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

Flexible synthesis of anthracycline aglycone mimics via domino carbopalladation reactions

• Markus Leibeling and
• Daniel B. Werz

Beilstein J. Org. Chem. 2013, 9, 2194–2201, doi:10.3762/bjoc.9.258

• groove of double-stranded DNA [4][5]. While the mode of action of anthracyclines is still not fully understood, it is widely accepted that these chemotherapeutic agents form a ternary complex with double-stranded DNA and topoisomerase II thereby leading to DNA damage and cell death [6][7]. They are used

The chemistry of isoindole natural products

• Klaus Speck and
• Thomas Magauer

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

• of staurosporine (26), is currently in clinical trials for the treatment of acute myeloid leukemia [20]. Although rebeccamycin (28) and its congeners only differ in the lack of the second glycosidic linkage, a completely different mode of action is effective. By stabilizing the topoisomerase I DNA

Organocatalyzed enantioselective desymmetrization of aziridines and epoxides

• Ping-An Wang

Beilstein J. Org. Chem. 2013, 9, 1677–1695, doi:10.3762/bjoc.9.192

• mode of action of OC-23. The chiral thioureas OC-28 to OC-44 for the desymmetrization of meso-aziridines. The chiral guanidines (OC-45 to OC-48). The proposed activation mode of OC-46. The chiral 1,2,3-triazolium chlorides OC-49 to OC-55. Early organocatalysts for enantioselective desymmetrization of

Synthesis and evaluation of cell-permeable biotinylated PU-H71 derivatives as tumor Hsp90 probes

• Tony Taldone,
• Anna Rodina,
• Erica M. DaGama Gomes,
• Matthew Riolo,
• Hardik J. Patel,
• Raul Alonso-Sabadell,
• Danuta Zatorska,
• Maulik R. Patel,
• Sarah Kishinevsky and
• Gabriela Chiosis

Beilstein J. Org. Chem. 2013, 9, 544–556, doi:10.3762/bjoc.9.60

• testament to this, there are numerous ongoing clinical trials evaluating Hsp90 inhibitors from a variety of chemotypes [4]. Although there are potentially numerous ways to block the activity of Hsp90, the most successful to date, as exemplified by its exclusivity in mode of action by those advanced to

Zanthoxoaporphines A–C: Three new larvicidal dibenzo[de,g]quinolin-7-one alkaloids from Zanthoxylum paracanthum (Rutaceae)

• Fidelis N. Samita,
• Louis P. Sandjo,
• Isaiah O. Ndiege,
• Ahmed Hassanali and
• Wilber Lwande

Beilstein J. Org. Chem. 2013, 9, 447–452, doi:10.3762/bjoc.9.47

• from the same family, and the mode of action of these alkaloids could be the same. Zanthoxoaporphine A (2) and liriodenine, which are oxoaporphines, are more active than dicentrine (aporphine). The isoquinoline moiety could be the pharmacophore of this class of compounds and the presence of a ketone at

Asymmetric Diels–Alder reaction with >C=P– functionality of the 2-phosphaindolizine-η¹-P-aluminium(O-menthoxy) dichloride complex: experimental and theoretical results

• Rajendra K. Jangid,
• Nidhi Sogani,
• Neelima Gupta,
• Raj K. Bansal,
• Moritz von Hopffgarten and
• Gernot Frenking

Beilstein J. Org. Chem. 2013, 9, 392–400, doi:10.3762/bjoc.9.40

• , namely C1 (δ = 132.7 ppm, 1JPC = 36.0 Hz), C3 (δ = 54.5 ppm, 1JPC = 31.7 Hz) and C9 (δ = 33.6 ppm, 1JPC = 44.5 Hz) are identified readily by large values of 1JPC [33][34]. The 13C NMR signals due to the O-menthoxy moiety were assigned on the basis of the reported results [35]. Mode of action of the

• theoretically the mode of action of the chiral auxiliary in directing the complete diastereoselectivity of the DA reactions. The following model DA reactions (Scheme 5) were calculated at the DFT (B3LYP/6-31+G*) level. Computational calculations It has been reported that for determining activation free energies

Modulating the activity of short arginine-tryptophan containing antibacterial peptides with N-terminal metallocenoyl groups

