Intramolecular carbolithiation of N-allyl-ynamides: an efficient entry to 1,4-dihydropyridines and pyridines – application to a formal synthesis of sarizotan

• Wafa Gati,
• Mohamed M. Rammah,
• Mohamed B. Rammah and
• Gwilherm Evano

Beilstein J. Org. Chem. 2012, 8, 2214–2222, doi:10.3762/bjoc.8.250

• clinical trials failed to confirm its efficiency [51], sarizotan is still under intense investigation [52][53][54] and was recently licensed to Newron Pharmaceuticals for further testing in new indications [55]. Motivated by the high potential of sarizotan and by the clear lack of structure-activity

• relationship studies on the pyridine core of this bioactive compound [56], we designed an efficient and modular synthesis of the disubstituted pyridine core of sarizotan that should enable the preparation of sarizotan analogues with different substitution on the pyridine ring. This synthesis is shown in Scheme

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

• ; fluorinated natural product analogues; structure-activity relationship; Introduction Cryptophycins form a class of cytotoxic sixteen-membered macrocyclic depsipeptides. Cryptophycin-1 (1) was isolated for the first time in 1990 from cyanobacteria Nostoc sp. ATCC 53789 [1] (Figure 1). Moore et al. isolated

• naturally occurring cryptophycins have been isolated up to this day [5][6][7], while numerous synthetic analogues have been synthesized in the frame of structure–activity-relationship studies [8][9]. Cryptophycins display remarkable biological activity against multi-drug-resistant (MDR) tumor cells. Such

• -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

Tricyclic flavonoids with 1,3-dithiolium substructure

• Lucian G. Bahrin,
• Peter G. Jones and
• Henning Hopf

Beilstein J. Org. Chem. 2012, 8, 1999–2003, doi:10.3762/bjoc.8.226

• led to the synthesis of derivative 1, a selective estrogen receptor β agonist (SERBA-1, Figure 1) [5]. Studies that focus on the structure–activity relationship were reported [6][7]. It was shown that a cyclopentane ring at the 3,4-carbon positions (labeled C, Figure 1) leads to a substantial rise in

Antifreeze glycopeptide diastereomers

• Lilly Nagel,
• Carsten Budke,
• Axel Dreyer,
• Thomas Koop and
• Norbert Sewald

Beilstein J. Org. Chem. 2012, 8, 1657–1667, doi:10.3762/bjoc.8.190

• whereas the peptides with one or two methylene spacers showed moderate activity. Results and Discussion In the frame of our ongoing studies on the structure–activity relationship of AFGPs, we became interested in the question of whether an inversion of the configuration at Cβ of threonine (replacement of

Organocatalytic asymmetric Michael addition of unprotected 3-substituted oxindoles to 1,4-naphthoquinone

• Jin-Sheng Yu,
• Feng Zhou,
• Yun-Lin Liu and
• Jian Zhou

Beilstein J. Org. Chem. 2012, 8, 1360–1365, doi:10.3762/bjoc.8.157

• because of the wide occurrence of this structural motif in natural products and pharmaceutically active compounds [1][2][3]. In addition, structure–activity relationship studies have revealed that the absolute configuration and the substituent of the C3 position of oxindole greatly influenced the

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

Unprecedented deoxygenation at C-7 of the ansamitocin core during mutasynthetic biotransformations

• Tobias Knobloch,
• Gerald Dräger,
• Wera Collisi,
• Florenz Sasse and
• Andreas Kirschning

Beilstein J. Org. Chem. 2012, 8, 861–869, doi:10.3762/bjoc.8.96

• pharmaceuticals because of their structural complexity and the difficulties associated with accessing analogues for structure–activity relationship studies. Total synthesis approaches are still a tour de force and are hardly employed, while commonly semisynthesis as well as biotechnological approaches are widely

Synthesis and characterization of Sant-75 derivatives as Hedgehog-pathway inhibitors

• Chao Che,
• Song Li,
• Bo Yang,
• Shengchang Xin,
• Zhixiong Yu,
• Taofeng Shao,
• Chuanye Tao,
• Shuo Lin and
• Zhen Yang

