760981-83-7Relevant academic research and scientific papers
Ribosome-Templated Azide-Alkyne Cycloadditions: Synthesis of Potent Macrolide Antibiotics by in Situ Click Chemistry
Glassford, Ian,Teijaro, Christiana N.,Daher, Samer S.,Weil, Amy,Small, Meagan C.,Redhu, Shiv K.,Colussi, Dennis J.,Jacobson, Marlene A.,Childers, Wayne E.,Buttaro, Bettina,Nicholson, Allen W.,MacKerell, Alexander D.,Cooperman, Barry S.,Andrade, Rodrigo B.
, p. 3136 - 3144 (2016)
Over half of all antibiotics target the bacterial ribosome-nature's complex, 2.5 MDa nanomachine responsible for decoding mRNA and synthesizing proteins. Macrolide antibiotics, exemplified by erythromycin, bind the 50S subunit with nM affinity and inhibit protein synthesis by blocking the passage of nascent oligopeptides. Solithromycin (1), a third-generation semisynthetic macrolide discovered by combinatorial copper-catalyzed click chemistry, was synthesized in situ by incubating either E. coli 70S ribosomes or 50S subunits with macrolide-functionalized azide 2 and 3-ethynylaniline (3) precursors. The ribosome-templated in situ click method was expanded from a binary reaction (i.e., one azide and one alkyne) to a six-component reaction (i.e., azide 2 and five alkynes) and ultimately to a 16-component reaction (i.e., azide 2 and 15 alkynes). The extent of triazole formation correlated with ribosome affinity for the anti (1,4)-regioisomers as revealed by measured Kd values. Computational analysis using the site-identification by ligand competitive saturation (SILCS) approach indicated that the relative affinity of the ligands was associated with the alteration of macrolactone+desosamine-ribosome interactions caused by the different alkynes. Protein synthesis inhibition experiments confirmed the mechanism of action. Evaluation of the minimal inhibitory concentrations (MIC) quantified the potency of the in situ click products and demonstrated the efficacy of this method in the triaging and prioritization of potent antibiotics that target the bacterial ribosome. Cell viability assays in human fibroblasts confirmed 2 and four analogues with therapeutic indices for bactericidal activity over in vitro mammalian cytotoxicity as essentially identical to solithromycin (1).
Ribosome-Templated Azide-Alkyne Cycloadditions Using Resistant Bacteria as Reaction Vessels: In Cellulo Click Chemistry
Jin, Xiao,Daher, Samer S.,Lee, Miseon,Buttaro, Bettina,Andrade, Rodrigo B.
, p. 907 - 911 (2018)
In situ click chemistry has been a powerful method for fragment-based drug design since its discovery in 2002. Recently, we demonstrated that the bacterial ribosome can template the azide-alkyne cycloaddition reaction to expedite the discovery of novel antibiotics. We now report this process can be performed in an antibiotic-resistant bacterial cell. The corresponding triazole products formed in cellulo are potent antibiotics that inhibit bacterial growth; moreover, the potency of each cycloadduct can be visualized using the traditional MIC assay in a 96-well plate format. We characterized the in cellulo clicked products by independent chemical synthesis and LC-MS analysis, which showed that mass count percent increase was directly proportional to 1/MIC. In other words, potent compounds detected by MIC were formed in greater amounts. Control experiments unambiguously showed the ribosome was responsible for templating triazole formation. Significantly, our method (1) obviates the need to isolate bacterial ribosomes; (2) could be applied to different bacterial strains, which broadens the scope and facilitates the discovery of narrow-spectrum antibiotics; and (3) does not require the knowledge of mode-of-action and thus could uncover novel antibiotic targets. We believe this method could be expanded and implemented as a novel approach for antibiotic drug discovery.
Synthesis, Biological Evaluation, and Computational Analysis of Biaryl Side-Chain Analogs of Solithromycin
Daher, Samer S.,Lee, Miseon,Jin, Xiao,Teijaro, Christiana N.,Wheeler, Steven E.,Jacobson, Marlene A.,Buttaro, Bettina,Andrade, Rodrigo B.
supporting information, p. 3368 - 3373 (2021/09/06)
There is an urgent need for new antibiotics to mitigate the existential threat posed by antibiotic resistance. Within the ketolide class, solithromycin has emerged as one of the most promising candidates for further development. Crystallographic studies of bacterial ribosomes and ribosomal subunits complexed with solithromycin have shed light on the nature of molecular interactions (π-stacking and H-bonding) between from the biaryl side-chain of the drug and key residues in the 50S ribosomal subunit. We have designed and synthesized a library of solithromycin analogs to study their structure-activity relationships (SAR) in tandem with new computational studies. The biological activity of each analog was evaluated in terms of ribosomal affinity (Kd determined by fluorescence polarization), as well as minimum inhibitory concentration assays (MICs). Density functional theory (DFT) studies of a simple binding site model identify key H-bonding interactions that modulate the potency of solithromycin analogs.
