüz,
• Tammo Winkler,
• René Gees and
• Bettina Böhlendorf

Beilstein J. Org. Chem. 2013, 9, 2579–2585, doi:10.3762/bjoc.9.293

• possible. Structure–activity relationship (SAR) studies on synthetic myxocoumarin derivatives as well as in-depth investigation of their antibacterial potential are currently performed in our laboratory and will be reported in due course. Experimental Cultivation and extraction. The preculture of S

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

• , have been widely reported as Aβ-imaging tracers (Scheme 2A). Structure–activity-relationship (SAR) studies on fluorinated chalcones 18a–l have shown that, in general, chalcones with tertiary amines in their structures demonstrate good affinity for Aβ plaques in in vitro models (Ki = 20–50 nM) (Table 1

• towards Aβ aggregates with Ki values ranging between 5.3 nM for 29a and 19.3 nM for 29c (Scheme 3A) [16]. SAR studies suggest that, as with chalcones, the tertiary amine in these flavones was important for binding and tracing Aβ aggregates in mouse models, as they consistently outperformed secondary and

• all cases. However, pharmacokinetics for these agents were less than ideal as both showed long retention in the brains of normal mice, which is indicative of nonspecific binding. A series of iodinated benzothiazoles 59a–o was synthesized using methods similar to those described above and SAR studies

Design and synthesis of tag-free photoprobes for the identification of the molecular target for CCG-1423, a novel inhibitor of the Rho/MKL1/SRF signaling pathway

• Jessica L. Bell,
• Andrew J. Haak,
• Susan M. Wade,
• Yihan Sun,
• Richard R. Neubig and
• Scott D. Larsen

Beilstein J. Org. Chem. 2013, 9, 966–973, doi:10.3762/bjoc.9.111

• 29 (Figure 4), i.e., an analogue of 2 with slightly greater potency (IC50 = 6.4 µM) that was identified in later SAR studies [23]. UV irradiation was applied for 30 min at room temperature by using the long-wavelength setting of a hand-held illuminator (366 nm, UVL-56 lamp, UltraViolet Products, San

Synthesis and physicochemical characterization of novel phenotypic probes targeting the nuclear factor-kappa B signaling pathway

• Paul M. Hershberger,
• Satyamaheshwar Peddibhotla,
• E. Hampton Sessions,
• Daniela B. Divlianska,
• Ricardo G. Correa,
• Anthony B. Pinkerton,
• John C. Reed and
• Gregory P. Roth

Beilstein J. Org. Chem. 2013, 9, 900–907, doi:10.3762/bjoc.9.103

• transduction in reporter cell lines containing either low or overexpressed NOD2 proteins. Probes 13 and 17 were also selective over the non-NOD-stimulated NF-κB pathways (TNF-α, doxorubicin and PMA/ionomycin) in these reporter assays. Both of the probes, and their close analogues as discovered through SAR

• studies, selectively inhibited IL-8 secretion and the biologically relevant terminal effect of NOD1 (γ-tri-DAP) dependent NF-κB activation. Additionally, they neither inhibited NOD2-dependent nor TNF-α-dependent IL-8 secretion in biologically relevant MCF-7 cells. While 13 is the more potent and selective

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

• (SAR) studies revealed that the thioether and pyridazine moieties were essential molecular components for increasing EAAT2 protein levels [16]. Of the analogues developed, several thiopyridazine derivatives (Figure 4) were found to increase EAAT2 levels greater than six-fold over endogenous levels in

• analogue was tested in SOD1 G93A transgenic mice that were treated daily by i.p. administration with 30 mg/kg of CHD derivative compound 15 starting at 6 weeks (prior to symptom presentation). A 13% increase in lifespan was observed in treated animals as compared to controls [34]. SAR studies with PYT

Development of peptidomimetic ligands of Pro-Leu-Gly-NH₂ as allosteric modulators of the dopamine D₂ receptor

• Swapna Bhagwanth,
• Ram K. Mishra and
• Rodney L. Johnson

Beilstein J. Org. Chem. 2013, 9, 204–214, doi:10.3762/bjoc.9.24

• mimicking type VI β-turn and polyproline II helix conformations Early SAR studies on PLG showed that when the glycinamide residue was substituted with both L-and D-prolinamide residues, active dopamine receptor modulating peptides 43 and 44 (Figure 6) were obtained [13]. Likewise, triproline analogues of

Asymmetric synthesis of host-directed inhibitors of myxoviruses

• Terry W. Moore,
• Kasinath Sana,
• Dan Yan,
• Pahk Thepchatri,
• John M. Ndungu,
• Manohar T. Saindane,
• Mark A. Lockwood,
• Michael G. Natchus,
• Dennis C. Liotta,
• Richard K. Plemper,
• James P. Snyder and
• Aiming Sun

