ML212: A small-molecule probe for investigating fluconazole resistance mechanisms in Candida albicans

• Willmen Youngsaye,
• Cathy L. Hartland,
• Barbara J. Morgan,
• Amal Ting,
• Partha P. Nag,
• Benjamin Vincent,
• Carrie A. Mosher,
• Joshua A. Bittker,
• Sivaraman Dandapani,
• Michelle Palmer,
• Luke Whitesell,
• Susan Lindquist,
• Stuart L. Schreiber and
• Benito Munoz

Beilstein J. Org. Chem. 2013, 9, 1501–1507, doi:10.3762/bjoc.9.171

• were eliminated. Results and Discussion Screening results In order to identify nonfungitoxic chemosensitizers of Candida albicans, compounds from the NIH’s Molecular Libraries Small Molecule Repository (MLSMR) [17] were evaluated in the screening cascade summarized in Figure 1. The C. albicans strains

• fluconazole-resistant Candida albicans clinical isolates. Among the numerous hits, 3-phenylindazole 1 was selected for chemical optimization, resulting in the identification of 3-(3-anisoyl)indazole 36 as new small-molecule probe (ML212) to facilitate investigation of the various mechanisms used by C

Synthesis of the tetracyclic core of Illicium sesquiterpenes using an organocatalyzed asymmetric Robinson annulation

• Lynnie Trzoss,
• Jing Xu,
• Michelle H. Lacoske and
• Emmanuel A. Theodorakis

Beilstein J. Org. Chem. 2013, 9, 1135–1140, doi:10.3762/bjoc.9.126

• . Keywords: natural products; neurodegenerative diseases; neurotrophic small molecule; organocatalysis; total synthesis; Introduction Neurotrophins are a family of endogenous proteins that are vital for neuron function, survival, and regeneration [1][2][3]. As such, they have prompted intense studies toward

Enhancement of efficiency in organic photovoltaic devices containing self-complementary hydrogen-bonding domains

• Rohan J. Kumar,
• Jegadesan Subbiah and
• Andrew B. Holmes

Beilstein J. Org. Chem. 2013, 9, 1102–1110, doi:10.3762/bjoc.9.122

• -processing, leading to cost and energy input advantages in device manufacture. Recently, a donor–acceptor small molecule with a cyanopyridone moiety as the acceptor motif and displaying moderate photovoltaic efficiency in a BHJ device with a fullerene was reported [20]. The efficiency of these optimized

The conjugation of nonsteroidal anti-inflammatory drugs (NSAID) to small peptides for generating multifunctional supramolecular nanofibers/hydrogels

• Jiayang Li,
• Yi Kuang,
• Junfeng Shi,
• Yuan Gao,
• Jie Zhou and
• Bing Xu

Beilstein J. Org. Chem. 2013, 9, 908–917, doi:10.3762/bjoc.9.104

• of small molecule hydrogels formed by NSAID derivatives [48][54][55][56] we intend to explore supramolecular hydrogels of other NSAIDs. Specifically, we use naproxen (denoted as Npx in this report), an over-the-counter NSAID, to generate a new hydrogelator 1a that only consists of naproxen and

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

• diseases and has recently been implicated in the onset of cancer. This report provides a synthetic and compound-based property summary of five pathway-related small-molecule chemical probes identified and optimized within the National Institutes of Health-Molecular Libraries Probe Center Network (NIH-MLPCN

• the small-molecule compounds discovered within the HTS process. The program then advanced a broader probe-production initiative (MLPCN) in 2008. This consortium resulted in the harnessing of chemical biology resources from four comprehensive centers and five specialty centers, which focused on either

• with advancing basic in vitro and in vivo studies for testing new hypotheses in disease modulation. Within this report, the outcomes of two Sanford-Burnham projects for chemical probe discovery are discussed, highlighting five examples of thematic small-molecule chemical probes discovered through our

Synthesis of skeletally diverse alkaloid-like molecules: exploitation of metathesis substrates assembled from triplets of building blocks

• Sushil K. Maurya,
• Mark Dow,
• Stuart Warriner and
• Adam Nelson

Beilstein J. Org. Chem. 2013, 9, 775–785, doi:10.3762/bjoc.9.88

• half of all known organic compounds are based on only 0.25% of the known molecular scaffolds [9]! This uneven coverage of chemical space is also typical of small-molecule screening collections [7][10]. Consequently, the biological relevance of most known scaffolds has been poorly explored. The field of