• H. Bauke Albada,
• Alina-Iulia Chiriac,
• Michaela Wenzel,
• Maya Penkova,
• Julia E. Bandow,
• Hans-Georg Sahl and
• Nils Metzler-Nolte

Beilstein J. Org. Chem. 2012, 8, 1753–1764, doi:10.3762/bjoc.8.200

• of ~90 µM, indicating a potentially interesting therapeutic window. Both the killing kinetics and growth inhibition studies presented in this work point to a membrane-based mode of action for these two peptides, each having different kinetic parameters. Keywords: antimicrobial peptides; arginine

• details on the mode of action. Specifically, proteomic analysis of the changes in the bacterial proteome as result of exposure to these synAMPs, and prokaryotic and eukaryotic membrane model systems will be used to precisely determine if it is simply a membrane-based mechanism or if there are more factors

• . While we attempt to elucidate the mode of action of these synAMPs, we are also interested in a detailed understanding of the effects of the organometallic fragment on the activity – for example by determining the contributions of hydrogen-bond forming processes in membrane environments – and the effect

Binaphthyl-anchored antibacterial tripeptide derivatives with hydrophobic C-terminal amino acid variations

• John B. Bremner,
• Paul A. Keller,
• Stephen G. Pyne,
• Mark J. Robertson,
• K. Sakthivel,
• Kittiya Somphol,
• Dean Baylis,
• Jonathan A. Coates,
• John Deadman,
• Dharshini Jeevarajah and
• David I. Rhodes

Beilstein J. Org. Chem. 2012, 8, 1265–1270, doi:10.3762/bjoc.8.142

• included in Table 2. This tripeptide derivative 9 showed similar, if slightly weaker, antibacterial activity against these strains, apart from VSE, against which it was significantly less potent than 2c. Although the mode of action of the tripeptide derivatives has not been established, our earlier results

• on compounds of type 1 (Figure 1) and related cyclic systems implicated the possibility of more than one mode of action [8]. As noted for other cationic peptide derivatives [9][10][11][12], cell membrane damage could well be one of these actions, together with some more specific interactions. Dual

Design of a novel tryptophan-rich membrane-active antimicrobial peptide from the membrane-proximal region of the HIV glycoprotein, gp41

• Evan F. Haney,
• Leonard T. Nguyen,
• David J. Schibli and
• Hans J. Vogel

Beilstein J. Org. Chem. 2012, 8, 1172–1184, doi:10.3762/bjoc.8.130

• are unstructured in solution, and they adopt amphipathic α-helices when bound to a phospholipid bilayer [3][23]. This binding to the bacterial membrane is often related to a membrane-destabilizing mode of action, which ultimately leads to bacterial cell death [24]. However, recent evidence suggests

• that membrane binding may be a part of a more complex mode of action involving multiple targets of inhibition [21][25]. In addition to their membrane-binding properties, many AMPs are typified by a high proportion of Trp and cationic amino acids [5][6]. The Trp residues are unique because of their

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

• ) structures of naturally occurring alkaloids bearing aminoacetal moieties and a proposed mode of action of quinocarcin. Four-step synthesis of hexacyclic skeleton 25. Four-step synthesis of hexacyclic skeleton 30. Parallel and four-step synthesis of tetracyclic skeletons 39–42 and 47–48. Synthesis of branched

Synthesis of szentiamide, a depsipeptide from entomopathogenic Xenorhabdus szentirmaii with activity against Plasmodium falciparum

• Friederike I. Nollmann,
• Andrea Dowling,
• Marcel Kaiser,
• Klaus Deckmann,
• Sabine Grösch,
• Richard ffrench-Constant and
• Helge B. Bode

Beilstein J. Org. Chem. 2012, 8, 528–533, doi:10.3762/bjoc.8.60

• bioactive natural products and the importance of a broad bioactivity testing of isolated compounds in order to find a biological activity and thus a biological function of such natural products. Work in the Bode lab currently concentrates on the identification of the mode of action of 1 in insects and

Planar-bilayer activities of linear oligoester bolaamphiphiles

• Jonathan K. W. Chui,
• Thomas M. Fyles and
• Horace Luong

Beilstein J. Org. Chem. 2011, 7, 1562–1569, doi:10.3762/bjoc.7.184

• underlying mechanism? One line of possibilities relates to the underlying “system property” mentioned earlier. It is known that pure lipids near their phase transitions can show single-channel conductance activities; while the specific mode of action depends on the identity of the lipid, discrete conductance