Beilstein J. Org. Chem. 2013, 9, 197–203, doi:10.3762/bjoc.9.23

• number of myxoviruses [8][12][14]. Structure–activity relationship (SAR) studies suggested both the 2-chloro-4-methylanilide and the central α-thiopropionamide to be moieties that confer good activity. Relatively unexplored in our previous work was the importance of the p-methoxyphenyl ring as well as

Total synthesis and biological evaluation of fluorinated cryptophycins

• Christine Weiß,
• Tobias Bogner,
• Benedikt Sammet and
• Norbert Sewald

Beilstein J. Org. Chem. 2012, 8, 2060–2066, doi:10.3762/bjoc.8.231

• -amino acid, usually β2-homoalanine. Finally, unit D is leucic acid, the hydroxy analogue of leucine. Numerous synthetic analogues have been obtained in the frame of structure–activity-relationship studies (SAR-studies), as reviewed in [17][18]. Unit A para-alkoxymethyl derivatives of cryptophycin-52

• tumor cell line KB-3-1 [21] (Figure 2). The chlorohydrin derived from 4 that also contained a fluorine substituent in the para-position of the unit A phenyl ring was patented as a promising candidate [22]. In the frame of our on-going SAR studies on cryptophycins [19][23][24][25][26][27][28][29][30], we

Parallel and four-step synthesis of natural-product-inspired scaffolds through modular assembly and divergent cyclization

• Hiroki Oguri,
• Haruki Mizoguchi,
• Hideaki Oikawa,
• Aki Ishiyama,
• Masato Iwatsuki,
• Kazuhiko Otoguro and
• Satoshi Ōmura

Beilstein J. Org. Chem. 2012, 8, 930–940, doi:10.3762/bjoc.8.105

• successfully applied to demonstrate the flexibility and scope of the unified four-step process for the generation of structural diversity in the fused scaffolds. Evaluation of in vitro antitrypanosomal activities of the collections and preliminary structure–activity relationship (SAR) studies were also

• groups comprising aminoacetal, β-ketoimide and indole groups [31][32][33][34]. Evaluation of in vitro antitrypanosomal activities of the synthetic collections and preliminary SAR studies are also described [35][36][37][38][39][40][41]. Results and Discussion First, we assembled a linear precursor 24 with

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• company [3]. From structure–activity relationship (SAR) studies it was found that the addition of substituents at the 3- and 4-position of the pyrrole scaffold significantly increases potency when compared to the more classical 2,5-disubstituted pyrroles. This study culminated in the discovery of

• of glucagon release. Consequently, insulin secretion increases leading to decreased blood glucose levels in diabetes type II patients. Structurally, this novel antihyperglycaemic consists of a fluorinated β-amino acid which is coupled to a trifluoromethylated triazolopiperazine (Scheme 55). In SAR

• studies this fused heterocycle was found to be more metabolically stable compared to earlier leads that contained a simple piperazine ring. Furthermore, the triazolopiperazine is not only involved in a tight H-bond network within the active site of DPP-IV, but also in π-stacking with the aromatic ring of

A two step synthesis of a key unit B precursor of cryptophycins by asymmetric hydrogenation

• Benedikt Sammet,
• Mathilde Brax and
• Norbert Sewald

Beilstein J. Org. Chem. 2011, 7, 243–245, doi:10.3762/bjoc.7.32

• interacting with the β-subunit of α/β-tubulin heterodimers. Numerous natural and artificial analogs have been analysed in structure–activity relationship (SAR) studies. The unit B of cryptophycins contains a considerably modified D-tyrosine derivative (Figure 1). Substituent variations at unit B are not well

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

• important targets in the treatment of diabetes and dyslipidemia. Azetidinone acid derivatives 110 were discovered to be new subtype-selective PPARα/γ agonists. For detailed structure–activity relationship (SAR) studies, diversity was introduced very efficiently by a copper-mediated N-arylation of

Synthesis of a novel analogue of DPP-4 inhibitor Alogliptin: Introduction of a spirocyclic moiety on the piperidine ring

• Arumugam Kodimuthali,
• Padala Lakshmi Prasunamba and
• Manojit Pal

Beilstein J. Org. Chem. 2010, 6, No. 71, doi:10.3762/bjoc.6.71

• comparison to Alogliptin in vitro. Nevertheless, to gain further insight we plan to conduct Structure-Activity-Relationship (SAR) studies for this class of compound that would eventually help to identify a potential lead possessing favorable pharmacological properties. Conclusion In conclusion, we have