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Peculiar hydrogen-bonded molecular chains are spontaneously created from the self-assembly on a gold surface of a porphyrin functionalized with four aromatic amine moieties. The molecular chains are formed by a sequence of dyads, where the same molecule behaves alternately as a hydrogen-bond acceptor or donor as a whole at all its four aromatic amino groups. This remarkable bifunctional behavior is due to the conformational flexibility of the functionalizing amino groups that switch from a planar, aniline-like conformation in donors to a pyramidal, amine-like one in acceptors. Furthermore, we show that the acceptor porphyrins can trap gold adatoms underneath their center. Combined scanning tunneling microscopy experiments and density functional theory calculations characterize the structural and electronic modifications suffered by such molecules to establish amino–amino interactions. Notably, scanning tunneling spectroscopy measurements show that the highest occupied molecular orbital–lowest unoccupied molecular orbital gaps of the acceptors and donors are, respectively, larger and smaller with respect to the isolated molecule according to the reduced extent of conjugation occurring in the acceptors. In summary, experimental and theoretical results reveal a remarkable hydrogen-bonded complex where the amino groups act as both hydrogen-bond donors and acceptors and suggest how hydrogen bonding can modify the geometrical and potentially also the electronic structures of highly conjugated molecules.

Resistance to aminoglycoside antibiotics is a serious problem, typically arising from inactivating enzymes, reduced uptake, or increased efflux in the important pathogens for which they are used as treatment. Conjugating aminoglycosides to proline-rich antimicrobial peptides (PrAMPs), which also target ribosomes and have a distinct bacterial uptake mechanism, might mutually benefit their individual activities. To this aim we have developed a strategy for noninvasively modifying tobramycin to link it to a Cys residue and through this covalently link it to a Cys-modified PrAMP by formation of a disulfide bond. Reduction of this bridge in the bacterial cytosol should release the individual antimicrobial moieties. We found that the conjugation of tobramycin to the well-characterized N-terminal PrAMP fragment Bac7(1–35) resulted in a potent antimicrobial capable of inactivating not only tobramycin-resistant bacterial strains but also those less susceptible to the PrAMP. To a certain extent, this activity also extends to the shorter and otherwise poorly active fragment Bac7(1–15). Although the mechanism that allows the conjugate to act when its individual components do not is as yet unclear, results are very promising and suggest this may be a way of resensitizing pathogens that have developed resistance to the antibiotic.

Despite the fact that HIV-Protease is an over 20 years old target, computational approaches to rational design of its inhibitors still have a great potential to stimulate the synthesis of new compounds and the discovery of new, potent derivatives, ever capable to overcome the problem of drug resistance. This review deals with successful examples of inhibitors identified by computational approaches, rather than by knowledge-based design. Such methodologies include the development of energy and scoring functions, docking protocols, statistical models, virtual combinatorial chemistry. Computations addressing drug resistance, and the development of related models as the substrate envelope hypothesis are also reviewed. In some cases, the identified structures required the development of synthetic approaches in order to obtain the desired target molecules; several examples are reported.

Marine toxins appear to be increasing in many areas of the world. An emerging problem in the Mediterranean Sea is represented by palytoxin (PlTX), one of the most potent marine toxins, frequently detected in seafood. Due to the high potential for human toxicity of PlTX, there is a strong and urgent need for sensitive methods toward its detection and quantification. We have developed an ultrasensitive electrochemiluminescence-based sensor for the detection of PlTX, taking advantage of the specificity provided by anti-PlTX antibodies, the good conductive properties of carbon nanotubes, and the excellent sensitivity achieved by a luminescence-based transducer. The sensor was able to produce a concentration-dependent light signal, allowing PlTX quantification in mussels, with a limit of quantification (LOQ = 2.2 μg/kg of mussel meat) more than 2 orders of magnitude more sensitive than that of the commonly used detection techniques, such as LC-MS/MS.

We present a method for designing artificial receptors capable of binding with high affinity to a chosen target organic molecule. The primary sequence of the peptide is optimized to maximize its binding affinity. Our algorithm builds on a combination of molecular dynamics, semiflexible docking, and replica exchange Monte Carlo and performs simultaneous sampling in sequence and conformational spaces carefully selecting the degree of flexibility in the mutated peptides. The approach is used to design a decapeptide able to bind efavirenz. The calculated binding energy of the designed peptide (approximately −12 kcal/mol) was confirmed experimentally by fluorescence measurements. NMR spectroscopy confirmed the interactions between the peptide and the efavirenz molecule predicted by the algorithm.