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

• protein levels in spinal-cord extracts. Due to the toxicity of the compound when administered in higher doses, compound 8 is unlikely to be useful for the treatment of ALS patients, although this screening strategy may prove relevant for the development of further small molecule inhibitors [25

• a screening strategy to analyze the ability of small molecules to reduce mutant SOD1 aggregates in a cell-culture model [28]. Using PC12 cells transfected with an inducible SOD1 G93A construct [29], a library of over 50,000 small-molecule compounds was initially screened for the ability to enhance

• the health and stability of motor neurons. Compounds that increase growth factor-induced neuronal support have been tested in both cellular and mouse models of ALS with moderate success. For example, in a study performed by Shimazawa et al. [49] a small molecule (SUN N8075, 22, Figure 11), which is

Synthesis and stability study of a new major metabolite of γ-hydroxybutyric acid

• Ida Nymann Petersen,
• Jesper Langgaard Kristensen,
• Christian Tortzen,
• Torben Breindahl and
• Daniel Sejer Pedersen

Beilstein J. Org. Chem. 2013, 9, 641–646, doi:10.3762/bjoc.9.72

• urine, which is of importance in the development of new analytical methods. Results and Discussion Synthesis and stability assessment Synthesis of GHB glucuronides 2 and d4-2 The synthesis of small molecule glucuronide derivatives can be carried out by a wide variety of synthetic [7][8] and biocatalytic

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

• Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA Department of Pharmacology, Weill Graduate School of Medical Sciences, 1300 York Avenue, New York, NY 10065, USA 10.3762/bjoc.9.60 Abstract The attachment of biotin to a small molecule provides a powerful tool in

• ., PU-H71 nonbinding) complexes. The attachment of biotin to a small molecule provides a powerful tool in biology. As research tools, biotin-labeled chemical tools have the potential to extend the study of single targets to a particular class of molecules or even to an entire proteome. In addition, the

• promoting molecular characterization of biomolecules both in vitro and within their natural biological contexts. In one application, biotinylated probes may be subjected to streptavidin-containing beads to identify potential direct and indirect interactors of the small molecule through affinity capture

From bead to flask: Synthesis of a complex β-amido-amide for probe-development studies

• Kevin S. Martin,
• Cristian Soldi,
• Kellan N. Candee,
• Hiromi I. Wettersten,
• Robert H. Weiss and
• Jared T. Shaw

Beilstein J. Org. Chem. 2013, 9, 260–264, doi:10.3762/bjoc.9.31

• the discovery of new small-molecule probes that modulate biological phenomena [1]. Although the use of solid-phase, split-pool combinatorial synthesis for the preparation of solutions of small-molecule libraries has declined, the use of these compounds for on-bead screening has resulted in recent

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

• /bjoc.9.24 Abstract A variety of stable, small-molecule peptidomimetic ligands have been developed to elucidate the mechanism by which the neuropeptide Pro-Leu-Gly-NH2 (PLG) modulates dopaminergic neurotransmission. Photoaffinity labeling ligands based upon PLG peptidomimetics have been used to

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

• : asymmetric synthesis; benzimidazole; host-directed; myxovirus; small molecule inhibitor; Introduction Myxoviruses are divided into two evolutionarily distinct yet related families: the orthomyxoviridae, which is composed largely of the influenza viruses, and the paramyxoviridae, which includes respiratory

• compounds with a narrow spectrum of antiviral activities, and such inhibitors will certainly face the inevitable challenge of resistance [7][8]. Our research group has been actively engaged in the identification of small molecule inhibitors against myxoviruses in recent years [8][9][10][11][12], with a

• principle, less susceptibility to the development of resistance. Using high-throughput screening, in combination with counter-screening for detecting a broadened viral target spectrum that extends to other pathogens of the myxovirus families, our research group has been successful in identifying small

An improved synthesis of a fluorophosphonate–polyethylene glycol–biotin probe and its use against competitive substrates

• Hao Xu,
• Hairat Sabit,
• Gordon L. Amidon and
• H. D. Hollis Showalter

Beilstein J. Org. Chem. 2013, 9, 89–96, doi:10.3762/bjoc.9.12

• these competition studies demonstrate a new application of FP-based probes seldom explored before. Keywords: biotin; fluorophosphonate; high turnover rate; reversible substrate; Introduction One of the goals of chemical biology is to develop small–molecule- and biomolecule-based probes to interrogate

• are required in order to observe a clear signal. Competition study The identification of novel serine hydrolases and the screening of their covalent inhibitors against FP-biotin type probes have been extensively studied [9][10][11]. The general approach for serine hydrolase small molecule inhibitor

