Identification of clickable HIV-1 capsid-targeting probes for viral replication inhibition.

Of the targets for HIV-1 therapeutics, the capsid core is a relatively unexploited but alluring drug target due to its indispensable roles throughout virus replication. Because of this, we aimed to identify "clickable" covalent modifiers of the HIV-1 capsid protein (CA) for future functionalization. We screened a library of fluorosulfate compounds that can undergo sulfur(VI) fluoride exchange (SuFEx) reactions, and five compounds were identified as hits. These molecules were further characterized for antiviral effects. Several compounds impacted in vitro capsid assembly. One compound, BBS-103, covalently bound CA via a SuFEx reaction to Tyr145 and had antiviral activity in cell-based assays by perturbing virus production, but not uncoating. The covalent binding of compounds that target the HIV-1 capsid could aid in the future design of antiretroviral drugs or chemical probes that will help study aspects of HIV-1 replication.

Synthesis and structure-activity relationships of aryl fluorosulfate-based inhibitors as novel antitubercular agents.

To identify new compounds that can effectively inhibit Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), we screened, synthesized, and evaluated a series of novel aryl fluorosulfate derivatives for their in vitro inhibitory activity against Mtb. Compound 21b exhibited an in vitro minimum inhibitory concentration (MIC) of 0.06 µM against Mtb, no cytotoxicity against both HEK293T and HepG2 mammalian cell lines, and had good in vivo mouse plasma exposure and lung concentration with a 20 mg/kg oral dose, which supports advanced development as a new chemical entity for TB treatment.

Synthesis of Sulfonyl Fluorides Using Direct Chloride/Fluoride Exchange in Potassium Fluoride and Water/Acetone.

A multitude of synthetic routes are available for the preparation of sulfonyl fluorides (R-SO2F) whose discovery is now almost a century old. These syntheses are often limited by the scope, hazardous materials, and elaborate procedures. The simple and mild procedure based on direct chloride/fluoride exchange from a sulfonyl chloride (R-SO2Cl) starting material in a KF and water/acetone biphasic mixture is investigated. Seventeen examples in high yield (84-100%) with wide scope are described.

Chemical Triphosphorylation of Oligonucleotides.

The 5'-triphosphate is an essential nucleic acid modification found throughout all life and increasingly used as a functional modification of oligonucleotides in biotechnology and synthetic biology. Oligonucleotide 5'-triphosphates have historically been prepared in vitro by enzymatic methods. However, these methods are limited to natural RNA oligonucleotides, have strong sequence preferences, and tend to produce heterogeneous products. New methods of chemical triphosphorylation complement both the reduced cost of automated oligonucleotide synthesis by phosphoramidite chemistry and the diverse range of nucleotide modifications now available. Thus, the synthesis of oligonucleotide triphosphates of arbitrary sequence and length, and optionally containing various nonnatural modifications, is now accessible. This paper presents the appropriate methods and techniques for chemical triphosphorylation of oligonucleotides using salicyl phosphorochloridite and pyrophosphate. This method uses commercially available reagents, is compatible with most oligonucleotides prepared by standard solid-phase synthesis methods, and can be completed in 2 h following oligonucleotide synthesis, before deprotection and purification. Two uses of chemically triphosphorylated oligonucleotides as substrates for catalytic RNA enzymes are demonstrated, including the synthesis of a mirror-image version of the hammerhead ribozyme from nonbiological L-RNA triphosphates.

Cross-Chiral, RNA-Catalyzed Exponential Amplification of RNA.

Informational macromolecules in biology are composed of subunits of a single handedness, d-nucleotides in nucleic acids and l-amino acids in proteins. Although this chiral uniformity may be expedient, it is not a chemical necessity, as demonstrated by the recent example of an RNA enzyme that catalyzes the RNA-templated polymerization of RNA molecules of the opposite handedness. This reaction, when carried out iteratively, can provide the basis for exponential amplification of RNA molecules and the information they contain. By carrying out thermal cycling, analogous to the polymerase chain reaction, and supplying oligonucleotide building blocks that comprise both the functional strand of RNA and its complement, cross-chiral exponential amplification was achieved. This process was used to amplify the l-RNA form of the hammerhead ribozyme, catalyzed by the d-RNA form of the polymerase. The resulting l-hammerhead exhibits the expected activity in cleaving a corresponding l-RNA substrate. Exponential amplification was also carried out within individual droplets of a water-in-oil emulsion. The ability to amplify enantio-RNAs, both in bulk solution and within compartments, provides a means to evolve cross-chiral RNA polymerases based on the function of the RNAs they produce.

Biocompatible SuFEx Click Chemistry: Thionyl Tetrafluoride (SOF4 )-Derived Connective Hubs for Bioconjugation to DNA and Proteins.

