Development of 1-(4-(Substituted)piperazin-1-yl)-2-((2-((4-methoxybenzyl)thio)pyrimidin-4-yl)oxy)ethanones That Target Poly (ADP-Ribose) Polymerase in Human Breast Cancer Cells

Deveshegowda, Suresha N.; Metri, Prashant K.; Shivakumar, Rashmi; Yang, Ji-Rui; Rangappa, Shobith; Swamynayaka, Ananda; Shanmugam, Muthu K.; Nagaraja, O.; Mahendra, M.; Shubha, Priya Babu; Chinnathambi, Arunachalam; Alharbi, Sulaiman Ali; Pandey, Vijay; Ahn, Kwang Seok; Lobie, Peter E.; Basappa, Basappa

doi:10.3390/molecules27092848

Cited by 11 publications

(9 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, pyrimidine-based amides were developed as inhibitors of poly (ADP-ribose) polymerase, which may provide novel drug-seeds for the development of target-based drugs for BC [14]. Earlier, the synthesis of 4-fluoro-biphenyl linked 1,2,4-triazolo[1,5a]pyrimidines via click chemistry was reported and it was observed that these small molecules targeted VEGFR1 in breast cancer cells [15].…”

Section: Chemical Synthesis Of Pcls (5a-h)mentioning

confidence: 99%

Discovery of Pyrimidine- and Coumarin-Linked Hybrid Molecules as Inducers of JNK Phosphorylation through ROS Generation in Breast Cancer Cells

Kim

Vishwanath

et al. 2023

Molecules

Self Cite

View full text Add to dashboard Cite

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer exhibits early relapses, poor prognoses, and high recurrence rates. Herein, a JNK-targeting compound has been developed that may be of utility in HER2-positive mammary carcinoma. The design of a pyrimidine-and coumarin-linked structure targeting JNK was explored and the lead structure PC-12 [4-(3-((2-((4-chlorobenzyl)thio) pyrimidin-4-yl)oxy)propoxy)-6-fluoro-2H-chromen-2-one (5d)] was observed to selectively inhibit the proliferation of HER2-positive BC cells. The compound PC-12 exerted DNA damage and induced apoptosis in HER-2 positive BC cells more significantly compared to HER-2 negative BC cells. PC-12 induced PARP cleavage and down-regulated the expression of IAP-1, BCL-2, SURVIVIN, and CYCLIN D1 in BC cells. In silico and theoretical calculations showed that PC-12 could interact with JNK, and in vitro studies demonstrated that it enhanced JNK phosphorylation through ROS generation. Overall, these findings will assist the discovery of new compounds targeting JNK for use in HER2-positive BC cells.

show abstract

Section: Chemical Synthesis Of Pcls (5a-h)mentioning

confidence: 99%

Discovery of Pyrimidine- and Coumarin-Linked Hybrid Molecules as Inducers of JNK Phosphorylation through ROS Generation in Breast Cancer Cells

Kim

Vishwanath

et al. 2023

Molecules

Self Cite

View full text Add to dashboard Cite

show abstract

“…Heterocycles have been widely studied and integrated into medicinal chemistry due to their diverse biological activities, including targeting specific cellular pathways, DNA binding, alkylation, and apoptosis induction [4,5]. Presently, extensive research is focusing on various natural and synthetic heterocyclic compounds, such as pyrimidines [6][7][8], coumarins [9,10], pyrazoles [11][12][13], triazoles [14][15][16], oxadiazoles [17][18][19], and piperazines [20,21], among others, which have displayed promising biological properties.…”

Section: Introductionmentioning

confidence: 99%

Electrochemical Synthesis of Versatile Pyrimidine and Oxadiazoles Tethered Triazoles as Inhibitors of VEGFR-2 in Human Breast Cancer Cells

Ravish,

Siddappa,

et al. 2023

Catalysts

Self Cite

View full text Add to dashboard Cite

Metastasis, the dissemination of tumor cells, stands as the second most prominent contributor to mortality arising from breast cancer. To counteract this phenomenon, the molecular markers associated with angiogenesis, particularly vascular endothelial growth factor (VEGF) and its receptor (VEGFR), have emerged as promising strategies for impeding the progression of tumor cells. Compounds like pyrimidines, coumarins, oxadiazoles, and triazoles have undergone comprehensive investigations due to their notable anticancer potential, highlighting their encouraging capacities in inhibiting VEGFR-2, an essential mediator of angiogenesis signaling. Herein, we have synthesized pyrimidine–triazoles and oxadiazole–triazoles using electrochemical and conventional methods. The newly synthesized compounds were evaluated for anticancer activity against MCF-7 breast cancer cells, and it was found that the compounds 8a and 8b showed IC50 values of 5.29 and 15.54 μM, respectively. Our in silico mode of action revealed that these compounds could target VEGFR-2, which was further evidenced by our in silico structure-based bioinformatic analysis. In conclusion, we reported an electrochemical method to prepare novel drug-like compounds, based on triazole and other heterocyclic hybrids, that could be used to design VGFR-targeting drugs.

show abstract

“…Novel piperazine compounds could suppress NF-κB translocation to the nucleus [22] and inhibit NF-κB by decreasing TNF-α levels [23]. Pyrimidines also play a vital role in anti-cancer drug discovery [24]. Ibudilast, spebrutinib, and dasatinib are a few pyrimidine-based drugs (Figure 1) that block the NF-κB pathway [25].…”

Section: Introductionmentioning

confidence: 99%

Development of Piperazine- and Oxazine-Linked Pyrimidines as p65 Subunit Binders of NF–κB in Human Breast Cancer Cells

Ravish,

Narasimhachar,

et al. 2023

Biomedicines

Self Cite

View full text Add to dashboard Cite

Nuclear factor kappa B (NF–κB) is a potential therapeutic target in breast cancer. In the current study, a new class of oxazine– and piperazine–linked pyrimidines was developed as inhibitors of NF–κB, overcoming the complexity of the oxazine structure found in nature and enabling synthesis under laboratory conditions. Among the series of synthesized and tested oxazine–pyrimidine and piperazine–pyrimidine derivatives, compounds 3a and 5b inhibited breast cancer cell (MCF–7) viability with an IC50 value of 9.17 and 6.29 µM, respectively. In silico docking studies showed that the pyrimidine ring of 3a and the 4–methoxybenzyl thiol group of 5b could strongly bind the p65 subunit of NF–κB, with the binding energies −9.32 and −7.32 kcal mol−1. Furthermore, compounds 3a and 5b inhibited NF–κB in MCF–7 breast cancer cells. In conclusion, we herein report newer structures that target NF–κB in BC cells.

show abstract

Development of 1-(4-(Substituted)piperazin-1-yl)-2-((2-((4-methoxybenzyl)thio)pyrimidin-4-yl)oxy)ethanones That Target Poly (ADP-Ribose) Polymerase in Human Breast Cancer Cells

Cited by 11 publications

References 48 publications

Discovery of Pyrimidine- and Coumarin-Linked Hybrid Molecules as Inducers of JNK Phosphorylation through ROS Generation in Breast Cancer Cells

Discovery of Pyrimidine- and Coumarin-Linked Hybrid Molecules as Inducers of JNK Phosphorylation through ROS Generation in Breast Cancer Cells

Electrochemical Synthesis of Versatile Pyrimidine and Oxadiazoles Tethered Triazoles as Inhibitors of VEGFR-2 in Human Breast Cancer Cells

Development of Piperazine- and Oxazine-Linked Pyrimidines as p65 Subunit Binders of NF–κB in Human Breast Cancer Cells

Contact Info

Product

Resources

About