New Chloramphenicol Derivatives from the Viewpoint of Anticancer and Antimicrobial Activity

Giannopoulou, Panagiota; Missiri, Dionissia A.; Kournoutou, Georgia G.; Sazakli, Eleni; Παπαδόπουλος, Γεώργιος; Papaioannou, Dionissios; Dinos, George P.; Athanassopoulos, Constantinos M.; Kalpaxis, Dimitrios L.

doi:10.3390/antibiotics8010009

Cited by 11 publications

(9 citation statements)

References 52 publications

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“…If we compare the TPP analogs of CHL with the nearest structural analogs exhibiting antimicrobial activity, in which two pharmacophores are conjugated through the alkyl linker, we can note that the antibacterial effect of these compounds is due to the fact that they either bind to bacterial ribosomes or inhibit translation in bacteria, like polyamide analogs of CHL [ 49 , 50 ], or disrupt the membrane potential of bacteria, since the alkyl TPP conjugates with fluorescein [ 22 , 23 ] or coumarin [ 20 , 21 ], while CAM-Cn-TPPs can exhibit both these effects.…”

Section: Resultsmentioning

confidence: 99%

“…CHL has been frequently used as a platform to obtain derivatives with an increased potency [ 46 ]. This drug is especially amenable to chemical derivatization, because its dichloroacetyl moiety can be easily replaced with a variety of other chemical scaffolds, such as amino acids [ 47 ], peptides [ 48 ], and an acyl group carrying the polyamine extension [ 49 , 50 ], endowing it with new properties. Thus, the synthesis of novel CHL analogs containing a TPP cation in their structure represents a promising challenge in terms of creating new potential dual-acting antibiotics and antiproliferative agents.…”

Section: Introductionmentioning

confidence: 99%

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Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents

et al. 2021

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In the current work, in continuation of our recent research, we synthesized and studied new chimeric compounds, including the ribosome-targeting antibiotic chloramphenicol (CHL) and the membrane-penetrating cation triphenylphosphonium (TPP), which are linked by alkyl groups of different lengths. Using various biochemical assays, we showed that these CAM-Cn-TPP compounds bind to the bacterial ribosome, inhibit protein synthesis in vitro and in vivo in a way similar to that of the parent CHL, and significantly reduce membrane potential. Similar to CAM-C4-TPP, the mode of action of CAM-C10-TPP and CAM-C14-TPP in bacterial ribosomes differs from that of CHL. By simulating the dynamics of CAM-Cn-TPP complexes with bacterial ribosomes, we proposed a possible explanation for the specificity of the action of these analogs in the translation process. CAM-C10-TPP and CAM-C14-TPP more strongly inhibit the growth of the Gram-positive bacteria, as compared to CHL, and suppress some CHL-resistant bacterial strains. Thus, we have shown that TPP derivatives of CHL are dual-acting compounds targeting both the ribosomes and cellular membranes of bacteria. The TPP fragment of CAM-Cn-TPP compounds has an inhibitory effect on bacteria. Moreover, since the mitochondria of eukaryotic cells possess qualities similar to those of their prokaryotic ancestors, we demonstrate the possibility of targeting chemoresistant cancer cells with these compounds.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents

et al. 2021

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“…This drug is especially amenable to chemical derivatization because its dichloracetyl moiety can be easily replaced with a variety of other chemical scaffolds, such as amino acids [ 13 ], peptides [ 14 ], or other acyl-carrying groups [ 15 ], rendering it with new properties. For example, in one of the previous studies, CHL analogs with the dichloroacetyl moiety replaced by a polyamine extension that carries a positive charge and hydrophobic phenyl groups showed improved antibacterial and antitumor activities compared to CHL [ 15 , 16 ]. Moreover, recently, we have synthesized several amino acid analogs of CHL and demonstrated that the histidyl-derivative of CHL, which carries aromatic and positively charged side chain, exhibits substantially higher affinity for the bacterial ribosome due to strong stacking interactions of the histidyl moiety of this compound with the nucleotide U2506 of the 23S rRNA [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Binding and Action of Triphenylphosphonium Analog of Chloramphenicol upon the Bacterial Ribosome