Beilstein J. Org. Chem. 2012, 8, 841–849, doi:10.3762/bjoc.8.94

• , Beijing 100871, China 10.3762/bjoc.8.94 Abstract Sant-75 is a newly identified potent inhibitor of the hedgehog pathway. We designed a diversity-oriented synthesis program, and synthesized a series of Sant-75 analogues, which lays the foundation for further investigation of the structure–activity

• relationship of this important class of hedgehog-pathway inhibitors. Keywords: chemical diversity; diversity-oriented; hedgehog pathway; inhibitor; Sant-75; synthesis; Introduction The Hedgehog (Hh) signaling pathway plays an essential role in embryonic development and adult tissue homeostasis in metazoans

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

• minor variations in its molecular structure, such as the introduction of a second sulfate or the replacement of the sulfate by a halogen, may become even more potent [49]. Further systematic tests are needed to investigate the structure–activity relationship. Experimental General Commercially available

Synthesis of 2-amino-3-arylpropan-1-ols and 1-(2,3-diaminopropyl)-1,2,3-triazoles and evaluation of their antimalarial activity

• Matthias D’hooghe,
• Stéphanie Vandekerckhove,
• Karen Mollet,
• Karel Vervisch,
• Stijn Dekeukeleire,
• Liesbeth Lehoucq,
• Carmen Lategan,
• Peter J. Smith,
• Kelly Chibale and
• Norbert De Kimpe

Beilstein J. Org. Chem. 2011, 7, 1745–1752, doi:10.3762/bjoc.7.205

• )aziridines by diethylamine [8]. Nonetheless, a number of challenges with regard to structure–activity relationship studies of functionalized aminopropanes remain unaddressed, especially concerning the screening of structural analogues of aminopropanes 1 and 2. In the present paper, the synthesis of racemic

• -resistant strain of P. falciparum (Dd2) revealed antiplasmodial activity for 2-aminopropan-1-ol 6a, 2-aminopropan-1,3-diols 9a,b and triaminopropane 16f with IC50-values between 8.5 and 13.6 μM. From a structure–activity relationship viewpoint, the presence of a chlorinated aromatic ring seems to contribute

Synthesis and characterization of new diiodocoumarin derivatives with promising antimicrobial activities

• Hany M. Mohamed,
• Ashraf H. F. Abd EL-Wahab,
• Ahmed M. EL-Agrody,
• Ahmed H. Bedair,
• Fathy A. Eid,
• Mostafa M. Khafagy and
• Kamal A. Abd-EL-Rehem

Beilstein J. Org. Chem. 2011, 7, 1688–1696, doi:10.3762/bjoc.7.199

• , compared with the standards ampicillin and calforan. In addition, compounds 2 and 5 in the series were found to be inactive against Escherichia coli (NCTC-10410), while compound 11 was inactive against Serratia marcescens (IMRU-70). An investigation of the structure–activity relationship (SAR) revealed

Directed aromatic functionalization in natural-product synthesis: Fredericamycin A, nothapodytine B, and topopyrones B and D

• Charles Dylan Turner and
• Marco A. Ciufolini

Beilstein J. Org. Chem. 2011, 7, 1475–1485, doi:10.3762/bjoc.7.171

• ][82][83][98][99]. The objective of the present effort was to obtain the target molecules by any means, as rapidly as possible, and in a fashion that might enable the production of analogs for structure–activity relationship studies. By contrast, our work on fredericamycin and nothapodytine had chiefly

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

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

• structure–activity relationship [49]. Federsel et al. used a piperazine derivative 6 and an aryl halide 5 for the preparation of a CNS-active substituted chiral aminotetralin 7 (Scheme 2) [50]. The 5-HT1B receptor antagonist 8 was developed for the treatment of certain neuronal disorders. Different

• 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

The C–F bond as a conformational tool in organic and biological chemistry

• Luke Hunter

Beilstein J. Org. Chem. 2010, 6, No. 38, doi:10.3762/bjoc.6.38

• pharmaceuticals A drug will bind its protein target with maximal affinity if it is pre-organised into the correct conformation prior to binding and this can be achieved in certain cases by judiciously incorporating fluorine atoms into the drug [4][17]. This concept is illustrated in structure–activity

