Category: Chemistry

Novel 3-phenylcoumarin-lipoic acid conjugates as multi-functional agents for potential treatment of Alzheimer’s disease

New series of triazole-containing 3-phenylcoumarin-lipoic acid conjugates were designed as multi-functional agents for treatment of Alzheimer’s disease. The target compounds 4a-o were synthesized via the azide-alkyne cycloaddition reaction and their biological activities were primarily evaluated in terms of neuroprotection against H2O2-induced cell death in PC12 cells and AChE/BuChE inhibition. The promising compounds 4j and 4i containing four carbons spacer were selected for further biological evaluations. Based on the obtained results, the benzocoumarin derivative 4j with IC50 value of 7.3 µM was the most potent AChE inhibitor and displayed good inhibition toward intracellular reactive oxygen species (ROS). This compound with antioxidant and metal chelating ability showed also protective effect on cell injury induced by Aβ1-42 in SH-SY5Y cells. Although the 8-methoxycoumarin analog 4i was slightly less active than 4j against AChE, but displayed higher protection ability against H2O2-induced cell death in PC12 and could significantly block Aβ-aggregation. The results suggested that the prototype compounds 4i and 4j might be promising multi-functional agents for the further development of the disease-modifying treatments of Alzheimer’s disease. ( 2018 Sep;79:223-234.)

Synthesis of peptide-protein conjugates using N-succinimidyl carbamate chemistry

Peptide-protein conjugates are useful tools in different fields of research as, for instance, the development of vaccines and drugs or for studying biological mechanisms, to cite only few applications. N-Succinimidyl carbamate (NSC) chemistry has been scarcely used in this area. We show that unprotected peptides, featuring one lysine residue within their sequences, can be converted in good yield into NSC derivatives by reaction with disuccinimidylcarbonate (DSC). No hydrolysis of the NSC group was observed during RP-HPLC purification, lyophilization, or storage. NSC peptides reacted efficiently within minutes with lysozyme used as model protein. To illustrate usefulness of the method consisting of the synthesis of a peptide-protein conjugate of biological interest, a NSC peptide derived from a peptide substrate for tyrosylprotein sulfotransferase (TS) was synthesized and ligated to receptor-binding nontoxic B-subunit of Shiga toxin (STxB). Immunofluorescence studies showed the intracellular delivery of the TS-STxB conjugate and its ability to circulate to the Golgi as the native STxB protein. Moreover, we demonstrate that the TS label could be sulfated by tyrosylprotein sulfotransferases present in the Golgi. Thus, NSC chemistry permitted rapid synthesis of a peptide-protein conjugate worthwhile for studying the transport of proteins from the plasma membrane to the Golgi. The second part of this article describes a more general method for synthesizing peptide-protein conjugates without any limitation of the peptide sequence. The conjugates were assembled by combining NSC chemistry and alpha-oxo semicarbazone ligation. To this end, a glyoxylyl NSC peptide was synthesized and reacted with lysozyme. The glyoxylyl groups on the protein were then reacted with a semicarbazide peptide to produce the target peptide-protein conjugate. Both reactions, namely, urea bond formation and alpha-oxo semicarbazone ligation, were carried at pH 8.0 using a one-pot procedure.(Bioconjug Chem. 2010 Feb 17;21(2):219-28. )

Amino alcohol fused Spirochromone conjugates

A series of 21 new amino alcohol fused Spirochromone conjugates have been synthesized, characterized with analytical data and evaluated their antimycobacterial activity against Mycobacterium tuberculosis (virulent strain H37Rv) in vitro. Some of the compounds exerted significant inhibition, in particular, compound 4f found to be the most potent derivative exhibiting MIC = 3.13 μg/mL.

Click Chemistry and Radiochemistry!

The advent of click chemistry has had a profound influence on almost all branches of chemical science. This is particularly true of radiochemistry and the synthesis of agents for positron emission tomography (PET), single photon emission computed tomography (SPECT), and targeted radiotherapy. The selectivity, ease, rapidity, and modularity of click ligations make them nearly ideally suited for the construction of radiotracers, a process that often involves working with biomolecules in aqueous conditions with inexorably decaying radioisotopes. In the following pages, our goal is to provide a broad overview of the first 10 years of research at the intersection of click chemistry and radiochemistry. The discussion will focus on four areas that we believe underscore the critical advantages provided by click chemistry: (i) the use of prosthetic groups for radiolabeling reactions, (ii) the creation of coordination scaffolds for radiometals, (iii) the site-specific radiolabeling of proteins and peptides, and (iv) the development of strategies for in vivo pretargeting. Particular emphasis will be placed on the four most prevalent click reactions—the Cu-catalyzed azide-alkyne cycloaddition (CuAAC), the strain-promoted azide-alkyne cycloaddition (SPAAC), the inverse electron demand Diels-Alder reaction (IEDDA), and the Staudinger ligation—although less well-known click ligations will be discussed as well. Ultimately, it is our hope that this review will not only serve to educate readers but will also act as a springboard, inspiring synthetic chemists and radiochemists alike to harness click chemistry in even more innovative and ambitious ways as we embark upon the second decade of this fruitful collaboration.

