Exploration of mercaptoacetamide-linked pyrimidine-1,3,4-oxadiazole derivatives as DNA intercalative topo II inhibitors: Cytotoxicity and apoptosis induction

Shaikh, Arbaz Sujat; Kiranmai, Gaddam; Devi, Ganthala Parimala; Makhal, Priyanka N.; Sigalapalli, Dilep Kumar; Tokala, Ramya; Kaki, Venkata Rao; Shankaraiah, Nagula; Nagesh, Narayana; Babu, Bathini Nagendra; Tangellamudi, Neelima D.

doi:10.1016/j.bmcl.2022.128697

Cited by 12 publications

(3 citation statements)

References 40 publications

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“…The dual mechanism design strategy was dictated by mimicking the general thematic features of DNA-binding agents and cyclin-dependent kinase inhibitors (Figure ). Accordingly, we exploited the pyrimidine and fused pyrimidine scaffolds that are highly represented in lead apoptotic inducers via DNA damage − or cyclin-dependent kinase inhibition, ,, while incorporating planar rings via carbonyl and amino ligation. Hence, hydrazones of novel pyrimidinones and 1,2,4-triazolo[4,3- a ]pyrimidinones were rationalized as our target dual-acting molecules.…”

Section: Rational Designmentioning

confidence: 99%

Triggering Breast Cancer Apoptosis via Cyclin-Dependent Kinase Inhibition and DNA Damage by Novel Pyrimidinone and 1,2,4-Triazolo[4,3-a]pyrimidinone Derivatives

Abd Al Moaty,

El Kilany,

Awad

et al. 2024

ACS Omega

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Combinations of apoptotic inducers are common clinical practice in breast cancer. However, their efficacy is limited by the heterogeneous pharmacokinetic profiles. An advantageous alternative is merging their molecular entities in hybrid multitargeted scaffolds exhibiting synergistic activities and uniform distribution. Herein, we report apoptotic inducers simultaneously targeting DNA and CDK-2 (cyclin-dependent kinase-2) inspired by studies revealing that CDK-2 inhibition sensitizes breast cancer to DNA-damaging agents. Accordingly, rationally substituted pyrimidines and triazolopyrimidines were synthesized and assayed by MTT against MCF-7, MDA-MB231, and Wi-38 cells compared to doxorubicin. The N-(4-amino-2-((2-hydrazinyl-2-oxoethyl)thio)-6-oxo-1,6-dihydropyrimidin-5-yl)acetamide 5 and its p-nitrophenylhydrazone 8 were the study hits against MCF-7 (IC 50 = 0.050 and 0.146 μM) and MDA-MB231 (IC 50 = 0.826 and 0.583 μM), induced DNA damage at 10.64 and 30.03 nM, and inhibited CDK-2 (IC 50 = 0.172 and 0.189 μM). 5 induced MCF-7 apoptosis by 46.75% and disrupted cell cycle during S phase. Docking and MD simulations postulated their stable key interactions.

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Section: Rational Designmentioning

confidence: 99%

Triggering Breast Cancer Apoptosis via Cyclin-Dependent Kinase Inhibition and DNA Damage by Novel Pyrimidinone and 1,2,4-Triazolo[4,3-a]pyrimidinone Derivatives

Abd Al Moaty,

El Kilany,

Awad

et al. 2024

ACS Omega

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“…Merccaptoacetamide-linked pyrimidine-1,3,4-oxadiazole hybrids ( 153 ) were designed and synthesized by Arbaz Sujat Shaikh and colleagues. The novel pyrimidine-1,3,4-oxadiazole hybrids were evaluated for their in vitro cytotoxic potential against 04 cancer cell lines, i.e., lung cancer cells (A549), prostate cancer cells (PC-3, DU-145), and human embryonic kidney cells (HEK) [ 133 ].…”

Section: Miscellaneous Anticancer Properties Of 134-oxadiazole Deriva...mentioning

confidence: 99%

An Understanding of Mechanism-Based Approaches for 1,3,4-Oxadiazole Scaffolds as Cytotoxic Agents and Enzyme Inhibitors

et al. 2023

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The world’s health system is plagued by cancer and a worldwide effort is underway to find new drugs to treat cancer. There has been a significant improvement in understanding the pathogenesis of cancer, but it remains one of the leading causes of death. The imperative 1,3,4-oxadiazole scaffold possesses a wide variety of biological activities, particularly for cancer treatment. In the development of novel 1,3,4-oxadiazole-based drugs, structural modifications are important to ensure high cytotoxicity towards malignant cells. These structural modification strategies have shown promising results when combined with outstanding oxadiazole scaffolds, which selectively interact with nucleic acids, enzymes, and globular proteins. A variety of mechanisms, such as the inhibition of growth factors, enzymes, and kinases, contribute to their antiproliferative effects. The activity of different 1,3,4-oxadiazole conjugates were tested on the different cell lines of different types of cancer. It is demonstrated that 1,3,4-oxadiazole hybridization with other anticancer pharmacophores have different mechanisms of action by targeting various enzymes (thymidylate synthase, HDAC, topoisomerase II, telomerase, thymidine phosphorylase) and many of the proteins that contribute to cancer cell proliferation. The focus of this review is to highlight the anticancer potential, molecular docking, and SAR studies of 1,3,4-oxadiazole derivatives by inhibiting specific cancer biological targets, such as inhibiting telomerase activity, HDAC, thymidylate synthase, and the thymidine phosphorylase enzyme. The purpose of this review is to summarize recent developments and discoveries in the field of anticancer drugs using 1,3,4-oxadiazoles.

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“…Also, during this year, A.S. Shaikh et al, reported68 the synthesis of pyrimidin-2-yl acetamide ISSN: ://aprh.journals.ekb.…”

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confidence: 99%

Pyrimidines as Anticancer and Antiviral: Synthesis & Reactions (A Review)

Fatahala

Mohamed²,

Khodair³

et al. 2022

Journal of Advanced Pharmacy Research

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Background:The interest of many medicinal and organic chemists has been attracted to the synthesis of pyrimidines and their analogues due to their highly biological and medicinal properties. Objectives& Methodology: Based on these activities, this review discusses the various recent methods for the synthesis of these heterocyclic compounds during the period of 2017 to 2021 with certain two main medicinal actions. Conclusion: Pyrimidine moiety bearing compounds, are synthesized, and reacted either through one-pot synthesis or multi-step synthesis pathways, in catalytic and solvent free condition or using catalysts and solvent.

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Exploration of mercaptoacetamide-linked pyrimidine-1,3,4-oxadiazole derivatives as DNA intercalative topo II inhibitors: Cytotoxicity and apoptosis induction

Cited by 12 publications

References 40 publications

Triggering Breast Cancer Apoptosis via Cyclin-Dependent Kinase Inhibition and DNA Damage by Novel Pyrimidinone and 1,2,4-Triazolo[4,3-a]pyrimidinone Derivatives

Triggering Breast Cancer Apoptosis via Cyclin-Dependent Kinase Inhibition and DNA Damage by Novel Pyrimidinone and 1,2,4-Triazolo[4,3-a]pyrimidinone Derivatives

An Understanding of Mechanism-Based Approaches for 1,3,4-Oxadiazole Scaffolds as Cytotoxic Agents and Enzyme Inhibitors

Pyrimidines as Anticancer and Antiviral: Synthesis & Reactions (A Review)

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