• relationship studies of Indinavir (17, Figure 2), an HIV protease inhibitor developed by Merck. It is a functionalised pseudopeptide containing a central hydroxyethylene moiety in place of a scissile peptide bond. X-ray crystallography shows that 17 binds to HIV protease with its central carbon chain in an

An efficient partial synthesis of 4′-O-methylquercetin via regioselective protection and alkylation of quercetin

• Nian-Guang Li,
• Zhi-Hao Shi,
• Yu-Ping Tang,
• Jian-Ping Yang and
• Jin-Ao Duan

Beilstein J. Org. Chem. 2009, 5, No. 60, doi:10.3762/bjoc.5.60

• functions such as sulfate or glucuronide groups. These compounds will allow structure–activity relationship studies of flavonoids to be carried out. Their easily obtained labeled forms will give access to isotopic dilution dosage by LC-MS or LC-MS/MS and will help in the identification of unknown flavonoid

Mitomycins syntheses: a recent update

• Jean-Christophe Andrez

Beilstein J. Org. Chem. 2009, 5, No. 33, doi:10.3762/bjoc.5.33

• different strategies that have been employed to improve the efficacy of mitomycins in vivo by structure activity relationship studies. As a matter of fact, the natural products themselves are so sensitive that only minor modifications have been possible in connection with medicinal chemistry studies

Recent progress on the total synthesis of acetogenins from Annonaceae

• Nianguang Li,
• Zhihao Shi,
• Yuping Tang,
• Jianwei Chen and
• Xiang Li

Beilstein J. Org. Chem. 2008, 4, No. 48, doi:10.3762/bjoc.4.48

• only the first total synthesis of molecules of contemporary interest and syntheses that have helped to correct structures. In addition, some significant results on the novel synthesis and structure–activity relationship studies of annonaceous acetogenins are also introduced. Keywords: annonaceous

Sordarin, an antifungal agent with a unique mode of action

• Huan Liang

Beilstein J. Org. Chem. 2008, 4, No. 31, doi:10.3762/bjoc.4.31

• the lack of extensive toxicity tests from the latter two companies. Diterpene skeleton analogs Structure-activity relationship studies of sordarin have been largely confined to the glycosyl moiety, while the exact roles of the different components of the aglycone, such as the isopropyl group, the

Synthesis of crispine A analogues via an intramolecular Schmidt reaction

• Ajoy Kapat,
• Ponminor Senthil Kumar and
• Sundarababu Baskaran

Beilstein J. Org. Chem. 2007, 3, No. 49, doi:10.1186/1860-5397-3-49

• developed for the synthesis of crispine A. [20][21][22][23][24][25][26][27][28] Interestingly, Schell and Smith reported the first synthesis of crispine A, even before its isolation, using the N-chloramine rearrangement reaction as a key step.[25] In order to understand the structure activity relationship

Flexible synthesis of poison- frog alkaloids of the 5,8-disubstituted indolizidine- class. II: Synthesis of (-)-209B, (-)-231C, (-)-233D, (-)-235B", (-)-221I, and an epimer of 193E and pharmacological effects at neuronal nicotinic acetylcholine receptors

• Soushi Kobayashi,
• Naoki Toyooka,
• Dejun Zhou,
• Hiroshi Tsuneki,
• Tsutomu Wada,
• Toshiyasu Sasaoka,
• Hideki Sakai,
• Hideo Nemoto,
• H. Martin Garraffo,
• Thomas F. Spande and
• John W. Daly

Beilstein J. Org. Chem. 2007, 3, No. 30, doi:10.1186/1860-5397-3-30

• into brain and, as shown in our research, some exhibit high affinity and selectivity for either α4β2 or α7 nicotinic receptors. Further structure-activity relationship studies of synthetic indolizidines may lead to the development of radioactive α4β2-selective or α7-selective ligands useful for in vivo