We have synthesized and evaluated a small set of dual action HIV-Protease inhibitors, consisting of a catalytic site reversible inhibitor conjugated with a dimerization peptidic inhibitor, linked via a suitable selective end-modified poly(ethylene glycol), in an effort to obtain a synergistic effect with improved biological behaviour and more powerful pharmacological features, such as water solubility, cell permeability and bioavailability.

The base-catalyzed hydroazidation of α‘-amino α,β-unsaturated ketones with in situ generated hydrazoic acid was found to proceed with high stereoselectivity in favor of the syn product. The stereoselectivity is controlled by the configuration of the enone and syn/anti ratios up to 7:1 were obtained with secondary and tertiary amines at low temperature. By this route the diamino alcohol core of HIV-PR inhibitors ritonavir and lopinavir was synthesized in 37% yield from phenylalanine.

Amidase antibody 312d6, obtained against the sulfonamide hapten 4 athat mimics the transition state for hydrolysis of a distorted amide, accelerates the hydrolysis of the corresponding amides 1 a–3 aby a factor of 103at pH 8. The mechanisms of both the uncatalyzed and antibody‐catalyzed reactions were studied. Between pH 8 and 12 the uncatalyzed hydrolysis of N‐toluoylindoles 1 aand 3 ashows a simple first‐order dependence on [OH−], while hydrolysis of 3 ais zeroth‐order in [OH−] below pH 8. The pH profile for hydrolysis of the corresponding tryptophan amide 2 ais more complex due to the dissociation of the zwitterion into an anion with pKa9.74; hydrolysis of the zwitterionic and the anionic form of 2 aboth show simple first‐order dependence on [OH−]. Absence of 18O exchange between H218O/18OH−and the substrate, a normal SKIE for both 1 a(kH/kD=1.12) and 3 a(kH/kD=1.24) and the value of the Hammett constant ρfor hydrolysis of p‐substituted amides 3 a–eare consistent with an ester‐like mechanism in which formation of the tetrahedral intermediate is rate‐determining and the amine departs as anion. The 312d6‐catalyzed hydrolysis of 3 awas studied between pH 7.5 and 9, and its independence of pH in this range indicates that water is the reacting nucleophile. Hydrolysis of 3 ais only partially inhibited by the sulfonamide hapten, and this indicates that non‐specific catalysis by the protein accompanies the specific process. Only the nonspecific process is observed in the hydrolysis of amides 3with parasubstituents other than methyl. Binding studies on the corresponding series of p‐substituted sulfonamides 5 a–econfirm the high specificity of antibody 312d6 for p‐methyl substituted substrates.

Amidase antibody 312d6, obtained against the sulfonamide hapten 4 a that mimics the transition state for hydrolysis of a distorted amide, accelerates the hydrolysis of the corresponding amides 1 a–3 a by a factor of 10³ at pH 8. The mechanisms of both the uncatalyzed and antibody-catalyzed reactions were studied. Between pH 8 and 12 the uncatalyzed hydrolysis of N-toluoylindoles 1 a and 3 a shows a simple first-order dependence on [OH⁻], while hydrolysis of 3 a is zeroth-order in [OH⁻] below pH 8. The pH profile for hydrolysis of the corresponding tryptophan amide 2 a is more complex due to the dissociation of the zwitterion into an anion with pKa 9.74; hydrolysis of the zwitterionic and the anionic form of 2 a both show simple first-order dependence on [OH⁻]. Absence of ¹⁸O exchange between H2¹⁸O/¹⁸OH⁻ and the substrate, a normal SKIE for both 1 a (kH/kD=1.12) and 3 a (kH/kD=1.24) and the value of the Hammett constant ρ for hydrolysis of p-substituted amides 3 a–e are consistent with an ester-like mechanism in which formation of the tetrahedral intermediate is rate-determining and the amine departs as anion. The 312d6-catalyzed hydrolysis of 3 a was studied between pH 7.5 and 9, and its independence of pH in this range indicates that water is the reacting nucleophile. Hydrolysis of 3 a is only partially inhibited by the sulfonamide hapten, and this indicates that non-specific catalysis by the protein accompanies the specific process. Only the nonspecific process is observed in the hydrolysis of amides 3 with para substituents other than methyl. Binding studies on the corresponding series of p-substituted sulfonamides 5 a–e confirm the high specificity of antibody 312d6 for p-methyl substituted substrates.