We report here the development of a suite of biocompatible SuFEx transformations from the SOF4 -derived iminosulfur oxydifluoride hub in aqueous buffer conditions. These biocompatible SuFEx reactions of iminosulfur oxydifluorides (R-N=SOF2 ) with primary amines give sulfamides (8 examples, up to 98 %), while the reaction with secondary amines furnish sulfuramidimidoyl fluoride products (8 examples, up to 97 %). Likewise, under mild buffered conditions, phenols react with the iminosulfur oxydifluorides (Ar-N=SOF2 ) to produce sulfurofluoridoimidates (13 examples, up to 99 %), which can themselves be further modified by nucleophiles. These transformations open the potential for asymmetric and trisubstituted linkages projecting from the sulfur(VI) center, including versatile S-N and S-O connectivity (9 examples, up to 94 %). Finally, the SuFEx bioconjugation of iminosulfur oxydifluorides to amine-tagged single-stranded DNA and to BSA protein demonstrate the potential of SOF4 -derived SuFEx click chemistry in biological applications.

Recent Developments on Phenstatins as Potent Antimitotic Agents.

BACKGROUND: Phenstatin and their derivatives display remarkable antiproliferative activity toward a wide variety of preclinical tumor models. Structural simplicity and excellent stability of phenstatins offer a stimulating premise for developing various derivatives with profound antimitotic activity and excellent cytotoxicity. OBJECTIVE: To do analysis of literature that phenstatins derivatives inhibit tubulin polymerization through their interaction at the colchicine binding site of microtubules and arrest the G2/M phase of the cell cycle. In addition, phenstatin derivatives are undergoing clinical evaluation as vascular targeting/disrupting agents and also exhibit direct antiangiogenic properties. METHODS: An organised well designed and appropriately managed search of bibliographic databases for peer-reviewed research literature using a focused review question and inclusion/ exclusion criteria has been done for this article. CONCLUSION: In this review article, the synthesis and structure-activity relationships of phenstatin and a wide number of their reported analogues with modifications to ring A, ring B, and to the keto position are discussed in the perspective of medicinal chemistry with proper conclusion.

A Heck-Matsuda Process for the Synthesis of ß-Arylethenesulfonyl Fluorides: Selectively Addressable Bis-electrophiles for SuFEx Click Chemistry.

A Heck-Matsuda process for the synthesis of the otherwise difficult to access compounds, ß-arylethenesulfonyl fluorides, is described. Ethenesulfonyl fluoride (i.e., vinylsulfonyl fluoride, or ESF) undergoes ß-arylation with stable and readily prepared arenediazonium tetrafluoroborates in the presence of the catalyst palladium(II) acetate to afford the E-isomer sulfonyl analogues of cinnamoyl fluoride in 43-97 % yield. The ß-arylethenesulfonyl fluorides are found to be selectively addressable bis-electrophiles for sulfur(VI) fluoride exchange (SuFEx) click chemistry, in which either the alkenyl moiety or the sulfonyl fluoride group can be the exclusive site of nucleophilic attack under defined conditions, making these rather simple cores attractive for covalent drug discovery.

Synthesis of a single G-quartet platform in water.

For over 50 years the G-quartet has been a defining self-assembled structure in biology and non-covalent synthesis. It is shown here for the first time that the G-quartet is isolatable in water in the absence of stabilizing G-quartet stacking or cations through the construction of a phosphate-linked template-assembled synthetic G-quartet. Synthetic design has facilitated preservation of the guanine base, ribose sugar, and phosphate components with correct linkage chemistry relative to G-quadruplex DNA. Thus, a minimal synthetic model of G-quadruplex DNA, as in that associated with human gene promoter or telomere regions, is represented by this system. An application as a probe for interactions between G-quadruplex DNA and potential anticancer therapeutical binding ligands is demonstrated. Binding constants of 10(5)-10(7) M(-1) magnitude and 1:1 stoichiometries for TMPyP4, piper, and azatrux ligands were determined, whereas perturbations in BSU1051 and BRACO19 ligand signal were not observed. These data suggest a unique test for critical end-stacking interactions at the exclusion of intercalative or looping interactions for G-quadruplex binding ligands.

A thymine tetrad assembly templated from thymidylic acid.

A template tetra-coupled with thymidylic acid through a phosphate linkage was characterized in methanol for emergent properties of nucleobase tetrad formation. Intramolecular hydrogen bonded base pairing in the absence of a cation was indicated for the thymidylic acid species supporting a monomeric template-assembled structure. Thus, an initial report of a stabilized individual thymine tetrad assembly is presented here. Consistent with previous investigations, a deoxyguanylic acid variant templated an analogous methanolic monomeric G-tetrad in comparison to the thymine species.