Thioester derivatives of the natural product psammaplin A as potent histone deacetylase inhibitors

• Matthias G. J. Baud,
• Thomas Leiser,
• Vanessa Petrucci,
• Mekala Gunaratnam,
• Stephen Neidle,
• Franz-Josef Meyer-Almes and
• Matthew J. Fuchter

Beilstein J. Org. Chem. 2013, 9, 81–88, doi:10.3762/bjoc.9.11

• oncogenesis [3][4] and small molecule inhibitors of these pathways have emerged as highly attractive targets for anticancer therapies [5][6]. Inhibitors of epigenetic pathways should not only be useful as anticancer drugs, but also as molecular probes to study the causative relationships between specific

Synthetic probes for the study of biological function

• Jeffrey Aubé

Beilstein J. Org. Chem. 2013, 9, 79–80, doi:10.3762/bjoc.9.10

• challenge of finding a small molecule that binds to a macromolecular target in a specific enough way to influence its function is considerable. The combination of a binding event with a physical property such as fluorescence leads to another sort of probe, where the goal is to inform the researcher where a

Chemical–biological characterization of a cruzain inhibitor reveals a second target and a mammalian off-target

• Jonathan W. Choy,
• Clifford Bryant,
• Claudia M. Calvet,
• Patricia S. Doyle,
• Shamila S. Gunatilleke,
• Siegfried S. F. Leung,
• Kenny K. H. Ang,
• Steven Chen,
• Jiri Gut,
• Juan A. Oses-Prieto,
• Jonathan B. Johnston,
• Michelle R. Arkin,
• Alma L. Burlingame,
• Jack Taunton,
• Matthew P. Jacobson,
• James M. McKerrow,
• Larissa M. Podust and
• Adam R. Renslo

Beilstein J. Org. Chem. 2013, 9, 15–25, doi:10.3762/bjoc.9.3

• Adam R. Renslo Small Molecule Discovery Center, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA Department of Cellular and Molecular

• intracellular replication and differentiation of the T. cruzi parasite [17]. A variety of small-molecule cruzain inhibitors have been described, the majority of which act irreversibly by reaction with the catalytic cysteine in the enzyme active site [18][19][20][21][22][23][24][25][26][27]. One of the earliest

Hydrophobic analogues of rhodamine B and rhodamine 101: potent fluorescent probes of mitochondria in living C. elegans

• Laurie F. Mottram,
• Safiyyah Forbes,
• Brian D. Ackley and
• Blake R. Peterson

Beilstein J. Org. Chem. 2012, 8, 2156–2165, doi:10.3762/bjoc.8.243

• have led some investigators interested in imaging fusion and fission of mitochondria in C. elegans [28] to forego the use of small-molecule fluorescent probes and instead to use time-consuming molecular biology methods to generate transgenic animals that express fluorescent proteins, such as mitoGFP

• , that are targeted to this organelle. In general, the choice to use small-molecule probes or molecular-biology-based approaches for these types of imaging applications can be challenging because of our limited understanding of the bioavailability and bioaccumulation of small molecules in this model

• conditions (Figure 5). Conclusion Genetically encoded fluorophores such as green fluorescent protein (GFP) have revolutionized cell biology and studies of physiological processes. However, fluorescent small-molecule probes continue to offer advantages for some imaging applications. One advantage illustrated

Automated three-component synthesis of a library of γ-lactams

• Erik Fenster,
• David Hill,
• Oliver Reiser and
• Jeffrey Aubé

Beilstein J. Org. Chem. 2012, 8, 1804–1813, doi:10.3762/bjoc.8.206

• as pharmacological probes and as starting points for drug-discovery campaigns, has primarily fuelled this interest, while enabling technologies, such as diversity-oriented synthesis (DOS), have improved access to small-molecule libraries [1][2][3][4][5]. Compounds containing a γ-lactam moiety have

Metal–ligand multiple bonds as frustrated Lewis pairs for C–H functionalization

• Matthew T. Whited

Beilstein J. Org. Chem. 2012, 8, 1554–1563, doi:10.3762/bjoc.8.177

• important contributor to the diverse reactivities exhibited by transition-metal systems with small-molecule substrates. The Dewar–Chatt–Duncanson model provides a paradigm for this sort of interaction, where molecules such as H2 and alkenes are activated by a combination of ligand-to-metal σ donation and

• –base pair is then capable of activating various substrates by synergistically polarizing bonds, often in a concerted fashion [6][11][12][13][14]. The reaction is favorable, because the small-molecule substrates facilitate a shift in electron density away from the electron-rich Lewis base and toward the