Three diastereoisomeric hydroxyethylene isosters of the Val-Ala dipeptide were synthesized from α,β-unsaturated ketones 1 derived from N-Boc- and N,N-dibenzyl-L-valine. The enones were hydrocyanated with diethylaluminum cyanide to give the corresponding β-cyano ketones with the stereoselectivity depending on the protecting group. N-Boc protected enone 1a gave a 1:1 mixture of anti and syn adducts 4a, 5a while the corresponding N,N-dibenzyl compound 1c gave a 6:1 mixture of anti, syn adducts 4c, 5c. Borohydride reduction of the resulting cyano ketones is also controlled by the protecting group, resulting in opposite stereoselectivities for N-Boc and N,N-dibenzyl compounds. The cyano alcohols thus obtained were converted, in several steps, into two series of enantiomerically pure hydroxyethylene isosters of the Val-Ala dipeptide. In the first series the hydroxy group and the N-terminal of the isoster are internally protected through the formation of an oxazolidine; in the second series the hydroxy group and the C-terminal are protected as lactone. Two oxazolidines (28, 29), corresponding to syn,syn and syn,anti 4-hydroxy-5-amino acid isosters, and three lactones (23−25), corresponding to syn,syn, syn,anti, and anti,anti isosters were obtained by this approach. (© Wiley-VCH Verlag GmbH & Co KGaA, 69451 Weinheim, Germany, 2003)

2,3-Epoxyalcohols react with diethylaluminium azide under mild conditions to give 3-azido-1,2-diols resulting from the regio- and stereoselective attack of the nucleophile at the epoxide C-3. The high regioselectivity (>25:1) observed with both cisand transsubstituted epoxides is not affected by bulky substituents at C-3. The method has been successfully applied also to the synthesis of diaminodiol dipeptide isosteres.

Screening of a large number of clones produced in a fusion is often the bottleneck in the isolation of catalytic antibodies. The usual approach requires two steps: clones are first selected for their high affinity to the antigen, and then the good binders are tested for their catalytic activity. To simplify this selection process, a competitive enzyme-linked immunosorbent assay (ELISA) has been developed that allows direct screening of the antibodies on the basis of their catalytic activity. In this assay, the product of the catalyzed reaction binds to an immobilized anti-product antibody in competition with a peroxidase–product conjugate. The screening assay has been developed for the antibody-catalyzed hydrolysis of esters ofp-aminophenylacetic acid and has been tested on the porcine liver esterase (PLE)-catalyzed hydrolysis of the same substrates. This test allows the detection of product formation at the nanomolar level, while, in a typical assay, the catalytic activity of PLE can be traced down to 200 fmol of enzyme. Under standard conditions for the screening of hybridomas obtained from a fusion, the competitive ELISA allows detection of catalytic species with values ofkcat≥ 5 × 10−7mol l−1s−1andkcat/kuncat≥ 50. While the assay has been designed for the selection of catalytic antibodies, other potential applications of this methodology are in the screening of libraries of engineered and designed enzymes and, in general, in the quantitative measurement of enzyme activity.

Diethylaluminium cyanide is a highly selective reagent for the ring opening of 2,3-epoxyalcohols under mild conditions; the reaction takes place at C-3, with inversion of configuration, to give 1-cyano-2,3-diols.

Multicomponent reactions (MCRs) represent very interesting tools to reach eco-friendly and sustainable transformations in organic chemistry. In particular, the Biginelli reaction furnishes a very easy approach to the synthesis of a library of biological active compounds in an academic course. Here we describe the realization of several experiments involving the synthesis of potential inhibitors of β-secretase by the Biginelli reaction. All of the obtained compounds were tested with a FRET fluorimetric assay. The experiments were proposed to students either at entry level or during advanced laboratory courses of organic and bioorganic chemistry. The learning objectives at the advanced level were to introduce the students to the practice of combinatorial synthesis and to the evaluation of biological activity of combinatorial libraries by enzyme inhibition assays. The meeting of the learning objectives was probed first by analyzing their daily performance in the laboratory and their increasing proactive attitude, and the contents of their final presentations. The resulting marks obtained by the students were compared with the average evaluation of their career. Second, the students were asked to evaluate the course and their own experience, and the outcome of their evaluation was compared with that of the teachers.

An unprecedented combination of high chemo- and stereoselectivity in the NaBH₄ reduction of 1∶1 complexes between albumin and aromatic 1,3-diketones results in the formation of anti 1,3-diols with de up to 96%.

Esterase antibody 522c2, the first example of a catalytic antibody specifically programmed to control the reactivity of functional groups on the side chain of tyrosine, accelerates the hydrolysis of benzoate esters of l-tyrosine and tyrosine-containing dipeptides by a factor of 10⁴ and is moderately active against other benzoate esters.

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ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.