Anticancer agents based on Plastoquinone analogs with N-phenylpiperazine: Structure-activity relationship and mechanism of action in breast cancer cells

Jannuzzi, Ayşe Tarbın; Yıldız, Mahmut; Bayrak, Nilüfer; Yıldırım, Hatice; Shilkar, Deepak; Jayaprakash, Venkatesan; Tuyun, Amaç Fatih

doi:10.1016/j.cbi.2021.109673

Cited by 11 publications

(20 citation statements)

References 45 publications

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“…In the period of 2017–2021, with the purpose of identification of new lead molecules based on natural products that specifically target leukemia cancer cell lines, we mainly focused on the quinones namely PQ analogs containing two important moieties (2,3-dimethyl-1,4-benzoquinone and primary/secondary amines or thiols) [ 27 , 28 , 29 , 30 , 31 ], encouraged by our previous results and experiences with 1,4-quinones [ 32 , 33 , 34 ]. Considering our previous findings that demonstrated greater anticancer activity by the introduction of an alkoxy group with a short alkyl chain [ 28 , 29 ], we also evaluated the effect of weak (methyl) or strong (methoxy) electron-donating group(s) to the PQ structure [ 27 ]. We recently reported the PQ analogs with aryl amines containing alkoxy substituent(s) as highly effective agents against two human cancer cell lines (K562 and Jurkat cells).…”

Section: Introductionmentioning

confidence: 99%

In Vitro and In Silico Study of Analogs of Plant Product Plastoquinone to Be Effective in Colorectal Cancer Treatment

et al. 2022

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Plants have paved the way for the attainment of molecules with a wide-range of biological activities. However, plant products occasionally show low biological activities and/or poor pharmacokinetic properties. In that case, development of their derivatives as drugs from the plant world has been actively performed. As plant products, plastoquinones (PQs) have been of high importance in anticancer drug design and discovery; we have previously evaluated and reported the potential cytotoxic effects of a series of PQ analogs. Among these analogs, PQ2, PQ3 and PQ10 were selected for National Cancer Institute (NCI) for in vitro screening of anticancer activity against a wide range of cancer cell lines. The apparent superior anticancer potency of PQ2 on the HCT-116 colorectal cancer cell line than that of PQ3 and PQ10 compared to other tested cell lines has encouraged us to perform further mechanistic studies to enlighten the mode of anti-colorectal cancer action of PQ2. For this purpose, its apoptotic effects on the HCT-116 cell line, DNA binding capacity and several crucial pharmacokinetic properties were investigated. Initially, MTT assay was conducted for PQ2 at different concentrations against HCT-116 cells. Results indicated that PQ2 exhibited significant cytotoxicity in HCT-116 cells with an IC50 value of 4.97 ± 1.93 μM compared to cisplatin (IC50 = 26.65 ± 7.85 μM). Moreover, apoptotic effects of PQ2 on HCT-116 cells were investigated by the annexin V/ethidium homodimer III staining method and PQ2 significantly induced apoptosis in HCT-116 cells compared to cisplatin. Based on the potent DNA cleavage capacity of PQ2, molecular docking studies were conducted in the minor groove of the double helix of DNA and PQ2 presented a key hydrogen bonding through its methoxy moiety. Overall, both in vitro and in silico studies indicated that effective, orally bioavailable drug-like PQ2 attracted attention for colorectal cancer treatment. The most important point to emerge from this study is that appropriate derivatization of a plant product leads to unique biologically active compounds.