Restructuring polymers via nanoconfinement and subsequent release

• Alan E. Tonelli

Beilstein J. Org. Chem. 2012, 8, 1318–1332, doi:10.3762/bjoc.8.151

• Alan E. Tonelli Fiber & Polymer Science Program, North Carolina State University, Campus Box 8391, Raleigh, NC, 27695-8301, USA 10.3762/bjoc.8.151 Abstract During the past several years my students and I have been utilizing certain small-molecule hosts to create nanostructured polymers. This is

• accomplished by first forming noncovalently bonded inclusion complexes (ICs) between these small-molecule hosts and guest polymers, followed by the careful removal of the host crystalline lattice to obtain a coalesced bulk polymer. We have repeatedly observed that such coalesced polymer samples behave

• consequence of the structural organization of the polymer–host-ICs. Polymer chains in host-IC crystals are confined to occupy narrow channels (diameter ~0.5–1.0 nm) formed by the small-molecule hosts around the included guest polymers during IC crystallization. This results in the separation and high

Exploring chemical diversity via a modular reaction pairing strategy

• Joanna K. Loh,
• Sun Young Yoon,
• Thiwanka B. Samarakoon,
• Alan Rolfe,
• Patrick Porubsky,
• Benjamin Neuenswander,
• Gerald H. Lushington and
• Paul R. Hanson

Beilstein J. Org. Chem. 2012, 8, 1293–1302, doi:10.3762/bjoc.8.147

• rapid advances in the fields of genomics and proteomics during the “post-genome era” have resulted in an increase in potential therapeutic targets for which there are no known small-molecule modulators [1]. The lack of adequate screening technologies, as well as screening collections of molecules, has

Similarity analysis, synthesis, and bioassay of antibacterial cyclic peptidomimetics

• Workalemahu M. Berhanu,
• Mohamed A. Ibrahim,
• Girinath G. Pillai,
• Alexander A. Oliferenko,
• Levan Khelashvili,
• Farukh Jabeen,
• Bushra Mirza,
• Farzana Latif Ansari,
• Ihsan ul-Haq,
• Said A. El-Feky and
• Alan R. Katritzky

Beilstein J. Org. Chem. 2012, 8, 1146–1160, doi:10.3762/bjoc.8.128

• affording opportunities for drug design and development. One strategy to create peptidomimetics couples a small-molecule scaffold with a peptide. Such scaffolds include aromatic rings or heterocycles, which may be positioned in the interior of the peptide chain [4][5] or at the C- [6][7][8] or N-terminus [9

• the Tanimoto coefficient or the Tversky index [34]. Although a well-established concept, molecular similarity has previously been used almost entirely in the design of small-molecule drugs, with very few applications in other chemical disciplines. To the best of our knowledge, despite their promise of

Synthesis of a library of tricyclic azepinoisoindolinones

• Bettina Miller,
• Shuli Mao,
• Kara M. George Rosenker,
• Joshua G. Pierce and
• Peter Wipf

Beilstein J. Org. Chem. 2012, 8, 1091–1097, doi:10.3762/bjoc.8.120

• carbon to be significant contributors. Regioisomeric library products 9 and 10 were submitted to the NIH Small Molecule Repository (SMR) [42], screened in the Molecular Libraries Probe Center Network (MLPCN) [43], and biological results were deposited in PubChem [44]. For example, 9{2} was tested in 188

Synthesis and in silico screening of a library of β-carboline-containing compounds

• Kay M. Brummond,
• John R. Goodell,
• Matthew G. LaPorte,
• Lirong Wang and
• Xiang-Qun Xie

Beilstein J. Org. Chem. 2012, 8, 1048–1058, doi:10.3762/bjoc.8.117

• ) C (CAS) UT (Pearlman at the University of Texas) metrics and Tanimoto coefficients (Tc) and this virtual compound library was mapped onto the existing chemical space of the NIH Molecular Libraries Small Molecule Repository (MLSMR) [4]. When considering the physical properties most important to

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

• flexibility and divergence of the synthetic process with high levels of stereoselectivity are promising for the development of small-molecule libraries with structural diversity and complexity. With collections of the natural-product-inspired molecules in hand, in vitro anti-trypanosomal activities [35][36

• insignificant activities (data not shown). Thus, this preliminary assessment supports the idea that the collections of natural-product-inspired scaffolds could have high hit rates against biological screenings, even without having structural information about the biological targets and small-molecule modulators