Abstract:Chloramphenicol (CAP) is a widely used broad-spectrum antibiotic. As the precursor of CAP, chloramphenicol bases are stereochemically pure agents and could be used as resolution agents, chiral catalysts and so on. This review summarizes these applications and discusses the structural modifications of chloramphenicol bases.
“…The position of the CAM scaffold, through which the PA is linked, is of paramount importance; connection of PA to the 3-position of the 2-aminopropane-1,3-diol moiety of CAM, instead of the dichloroacetyl tail, leads to a strong reduction of potency as well as to an enhancement of the k off value (compare compounds 2 and 7 ). This is in agreement with previous studies indicating that the conformation and integrity of the 2-aminopropane-1,3-diol portion of CAM are both essential for the activity of the drug (22,45). The design of compound 7 was based on X-ray crystallographic observations in Deinococcus radiodurans 50S ribosomal subunit complexed with CAM (46), according to which the primary hydroxyl group of CAM interacts with the O 4 of U2506 ( E. coli numbering is used throughout the text), through a Mg 2+ ion that coordinates both groups.…”
Section: Discussionsupporting
confidence: 93%
“…For this reason, CAM has been modified using a variety of synthetic approaches to acquire an optimized pharmaceutically profile (4,21,22). This fact motivated us to design and synthesize a series of PA–CAM conjugates.…”
Chloramphenicol (CAM) is a broad-spectrum antibiotic, limited to occasional only use in developed countries because of its potential toxicity. To explore the influence of polyamines on the uptake and activity of CAM into cells, a series of polyamine–CAM conjugates were synthesized. Both polyamine architecture and the position of CAM-scaffold substitution were crucial in augmenting the antibacterial and anticancer potency of the synthesized conjugates. Compounds 4 and 5, prepared by replacement of dichloro-acetyl group of CAM with succinic acid attached to N4 and N1 positions of N8,N8-dibenzylspermidine, respectively, exhibited higher activity than CAM in inhibiting the puromycin reaction in a bacterial cell-free system. Kinetic and footprinting analysis revealed that whereas the CAM-scaffold preserved its role in competing with the binding of aminoacyl-tRNA 3′-terminus to ribosomal A-site, the polyamine-tail could interfere with the rotatory motion of aminoacyl-tRNA 3′-terminus toward the P-site. Compared to CAM, compounds 4 and 5 exhibited comparable or improved antibacterial activity, particularly against CAM-resistant strains. Compound 4 also possessed enhanced toxicity against human cancer cells, and lower toxicity against healthy human cells. Thus, the designed conjugates proved to be suitable tools in investigating the ribosomal catalytic center plasticity and some of them exhibited greater efficacy than CAM itself.
“…The position of the CAM scaffold, through which the PA is linked, is of paramount importance; connection of PA to the 3-position of the 2-aminopropane-1,3-diol moiety of CAM, instead of the dichloroacetyl tail, leads to a strong reduction of potency as well as to an enhancement of the k off value (compare compounds 2 and 7 ). This is in agreement with previous studies indicating that the conformation and integrity of the 2-aminopropane-1,3-diol portion of CAM are both essential for the activity of the drug (22,45). The design of compound 7 was based on X-ray crystallographic observations in Deinococcus radiodurans 50S ribosomal subunit complexed with CAM (46), according to which the primary hydroxyl group of CAM interacts with the O 4 of U2506 ( E. coli numbering is used throughout the text), through a Mg 2+ ion that coordinates both groups.…”
Section: Discussionsupporting
confidence: 93%
“…For this reason, CAM has been modified using a variety of synthetic approaches to acquire an optimized pharmaceutically profile (4,21,22). This fact motivated us to design and synthesize a series of PA–CAM conjugates.…”
Chloramphenicol (CAM) is a broad-spectrum antibiotic, limited to occasional only use in developed countries because of its potential toxicity. To explore the influence of polyamines on the uptake and activity of CAM into cells, a series of polyamine–CAM conjugates were synthesized. Both polyamine architecture and the position of CAM-scaffold substitution were crucial in augmenting the antibacterial and anticancer potency of the synthesized conjugates. Compounds 4 and 5, prepared by replacement of dichloro-acetyl group of CAM with succinic acid attached to N4 and N1 positions of N8,N8-dibenzylspermidine, respectively, exhibited higher activity than CAM in inhibiting the puromycin reaction in a bacterial cell-free system. Kinetic and footprinting analysis revealed that whereas the CAM-scaffold preserved its role in competing with the binding of aminoacyl-tRNA 3′-terminus to ribosomal A-site, the polyamine-tail could interfere with the rotatory motion of aminoacyl-tRNA 3′-terminus toward the P-site. Compared to CAM, compounds 4 and 5 exhibited comparable or improved antibacterial activity, particularly against CAM-resistant strains. Compound 4 also possessed enhanced toxicity against human cancer cells, and lower toxicity against healthy human cells. Thus, the designed conjugates proved to be suitable tools in investigating the ribosomal catalytic center plasticity and some of them exhibited greater efficacy than CAM itself.
“…Autophagy occurs at a basal level in every cell as housekeeping and plays key roles in cell development, immunity, tissue remodeling, and orientation with the surrounding environment. In addition, in the tumor microenvironment, autophagy is also activated in response to multiple metabolic stressors (Figure 2 a), such as oxygen/nutrient deprivation, and degradation of the extracellular matrix (ECM) [ 19 , 20 ]. Figure 2 Paradoxical roles of autophagy induced by the tumor microenvironment during different stages of tumor development.…”
Development of a tumor is a very complex process, and invasion and metastasis of malignant tumors are hallmarks and are difficult problems to overcome. The tumor microenvironment plays an important role in controlling tumor fate and autophagy induced by the tumor microenvironment is attracting more and more attention. Autophagy can be induced by several stressors in the tumor microenvironment and autophagy modifies the tumor microenvironment, too. Autophagy has dual roles in tumor growth. In this review, we discussed the interaction between autophagy and the tumor microenvironment and the paradoxical roles of autophagy on tumor growth at different stages of tumor development.
“…Indeed, during the last two decades, many reports have disclosed the wide applications of chiral ANP in both academia and industry, including the use of ANP as a resolution agent, a chiral catalyst and a building block and in new drug discovery . In this Minireview, we will highlight our contributions in designing ANP‐derived chiral catalysts over the past decades and our application to the asymmetric synthesis of pharmaceutical drugs in the context of major discoveries reported by other groups.…”
This Minireview focuses on the synthetic application of a chloramphenicol base (ANP)‐derived catalyst. In the illustrated examples, ANP derivatives have proven to be readily available and highly versatile catalysts in a wide range of asymmetric transformations, showing high proficiency as both chiral ligands (amino alcohol, Schiff base and oxazoline‐containing ligand) and organocatalyst (hydrogen bonding‐based bifunctional catalyst and phase transfer catalyst).
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