Bioorthogonal click ligations satisfy all of the requirements of standard click reactions but are also inert within biological systems. Not surprisingly, these reactions are hard to come by, yet a handful (most notably the Staudinger ligation, the strain-promoted azide–alkyne cycloaddition reaction, and the inverse electron demand Diels–Alder cycloaddition) have been developed and proven powerful in the hands of chemical biologists, biochemists, and biomedical scientists (Bioconjug Chem. 2016 Dec 21;27(12):2791-2807.)

Organic Carbamates in Drug Design!

Carbamate-bearing molecules play an important role in modern drug discovery and medicinal chemistry. Organic carbamates (or urethanes) are structural elements of many approved therapeutic agents. Structurally, the carbamate functionality is related to amide-ester hybrid features and, in general, displays very good chemical and proteolytic stabilities. Carbamates are widely utilized as a peptide bond surrogate in medicinal chemistry. This is mainly due to their chemical stability and capability to permeate cell membranes. Another unique feature of carbamates is their ability to modulate inter- and intramolecular interactions with the target enzymes or receptors. The carbamate functionality imposes a degree of conformational restriction due to the delocalization of nonbonded electrons on nitrogen into the carboxyl moiety. In addition, the carbamate functionality participates in hydrogen bonding through the carboxyl group and the backbone NH. Therefore, substitution on the O- and N-termini of a carbamate offers opportunities for modulation of biological properties and improvement in stability and pharmacokinetic properties. Carbamates have been manipulated for use in the design of prodrugs as a means of achieving first-pass and systemic hydrolytic stability. Carbamate derivatives are widely represented in agricultural chemicals, such as pesticides, fungicides, and herbicides. They play a major role in the chemical and paint industry as starting materials, intermediates, and solvents. Furthermore, organic carbamates serve a very important role as optimum protecting groups for amines and amino acids in organic synthesis and peptide chemistry.

Peptide-based molecules are an important starting point for drug discovery, especially in the design of enzyme inhibitors. Because of their high affinity and specificity toward biological functions, peptide-based molecules also serve as valuable research tools. However, the poor in vivo stability, inadequate pharmacokinetic properties, and low bioavailability have generally limited their broader utility. Hence, a variety of peptide mimics are being developed to improve drug-like character along with increased potency, target specificity, and longer duration of action. To this end, several classes of peptidomimetics are tailored by replacing the native amide bond with unnatural linkages such as retro-amide, urea, carbamate, and heterocycles as peptide bond surrogates. These functionalities confer metabolic stability toward aminopeptidases, the enzymes involved in the metabolism of peptide-like drugs. The carbamate’s emerging role in medicinal chemistry is also due to its chemical stability and to its capability to increase permeability across cellular membranes. These attributes of organic carbamates have been exploited in drug design. As a result, the carbamate motif is becoming the choice for peptide bond surrogates.

Over the years, a variety of carabamates have been prepared by utilizing the Hofmann rearrangement of amides, the Curtius rearrangement of acyl azides,the reductive carbonylation of nitroaromatics, the carbonylation of amines, the reaction of alcohols with isocyanates, and carbon dioxide alkylation.The Hofmann rearrangement is well-recognized as a useful method to convert primary carboxamides to amines or carbamates, characterized by the reduction of one carbon in the structure.Much effort has been devoted to the development of modified reagents to optimize the Hofmann rearrangement since the classical method for this transformation, involving the use of an alkaline solution of bromine, is unsatisfactory and unreliable. A variety of oxidants and bases have been proposed as modified agents, e.g., iodine(III) reagents such as PhI(OAc)2, MeOBr, NBS-CH3ONa, NBS-KOH, lead tetraacetate, and benzyltrimethylammonium tribromide. These modified methods, however, require more than 1 equiv or an excess amount of the oxidizing reagent, which is not very convenient.The Curtius rearrangement is the thermal decomposition of acyl azides into the isocyanate intermediate. This method is widely employed in the transformation of carboxylic acids into carbamates and ureas. Acyl azides are usually prepared from carboxylic acid derivatives such as acyl chlorides, mixed anhydrides, and hydrazides. Subsequent isocyanate intermediates can be trapped by a variety of nucleophiles to provide the carbamate derivatives. The acid chloride method is not suitable for acid-sensitive functionalities. One-pot transformations of carboxylic acids into carbamates avoids the isolation of unstable acyl azides. However, protocols involving the use of diphenylphosphoryl azide (DPPA) for the one-pot Curtius reaction are also characterized by issues related to toxicity and the high boiling point of DPPA, which creates difficulties during workup and purification. Other general methods for carbamate preparation involve the use of the highly toxic phosgene,61 phosgene derivatives, or isocyanates. (J Med Chem. 2015 Apr 9; 58(7): 2895–2940.)