Replacing <scp>d</scp>-Glucosamine with Its <scp>l</scp>-Enantiomer in Glycosylated Antitumor Ether Lipids (GAELs) Retains Cytotoxic Effects against Epithelial Cancer Cells and Cancer Stem Cells

Ogunsina, Makanjuola; Samadder, Pranati; Idowu, Temilolu; Arthur, Gilbert; Schweizer, Frank

doi:10.1021/acs.jmedchem.6b01773

Cited by 13 publications

(50 citation statements)

References 30 publications

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“…For instance, reports show that increasing the lipophilicity of FQs results in a commensurate improvement in antiproliferative efficacy [ 167 ]. This is consistent with published evidences that support the correlation between lipophilicity of compounds and antitumor efficacy [ 168 , 169 , 170 , 171 , 172 , 173 , 174 ]. Several derivatives of ciprofloxacin have been shown to display more potent in vitro antitumor activity than the parent compound, culminating into analogs whose inhibitory concentration (IC 50 ) values are as low as ≤10 μM in various cancer cell lines [ 175 ].…”

Section: Selectivity and Amplification Of Desirable Properties In supporting

confidence: 93%

Ubiquitous Nature of Fluoroquinolones: The Oscillation between Antibacterial and Anticancer Activities

Idowu

Schweizer

2017

Antibiotics

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Fluoroquinolones are synthetic antibacterial agents that stabilize the ternary complex of prokaryotic topoisomerase II enzymes (gyrase and Topo IV), leading to extensive DNA fragmentation and bacteria death. Despite the similar structural folds within the critical regions of prokaryotic and eukaryotic topoisomerases, clinically relevant fluoroquinolones display a remarkable selectivity for prokaryotic topoisomerase II, with excellent safety records in humans. Typical agents that target human topoisomerases (such as etoposide, doxorubicin and mitoxantrone) are associated with significant toxicities and secondary malignancies, whereas clinically relevant fluoroquinolones are not known to exhibit such propensities. Although many fluoroquinolones have been shown to display topoisomerase-independent antiproliferative effects against various human cancer cells, those that are significantly active against eukaryotic topoisomerase show the same DNA damaging properties as other topoisomerase poisons. Empirical models also show that fluoroquinolones mediate some unique immunomodulatory activities of suppressing pro-inflammatory cytokines and super-inducing interleukin-2. This article reviews the extended roles of fluoroquinolones and their prospects as lead for the unmet needs of “small and safe” multimodal-targeting drug scaffolds.

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Section: Selectivity and Amplification Of Desirable Properties In supporting

confidence: 93%

Ubiquitous Nature of Fluoroquinolones: The Oscillation between Antibacterial and Anticancer Activities

Idowu

Schweizer

2017

Antibiotics

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“…On the other hand, minocycline (75 mg/kg) or hybrid 14 alone (75 mg/kg) resulted in 0% survival after 24 h. Tobramycin-NMP hybrid 14 was shown to be nonhemolytic (Յ5% hemolysis of ovine erythrocytes at 1,000 g/ml) and displayed low cytotoxicity to human epithelial cancer cell lines (50% cytotoxic concentration [CC 50 ] of Ͼ30 M). CC 50 is the concentration of a drug required to reduce the viability of a cell population by 50% relative to untreated controls (294,295). This rules out the suspicion of a nonspecific mode of action (296), as the hybrid molecule could discriminate prokaryotic from eukaryotic cells.…”

Section: Antibiotic Hybrids Can Adopt New Mechanistic Actions That DImentioning

confidence: 99%

Antibiotic Hybrids: the Next Generation of Agents and Adjuvants against Gram-Negative Pathogens?

