Antibacterial AZT derivative regulates metastasis of breast cancer cells

Chirumarry, Sridhar; Soung, Nak-Kyun; Han, Junyeol; Kim, Eun Young; Ryu, Eung K.; Lee, Young-Ho; Shin, Song Yub; Gunasekaran, P.; Bang, Jeong Kyu

doi:10.1016/j.ejmech.2020.112233

Cited by 13 publications

(11 citation statements)

References 43 publications

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“…As part of anticancer drug discovery (Chirumarry et al 2020;Gunasekaran et al 2021), recently, we reported a pyrazolopyrimidine-fused small molecule, KBJK557, as a Plk1 PBD inhibitor with significant potency and selectivity (Gunasekaran et al 2020). In vitro inhibition of Plk1 by KBJK557 induced cell cycle arrest and consecutive apoptosis.…”

Section: Introductionmentioning

confidence: 99%

An investigation of Plk1 PBD inhibitor KBJK557 as a tumor growth suppressor in non-small cell lung cancer

Gunasekaran

Lee²,

Hwang

et al. 2022

J Anal Sci Technol

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Lung cancer is the second most commonly reported type of cancer worldwide. Approximately 80–85% of lung cancer occurrences are accounted by non-small cell lung cancer (NSCLC). Polo-like kinase-1 (Plk1) plays multiple roles in cell cycle progression and its overexpression is observed in majority of malignancies, including NSCLC. A combination of frontline drugs and inhibitors targeting the Plk kinase domain (KD) has been used to overcome drug resistance in NSCLC. Plk1 KD inhibitors are highly prone to cross-reactivity with similar kinases, eventually leading to undesirable side effects. Moreover, there have been no reports of Plk1 PBD inhibitors showing antitumorigenic effects on NSCLC cells or animal models so far. To address this issue herein, for the first time, our recently reported Plk1 PBD inhibitor KBJK557 was evaluated for the anticancer potential against NSCLC cells. KBJK557 displayed notable cytotoxic effects in A549, PC9, and H1975 cells. Mechanistic investigations revealed that KBJK557-treated cells underwent G2/M cell cycle arrest, triggering subsequent apoptosis. In vivo antitumorigenic activity in xenograft mice model demonstrates that KBJK557-treated mice showed a considerable decrease in tumor size, proving the significances of Plk1 in lung cancer. Collectively, this study demonstrates that KBJK557 can serve as a promising drug candidate for treating the lung cancer through Plk1 PBD inhibition.

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Section: Introductionmentioning

confidence: 99%

An investigation of Plk1 PBD inhibitor KBJK557 as a tumor growth suppressor in non-small cell lung cancer

Gunasekaran

Lee²,

Hwang

et al. 2022

J Anal Sci Technol

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“…Several cationic groups have been widely used to endow the cationic characteristics of antibacterial agents, such as amine groups, guanidine group, and arginine that provides cation for natural AMPs. − To study the effect of different cationic substituents on the antibacterial activity of nonivamide derivatives, the raw material nonivamide with a length of four-carbon spacer was coupled with primary amine, guanidine, H-arginine (Arg)-OMe, H-Arg-Arg-Arg-OMe, tertiary amine (diethylamine-coupled), secondary amine (ethylamine-coupled), and tertiary amine ( N 1 -(3-(dimethylamino)propyl)- N 3 , N 3 -dimethylpropane-1,3-diamine-coupled) to yield compounds 11 , 19 , 27 , 28 , 29 , 30 , and 31 , respectively. As shown in Table , among these compounds, the guanidine-coupled 19 displayed the best antibacterial activity against Gram-positive bacteria (MICs = 6.25–12.5 μg/mL), while the alkylamine-coupled compounds 11 and 29 – 31 showed the worst antibacterial activity (MICs >50 μg/mL).…”

Section: Resultsmentioning

confidence: 99%

“…13 C NMR (100 MHz, CD 3 OD) δ 176. 13, 150.88, 149.02, 133.25, 121.16, 114.64, 112.94, 101.34, 70.06, 56.44, 43.80, 42.37, 37.11, 32.96, 30.41, 30.32, 30.27, 29.91, 29.62, 27.11, 24.40, 23.71, 14.43 (21). Following the general procedure, compound 5 (50 mg, 0.11 mmol), ammonia (5 mL, 7.0 M solution in methanol), and MeOH (2 mL) were used to prepare compound 13.…”

