Abstract
Over the last years, we have been focused on chloramphenicol conjugates that combine in their structure chloramphenicol base with natural polyamines, spermine, spermidine and putrescine, and their modifications. Conjugate 3, with spermidine (SPD) as a natural polyamine linked to chloramphenicol base, showed the best antibacterial and anticancer properties. Using 3 as a prototype, we here explored the influence of the antibacterial and anticancer activity of additional benzyl groups on N1 amino moiety together with modifications of the alkyl length of the aminobutyl fragment of SPD. Our data demonstrate that the novel modifications did not further improve the antibacterial activity of the prototype. However, one of the novel conjugates (4) showed anticancer activity without affecting bacterial growth, thus emerging as a promising anticancer agent, with no adverse effects on bacterial microflora when taken orally.
Highlights
Chloramphenicol (CAM) is an effective antibiotic with bacteriostatic action against Gram-positive and Gram-negative bacteria and was the first broad-spectrum antibiotic to be used clinically
We have recently reported the synthesis of a series of conjugates (PA–CAM conjugates) of the naturally occurring PAs—PUT, SPD and SPM, with CAM—which showed comparable binding affinities to CAM for the 70S E. coli ribosome [10]
Taking conjugate 3 as a prototype, we present the synthesis and the evaluation of the antimicrobial and antitumor activity of new conjugates, which were designed in such a way to allow conclusions regarding the effect of (a) introducing additional benzyl moieties on the N1 of the SPD
Summary
Chloramphenicol (CAM) is an effective antibiotic with bacteriostatic action against Gram-positive and Gram-negative bacteria and was the first broad-spectrum antibiotic to be used clinically. The undesired toxicity resulting from CAM administration restricts its clinical use. Case reports indicate that CAM is responsible for hematological disorders such as bone marrow depression and aplastic anemia. While the first is a rare complication, the second is more frequent and was ascribed as a mitochondrial protein synthesis disorder [1,2,3,4]. CAM remains one of the best-studied protein synthesis inhibitors, and efforts towards its derivatization have continued in order to provide a new generation of compounds with better antibacterial activity and minimal side effects [5]. Numerous functional and structural studies have concluded that CAM binds to the large ribosomal subunit occupying the A-site of the peptidyltransferase center (PTC) [6,7,8]. Its binding allows the delivery and initial binding of the A-site aminoacyl-tRNA but prevents its full accommodation at Antibiotics 2019, 8, 9; doi:10.3390/antibiotics8010009 www.mdpi.com/journal/antibiotics
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