et al. 2018

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The global incidence of drug-resistant Gram-negative bacillary infections has been increasing, and there is a dire need to develop novel strategies to overcome this problem. Intrinsic resistance in Gram-negative bacteria, such as their protective outer membrane and constitutively overexpressed efflux pumps, is a major survival weapon that renders them refractory to current antibiotics. Several potential avenues to overcome this problem have been at the heart of antibiotic drug discovery in the past few decades. We review some of these strategies, with emphasis on antibiotic hybrids either as stand-alone antibacterial agents or as adjuvants that potentiate a primary antibiotic in Gram-negative bacteria. Antibiotic hybrid is defined in this review as a synthetic construct of two or more pharmacophores belonging to an established agent known to elicit a desired antimicrobial effect. The concepts, advances, and challenges of antibiotic hybrids are elaborated in this article. Moreover, we discuss several antibiotic hybrids that were or are in clinical evaluation. Mechanistic insights into how tobramycin-based antibiotic hybrids are able to potentiate legacy antibiotics in multidrug-resistant Gram-negative bacilli are also highlighted. Antibiotic hybrids indeed have a promising future as a therapeutic strategy to overcome drug resistance in Gram-negative pathogens and/or expand the usefulness of our current antibiotic arsenal.

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“…The cells were dispersed into 96-well plates, and after 24 h, C 12 -PRP, colistin, or adriamycin was added as described in the proliferation assay. After incubation for 48 h, the viability of the cells was determined with the MTS reagent (Promega, Canada) as previously described (42).…”

Section: Methodsmentioning

confidence: 99%

Short Proline-Rich Lipopeptide Potentiates Minocycline and Rifampin against Multidrug- and Extensively Drug-Resistant Pseudomonas aeruginosa

Domalaon

Sanchak

Koskei

et al. 2018

Antimicrob Agents Chemother

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A series of 16 short proline-rich lipopeptides (SPRLPs) were constructed to mimic longer naturally existing proline-rich antimicrobial peptides. Antibacterial assessment revealed that lipopeptides containing hexadecanoic acid (C) possess optimal antibacterial activity relative to others with shorter lipid components. SPRLPs were further evaluated for their potential to serve as adjuvants in combination with existing antibiotics to enhance antibacterial activity against drug-resistant Out of 16 prepared SPRLPs, C-PRP was found to significantly potentiate the antibiotics minocycline and rifampin against multidrug- and extensively drug-resistant (MDR/XDR) clinical isolates. This nonhemolytic C-PRP is comprised of the heptapeptide sequence PRPRPRP-NH acylated to dodecanoic acid (C) at the N terminus. The adjuvant potency of C-PRP was apparent by its ability to reduce the MIC of minocycline and rifampin below their interpretative susceptibility breakpoints against MDR/XDR An attempt to optimize C-PRP through peptidomimetic modification was performed by replacing all l- to d-amino acids. C-PRP demonstrated that it was amenable to optimization, since synergism with minocycline and rifampin were retained. Moreover, C-PRP displayed no cytotoxicity against human liver carcinoma HepG2 and human embryonic kidney HEK-293 cell lines. Thus, the SPRLP C-PRP is a lead adjuvant candidate that warrants further optimization. The discovery of agents that are able to resuscitate the activity of existing antibiotics against drug-resistant Gram-negative pathogens, especially , is of great clinical interest.

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Replacing d-Glucosamine with Its l-Enantiomer in Glycosylated Antitumor Ether Lipids (GAELs) Retains Cytotoxic Effects against Epithelial Cancer Cells and Cancer Stem Cells

Cited by 13 publications

References 30 publications

Ubiquitous Nature of Fluoroquinolones: The Oscillation between Antibacterial and Anticancer Activities

Ubiquitous Nature of Fluoroquinolones: The Oscillation between Antibacterial and Anticancer Activities

Antibiotic Hybrids: the Next Generation of Agents and Adjuvants against Gram-Negative Pathogens?

Short Proline-Rich Lipopeptide Potentiates Minocycline and Rifampin against Multidrug- and Extensively Drug-Resistant Pseudomonas aeruginosa

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