A preparation of a macrocyclic lactone method
-
, (2017/12/28)
The invention relates to a new preparation method of macrolides, belonging to the field of medicinal chemistry. The invention further relates to a preparation method of Solithromycin. The new preparation method comprises the following step of carrying out 7-th position saccharide ring removal, hydroxyl oxidation and reductive amination with a side chain to obtain an important intermediate (5) having a formula shown in the specification. The preparation method of Solithromycin, disclosed by the invention, has the advantages of few side reactions, operation simpleness and convenience, high yield and high suitability for industrial production. The structure of the intermediate (5) is as shown in the specification.
A NOVEL SYNTHETIC PATHWAY TOWARDS SOLITHROMYCIN AND PURIFICATION THEREOF
-
Page/Page column 25, (2017/08/01)
The present invention relates to an efficient route of synthesis of solithromycin and to a method of its purification which obviates the necessity of chromatographic purifications and improves the quality of the product by efficiently removing impurities.
Method for preparing Solithromycin compound
-
, (2017/08/28)
The invention provides a method for preparing a macrolide antibiotic, namely Solithromycin. The method includes the steps of fluorination, side chain condensation, deprotection and the like or includes the steps of side chain condensation, fluorination, deprotection and the like. Time when triazole side chains large in polarity are introduced is late, the defect that purification is not easy is avoided, and cost of Solithromycin is also reduced.
A platform for the discovery of new macrolide antibiotics
Seiple, Ian B.,Zhang, Ziyang,Jakubec, Pavol,Langlois-Mercier, Audrey,Wright, Peter M.,Hog, Daniel T.,Yabu, Kazuo,Allu, Senkara Rao,Fukuzaki, Takehiro,Carlsen, Peter N.,Kitamura, Yoshiaki,Zhou, Xiang,Condakes, Matthew L.,Szczypiński, Filip T.,Green, William D.,Myers, Andrew G.
, p. 338 - 345 (2016/06/06)
The chemical modification of structurally complex fermentation products, a process known as semisynthesis, has been an important tool in the discovery and manufacture of antibiotics for the treatment of various infectious diseases. However, many of the therapeutics obtained in this way are no longer effective, because bacterial resistance to these compounds has developed. Here we present a practical, fully synthetic route to macrolide antibiotics by the convergent assembly of simple chemical building blocks, enabling the synthesis of diverse structures not accessible by traditional semisynthetic approaches. More than 300 new macrolide antibiotic candidates, as well as the clinical candidate solithromycin, have been synthesized using our convergent approach. Evaluation of these compounds against a panel of pathogenic bacteria revealed that the majority of these structures had antibiotic activity, some efficacious against strains resistant to macrolides in current use. The chemistry we describe here provides a platform for the discovery of new macrolide antibiotics and may also serve as the basis for their manufacture.
Method for preparing solithromycin
-
, (2016/10/07)
The invention discloses a novel method for preparing solithromycin. Compared with the conventional solithromycin preparation process, a designed synthesis process adopted by the novel method has the advantages that the occurrences of side reactions are effectively reduced, the dangerous and toxic operating steps are avoided, and the reaction conversion rate is improved, so that the production cost is reduced, and the novel method is suitable for industrialized production.
14-MEMBERED KETOLIDES AND METHODS OF THEIR PREPARATION AND USE
-
, (2016/05/02)
Provided herein are methods of preparing new 14-membered ketolides via coupling of an eastern and western half moiety, followed by macrocyclization, and optional functionalization. Intermediates in the synthesis of these ketolides including the eastern and western halves are also provided. Pharmaceutical compositions and methods of treating infectious diseases and inflammatory conditions using these ketolides are also provided.
Antibacterial agents
-
Page/Page column 49, (2015/12/18)
Described herein are novel macrolides, the preparation of novel macrolides, the use of novel macrolides for preventing, treating, or ameliorating various conditions, and the use of novel macrolides as antibacterial agents.
