Enhancing Hoogsteen interactions: a pyrrole-containing purine nucleoside that competes with guanosine self-assembly

A pyrrole-appended purine nucleoside 1 is described that can form an "extended" three-point Hoogsteen-type interaction due to the stabilization of the donor-acceptor-acceptor (DAA) motif. Nucleoside 1 is shown to bind guanosine 10 (a classic ADD motif) to form ensemble I. This interaction competes effectively with guanosine self-assembly and, as such, is capable of disrupting guanosine quadruplex formation.     

Copper-Catalyzed Cross-Coupling Reactions of Methyl 13-Iodo-O-methylpodocarpate and Alcohols

Copper iodide was utilized as a relatively inexpensive catalyst for the synthesis of podocarpic acid ether derivatives in excellent yields through the one-step cross-coupling reaction of methyl 13-iodo-O-methylpodocarpate with alcohols.     

Mechanism-based inactivation by aromatization of the transaminase BioA involved in biotin biosynthesis in Mycobaterium tuberculosis

BioA catalyzes the second step of biotin biosynthesis, and this enzyme represents a potential target to develop new antitubercular agents. Herein we report the design, synthesis, and biochemical characterization of a mechanism-based inhibitor (1) featuring a 3,6-dihydropyrid-2-one heterocycle that covalently modifies the pyridoxal 5'-phosphate (PLP) cofactor of BioA through aromatization. The structure of the PLP adduct was confirmed by MS/MS and X-ray crystallography at 1.94 ? resolution. Inactivation of BioA by 1 was time- and concentration-dependent and protected by substrate. We used a conditional knock-down mutant of M. tuberculosis to demonstrate the antitubercular activity of 1 correlated with BioA expression, and these results provide support for the designed mechanism of action.     

Parameterization and Application of the General Amber Force Field to Model Fluoro Substituted Furanose Moieties and Nucleosides

Molecular mechanics force field calculations have historically shown significant limitations in modeling the energetic and conformational interconversions of highly substituted furanose rings. This is primarily due to the gauche effect that is not easily captured using pairwise energy potentials. In this study, we present a refinement to the set of torsional parameters in the General Amber Force Field (gaff) used to calculate the potential energy of mono, di-, and gem-fluorinated nucleosides. The parameters were optimized to reproduce the pseudorotation phase angle and relative energies of a diverse set of mono- and difluoro substituted furanose ring systems using quantum mechanics umbrella sampling techniques available in the IpolQ engine in the Amber suite of programs. The parameters were developed to be internally consistent with the gaff force field and the TIP3P water model. The new set of angle and dihedral parameters and partial charges were validated by comparing the calculated phase angle probability to those obtained from experimental nuclear magnetic resonance experiments.     

Simultaneously bound guests and chiral recognition: a chiral self-assembled supramolecular host encapsulates hydrophobic guests

Driven by the hydrophobic effect, a water-soluble, chiral, self-assembled supramolecular host is able to encapsulate hydrophobic organic guests in aqueous solution. Small aromatics can be encapsulated in the supramolecular assembly, and the simultaneous encapsulation of multiple species is observed in many cases. The molecular host assembly is able to recognize different substitutional isomers of disubstituted benzenes with ortho substitution leading to the encapsulation of two guests, but meta or para substitution leading to the encapsulation of only one guest. The scope of hydrophobic guest encapsulation is further explored with chiral natural products. Upon encapsulation of chiral molecules into the racemic host, diastereomeric host-guest complexes are formed with observed diastereoselectivities of up to 78:22 in the case of fenchone.     

Rational tuning of the thiolate donor in model complexes of superoxide reductase: direct evidence for a trans influence in Fe(III)-OOR complexes

Iron peroxide species have been identified as important intermediates in a number of nonheme iron as well as heme-containing enzymes, yet there are only a few examples of such species either synthetic or biological that have been well characterized. We describe the synthesis and structural characterization of a new series of five-coordinate (N4S(thiolate))Fe(II) complexes that react with tert-butyl hydroperoxide ((t)BuOOH) or cumenyl hydroperoxide (CmOOH) to give metastable alkylperoxo-iron(III) species (N4S(thiolate)Fe(III)-OOR) at low temperature. These complexes were designed specifically to mimic the nonheme iron active site of superoxide reductase, which contains a five-coordinate iron(II) center bound by one Cys and four His residues in the active form of the protein. The structures of the Fe(II) complexes are analyzed by X-ray crystallography, and their electrochemical properties are assessed by cyclic voltammetry. For the Fe(III)-OOR species, low-temperature UV-vis spectra reveal intense peaks between 500-550 nm that are typical of peroxide to iron(III) ligand-to-metal charge-transfer (LMCT) transitions, and EPR spectroscopy shows that these alkylperoxo species are all low-spin iron(III) complexes. Identification of the vibrational modes of the Fe(III)-OOR unit comes from resonance Raman (RR) spectroscopy, which shows nu(Fe-O) modes between 600-635 cm(-1) and nu(O-O) bands near 800 cm(-1). These Fe-O stretching frequencies are significantly lower than those found in other low-spin Fe(III)-OOR complexes. Trends in the data conclusively show that this weakening of the Fe-O bond arises from a trans influence of the thiolate donor, and density functional theory (DFT) calculations support these findings. These results suggest a role for the cysteine ligand in SOR, and are discussed in light of the recent assessments of the function of the cysteine ligand in this enzyme.     

Synthesis and crystal structures of magnesium complexes with NNO Schiff base ligands bearing quinolyl pendant donors

A series of ketoimines bearing quinolyl pendants was prepared through Schiff base condensation of 1,3-diketones (2,4-pentanedione, benzoylmethane, and 1-benzoylacetone) and 8-aminoquinoline or 8-amino-2-methylquinoline. The ketoimines were isolated in 46–90% yield and characterized spectroscopically and crystallographically. Reaction of the ketoimines with magnesium 4-methylbenzylalkoxide yielded octahedral magnesium complexes in 67–90% yield. The spectroscopic and crystallographic properties of the magnesium complexes were explored. Structures of 1, 4, 8, 10, and 11 are reported.     

Cephem-Pyrazinoic Acid Conjugates: Circumventing Resistance in Mycobacterium tuberculosis

Tuberculosis (TB) is a leading source of infectious disease mortality globally. Antibiotic-resistant strains comprise an estimated 10 % of new TB cases and present an urgent need for novel therapeutics. β-lactam antibiotics have traditionally been ineffective against M. tuberculosis (Mtb), the causative agent of TB, due to the organism's inherent expression of β-lactamases that destroy the electrophilic β-lactam warhead. We have developed novel β-lactam conjugates, which exploit this inherent β-lactamase activity to achieve selective release of pyrazinoic acid (POA), the active form of a first-line TB drug. These conjugates are selectively active against M. tuberculosis and related mycobacteria, and activity is retained or even potentiated in multiple resistant strains and models. Preliminary mechanistic investigations suggest that both the POA “warhead” as well as the β-lactam “promoiety” contribute to the observed activity, demonstrating a codrug strategy with important implications for future TB therapy.