Section: N-(4-((5-guanidinopentyl)oxy)-3-methoxybenzyl)nonanamide (20)mentioning

confidence: 99%

“…1 H NMR (400 MHz, CD 3 OD) δ 6.92−6.85 (m, 2H), 6.81 (d, J = 9.5 Hz, 1H), 4.28 (s, 2H), 3.99 (t, J = 6.2 Hz, 2H), 3.82 (s, 3H), 3.24−3.16 (m, 2H), 2.22 (t, J = 7.4 Hz, 2H), 1.88−1.76 (m, 2H), 1.70−1.52 (m, 6H), 1.33−1.24 (m, 10H), 0.89 (t, J = 6.8 Hz, 3H). 13 (21). Following the general procedure, compound 5 (50 mg, 0.11 mmol), ammonia (5 mL, 7.0 M solution in methanol), and MeOH (2 mL) were used to prepare compound 13.…”

Section: N-(4-((5-guanidinopentyl)oxy)-3-methoxybenzyl)nonanamide (20)mentioning

confidence: 99%

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Membrane-Active Nonivamide Derivatives as Effective Broad-Spectrum Antimicrobials: Rational Design, Synthesis, and Biological Evaluation

Cai

Liang

et al. 2022

J. Med. Chem.

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Antibiotic resistance is emerging as a "global public health concern". To address the growing epidemic of multidrugresistant pathogens, the development of novel antimicrobials is urgently needed. In this study, by biomimicking cationic antibacterial peptides, we designed and synthesized a series of new membrane-active nonivamide and capsaicin derivatives as peptidomimetic antimicrobials. Through modulating charge/ hydrophobicity balance and rationalizing structure−activity relationships of these peptidomimetics, compound 51 was identified as the lead compound. Compound 51 exhibited potent antibacterial activity against both Gram-positive bacteria (MICs = 0.39−0.78 μg/mL) and Gram-negative bacteria (MICs = 1.56− 6.25 μg/mL), with low hemolytic activity and low cytotoxicity. Compound 51 displayed a faster bactericidal action through a membrane-disruptive mechanism and avoided bacterial resistance development. Furthermore, compound 51 significantly reduced the microbial burden in a murine model of keratitis infected by Staphylococcus aureus or Pseudomonas aeruginosa. Hence, this design strategy can provide a promising and effective solution to overcome antibiotic resistance.

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“…Considering the limitations mentioned above, significant efforts have been taken for the synthesis of small molecular mimetics [11,12], polymers [13], arylamide foldamers [14], and dipeptides [15]. In addition, incorporation of unnatural amino acids into biologically active peptides was found to modify its activity and stability [16].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Fmoc-Triazine Amino Acids and Its Application in the Synthesis of Short Antibacterial Peptidomimetics

Gunasekaran

Kim

Lee

et al. 2020

IJMS

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To combat the escalating rise of antibacterial resistance, the development of antimicrobial peptides (AMPs) with a unique mode of action is considered an attractive strategy. However, proteolytic degradation of AMPs remains the greatest challenge in their transformation into therapeutics. Herein, we synthesized Fmoc-triazine amino acids that differ from each other by anchoring either cationic or hydrophobic residues. These unnatural amino acids were adopted for solid-phase peptide synthesis (SPPS) to synthesize a series of amphipathic antimicrobial peptidomimetics. From the antimicrobial screening, we found that the trimer, BJK-4 is the most potent short antimicrobial peptidomimetic without showing hemolytic activity and it displayed enhanced proteolytic stability. Moreover, the mechanism of action to kill bacteria was found to be an intracellular targeting.

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Antibacterial AZT derivative regulates metastasis of breast cancer cells

Cited by 13 publications

References 43 publications

An investigation of Plk1 PBD inhibitor KBJK557 as a tumor growth suppressor in non-small cell lung cancer

An investigation of Plk1 PBD inhibitor KBJK557 as a tumor growth suppressor in non-small cell lung cancer

Membrane-Active Nonivamide Derivatives as Effective Broad-Spectrum Antimicrobials: Rational Design, Synthesis, and Biological Evaluation

Synthesis of Fmoc-Triazine Amino Acids and Its Application in the Synthesis of Short Antibacterial Peptidomimetics

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