Highly efficient cyclosarin degradation mediated by a β-cyclodextrin derivative containing an oxime-derived substituent

• Michael Zengerle,
• Florian Brandhuber,
• Christian Schneider,
• Franz Worek,
• Georg Reiter and
• Stefan Kubik

Beilstein J. Org. Chem. 2011, 7, 1543–1554, doi:10.3762/bjoc.7.182

• degradation and, in particular, the observed enantioselectivity are good indications that noncovalent interactions between the cyclodextrin ring and the substrate, presumably involving the inclusion of the cyclohexyl moiety of cyclosarin into the cyclodextrin cavity, contribute to the mode of action. Among

• , acetylcholinesterase (AChE). Moreover, the results indicate that the mode of action of these cyclodextrin derivatives involves the formation of an inclusion complex with the OP. The question thus arises as to whether suitable cyclodextrin derivatives could also be used in vivo as antidotes against OP poisonings. Such

• treatment of OP poisonings. Their mode of action involves reactivation of the OP-inhibited acetylcholinesterase [29], yet previous work has also indicated that certain oximes are able to cleave OPs directly [30]. We show that some of our cyclodextrin derivatives efficiently reduce GF concentrations in

Synthesis of (−)-julocrotine and a diversity oriented Ugi-approach to analogues and probes

• Ricardo A. W. Neves Filho,
• Bernhard Westermann and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2011, 7, 1504–1507, doi:10.3762/bjoc.7.175

• Leishmania amazonensis (L.). It could be helpful to elucidate the to-date unknown mode of action of this natural product in the parasite. Conclusion In summary, a highly efficient method to synthesize (−)-julocrotine (1) in three steps from Cbz-glutamine 2 was developed. The approach affords the natural

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

• carvedilol has an additional antioxidant mode of action. It has been proposed that the carbazole ring may be involved in scavenging oxygen radicals thereby accounting for reduced myocardial damage [41]. Since carbazoles are similar to indoles, analogous methods can be used for their synthesis. The key

The allylic chalcogen effect in olefin metathesis

• Yuya A. Lin and
• Benjamin G. Davis

Beilstein J. Org. Chem. 2010, 6, 1219–1228, doi:10.3762/bjoc.6.140

• ]. a) Acceleration of ring-closing enyne metathesis by the allylic hydroxy group [23]. b) Proposed mode of action by the allylic hydroxy group in this reaction. a) Effect of the hydroxy group on the rate and steroselectivity of ROCM [24]. b) Proposed H-bonded ruthenium complex for stereoselective ROCM

Kinetics and mechanism of vanadium catalysed asymmetric cyanohydrin synthesis in propylene carbonate

• Michael North and
• Marta Omedes-Pujol

Beilstein J. Org. Chem. 2010, 6, 1043–1055, doi:10.3762/bjoc.6.119

• used by other groups as part of synthetic studies [44][45][46]. Mechanistically, the mode of action of catalyst 1 is well understood [15][20][47][48][49], involving a bimetallic transition state in which one titanium atom acts as a Lewis acid, coordinating to the aldehyde, and the other forms a

• titanium–cyanide bond, thus allowing transfer of cyanide to the carbonyl to occur intramolecularly in a highly organized transition state structure. The mode of action of vanadium based catalysts such as 2 is believed to involve two parallel catalytic cycles, the slower of which involves only monometallic

Mitomycins syntheses: a recent update

• Jean-Christophe Andrez

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

• unique activity was thought to originate from their ability to transform in vivo to generate the active metabolite. This was followed by decades of investigations to understand in detail their singular mode of action. It was found that the aziridine played a crucial role, allowing an irreversible bis

• ), D-glucosamine 21 and carbamoyl phosphate (Scheme 4) [29][30][31][32]. The key intermediate, AHBA, is also a common precursor to other anticancer drugs, such as rifamycin and ansamycin. 2.2. Mode of action Mitomycins are quinone antitumor antibiotics that exert their biological activity through DNA

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

• fungi by stabilizing the ribosome/EF2 complex. This mode of action is in contrast to typical antifungals, which target the cell membrane. This unusual bioactivity makes sordarin a promising candidate for the development of new fungicidal agents, and provided the motivation for extensive research. Three