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Section: Introductionmentioning

confidence: 99%

In Vitro and In Silico Study of Analogs of Plant Product Plastoquinone to Be Effective in Colorectal Cancer Treatment

et al. 2022

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“…4.6. Molecular docking S. aureus DNA gyrase X-ray crystal structure (PDB code 3G75) [9] was retrieved from Protein Data Bank to be utilized as a model in the present study. The protein structure was prepared using QuickPrep module of MOE (version 2019.01, Chemical Computing Group Inc., Montreal, QCstate abbrev, Canada).…”

Section: Discussionmentioning

confidence: 99%

Natural-product-inspired design and synthesis of thiolated coenzyme Q analogs as promising agents against Gram-positive bacterial strains: insights into structure–activity relationship, activity profile, mode of action, and molecular docking

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“…For some time in our laboratory, we have focused on the construction of 1,4-quinones with different substitution patterns, along with detailed studies on their potential biological performances, in order to discover new compounds that have the potential to be lead molecules in the fight against cancer and antimicrobial resistance [ 27 , 28 , 29 ]. To date, the biologically important lead structures have been obtained and gathered for the tuning of pharmacological efficacy as an antimicrobial and/or anticancer agent.…”

Section: Introductionmentioning

confidence: 99%

“…To date, the biologically important lead structures have been obtained and gathered for the tuning of pharmacological efficacy as an antimicrobial and/or anticancer agent. It is mainly understood that incorporating amino groups (i.e., aryl amines, piperazines, and piperidines) into 1,4-quinone moiety with different side groups (i.e., phenyl, dimethyl, and pyridinyl) has mainly increased the biological potency of the target molecules [ 27 , 28 , 29 ]. On the other hand, we have previously accessed the C2- and/or C2C3-thiolated 1,4-quinones with different side groups, such as the dimethyl or pyridinyl group [ 30 , 31 ].…”

Section: Introductionmentioning

confidence: 99%

Promising Antibacterial and Antifungal Agents Based on Thiolated Vitamin K3 Analogs: Synthesis, Bioevaluation, Molecular Docking

et al. 2022

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In the present study, we designed and synthesized thiolated VK3 analogs (VK3a–g) along with an extensive antimicrobial study. After the evaluation of the antibacterial and antifungal activity against various bacterial and fungal strains, we presented an initial structure–activity relationship study on these VK3 analogs. In particular, four thiolated VK3 analogs exhibited superior biological potency against some Gram-positive bacterial strains, including Staphylococcus aureus (ATCC® 29213) and Enterococcus faecalis (ATCC® 29212). Next, all thiolated VK3 analogs were evaluated for their potential of cell growth inhibition on the NCI-60 cancer cell lines panel. This screening underlined that the thiolated VK3 analogs have no visible cytotoxicity on different cancer cell lines. The selected two thiolated VK3 analogs (VK3a and VK3b), having minimal hemolytic activity, which also have the lowest MIC values on S. aureus and E. faecalis, were further evaluated for their inhibition capacities on biofilm formation after evaluating their potential in vitro antimicrobial activity against each of the 20 clinically obtained resistant strains of Staphylococcus aureus. VK3b showed excellent antimicrobial activity against clinically resistant S. aureus isolates. Furthermore, the tested molecules showed nearly two log10 reduction in the viable cell count at six hours according to the time kill curve studies. Although these molecules decreased biofilm attachment about 50%, when sub-MIC concentrations were used these molecules increased the percentage of biofilm formation. The molecular docking of VK3a and VK3b in S. aureus thymidylate kinase was conducted in order to predict their molecular interactions. VK3a and VK3b exhibited excellent lead-likeness properties and pharmacokinetic profiles that qualify them for further optimization and development. In conclusion, since investigating efficient novel antimicrobial molecules is quite difficult, these studies are of high importance, especially in the present era of antimicrobial resistance.

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Anticancer agents based on Plastoquinone analogs with N-phenylpiperazine: Structure-activity relationship and mechanism of action in breast cancer cells

Cited by 11 publications

References 45 publications

In Vitro and In Silico Study of Analogs of Plant Product Plastoquinone to Be Effective in Colorectal Cancer Treatment

In Vitro and In Silico Study of Analogs of Plant Product Plastoquinone to Be Effective in Colorectal Cancer Treatment

Natural-product-inspired design and synthesis of thiolated coenzyme Q analogs as promising agents against Gram-positive bacterial strains: insights into structure–activity relationship, activity profile, mode of action, and molecular docking

Promising Antibacterial and Antifungal Agents Based on Thiolated Vitamin K3 Analogs: Synthesis, Bioevaluation, Molecular Docking

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