et al. 2021

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Chloramphenicol (CHL) is a ribosome-targeting antibiotic that binds to the peptidyl transferase center (PTC) of the bacterial ribosome and inhibits peptide bond formation. As an approach for modifying and potentially improving the properties of this inhibitor, we explored ribosome binding and inhibitory properties of a semi-synthetic triphenylphosphonium analog of CHL—CAM-C4-TPP. Our data demonstrate that this compound exhibits a ~5-fold stronger affinity for the bacterial ribosome and higher potency as an in vitro protein synthesis inhibitor compared to CHL. The X-ray crystal structure of the Thermus thermophilus 70S ribosome in complex with CAM-C4-TPP reveals that, while its amphenicol moiety binds at the PTC in a fashion identical to CHL, the C4-TPP tail adopts an extended propeller-like conformation within the ribosome exit tunnel where it establishes multiple hydrophobic Van der Waals interactions with the rRNA. The synthesized compound represents a promising chemical scaffold for further development by medicinal chemists because it simultaneously targets the two key functional centers of the bacterial ribosome—PTC and peptide exit tunnel.

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“…Lomefloxacin arrested cell cycle likely due to topoisomerase II inhibition and also caused DNA breakdown at high doses in cultured melanoma human cells [54]. Chloramphenicol and its derivatives inhibited mitochondrial protein synthesis, killing the cancer stem cells [55,56]. Vancomycin has been shown to increase the activity of radiation therapy [57].…”

Section: Discussionmentioning

confidence: 99%

Broad-Spectrum Antibiotic Use and Disease Progression in Early-Stage Melanoma Patients: A Retrospective Cohort Study

Acharya

Kim

2021

Cancers

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Animal studies and a few clinical studies have reported mixed findings on the association between antibiotics and cancer incidence. Antibiotics may inhibit tumor cell growth, but could also alter the gut-microbiome-modulated immune system and increase the risk of cancer. Studies that assess how antibiotics affect the progression of cancer are limited. We evaluated the association between broad-spectrum antibiotic use and melanoma progression. We conducted a retrospective cohort study using IQVIA PharMetrics® Plus data (2008–2018). We identified patients with malignant melanoma who underwent wide local excision or Mohs micrographic surgery within 90 days of first diagnosis. Surgery date was the index date. Patients were excluded if they had any other cancer diagnosis or autoimmune disorders in 1 year before the index date (“baseline”). Exposure to broad-spectrum antibiotics was identified in three time windows using three cohorts: 3 months prior to the index date, 1 month after the index date, and 3 months after the index date. The covariates were patients’ demographic and clinical characteristics identified in the 1-year baseline period. The patients were followed from the index date until cancer progression, loss of enrollment, or the end of 2 years after the index date. Progression was defined as: (i) any hospice care after surgery, (ii) a new round of treatment for melanoma (surgery, chemotherapy, immunotherapy, targeted therapy, or radiotherapy) 180 days after prior treatment, or (iii) a metastasis diagnosis or a diagnosis of a new nonmelanoma primary cancer at least 180 days after first melanoma diagnosis or prior treatment. A high-dimensional propensity score approach with inverse weighting was used to adjust for the patients’ baseline differences. Cox proportional hazard regression was used for estimating the association. The final samples included 3930, 3831, and 3587 patients (mean age: 56 years). Exposure to antibiotics was 16% in the prior-3-months, 22% in the post-1-month, and 22% in the post-3-months. In the pre-3-months analysis, 9% of the exposed group and 9% of the unexposed group had progressed. Antibiotic use was not associated with melanoma progression (HR: 0.81; 95% CI: 0.57–1.14). However, antibiotic use in subsequent 1 month and subsequent 3 months was associated with 31% reduction (HR: 0.69; 95% CI: 0.51–0.92) and 32% reduction (HR: 0.68; 95% CI: 0.51–0.91) in progression, respectively. In this cohort of patients with likely early-stage melanoma cancer, antibiotic use in 1 month and 3 months after melanoma surgery was associated with a lower risk of melanoma progression. Future studies are warranted to validate the findings.

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New Chloramphenicol Derivatives from the Viewpoint of Anticancer and Antimicrobial Activity

Cited by 11 publications

References 52 publications

Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents

Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents

Binding and Action of Triphenylphosphonium Analog of Chloramphenicol upon the Bacterial Ribosome

Broad-Spectrum Antibiotic Use and Disease Progression in Early-Stage Melanoma Patients: A Retrospective Cohort Study

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