New N‐benzhydrylpiperazine/1,3,4‐oxadiazoles conjugates inhibit the proliferation, migration, and induce apoptosis in HeLa cancer cells via oxidative stress–mediated mitochondrial pathway

Abstract

N-benzhydrylpiperazine and 1,3,4-oxadiazoles are pharmacologically active scaffolds which exhibits significant inhibitory growth effects against various cancer cells, however, antiproliferation effects and the underlying mechanism for inducing apoptosis for aforementioned scaffolds addressing HeLa cancer cells remains uncertain. In this study, N-benzhydrylpiperazine clubbed with 1,3,4-oxadiazoles (4a-4h) were synthesized, subsequently characterized using high resolution spectroscopic techniques and eventually evaluated for their antiproliferation potential by inducing apoptosis in HeLa cancer cells. The MTT assay screening results revealed that among all, compound 4d ( N-benzhydryl-4-((5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)methyl)piperazine) in particular, exhibited IC value of 28.13 ± 0.21 μg/mL and significantly inhibited the proliferation of HeLa cancer cells in concentration-dependent manner. The in vitro anticancer assays for treated HeLa cells resulted in alterations in the cell morphology, reduction in colony formation, and inhibition of cell migration in concentration-dependent treatment. Furthermore, G2/M phase arrest, variations in the nuclear morphology, degradation of chromosomal DNA confirmed the ongoing apoptosis in treated HeLa cells. Increase in the expression of cytochrome C and caspase-3 confirmed the involvement of intrinsic mitochondrial pathway regulating the cell death. Also, elevation in reactive oxygen species level and loss of mitochondrial membrane potential signified that compound 4d induced apoptosis in HeLa cells by generating the oxidative stress. Therefore, compound 4d may act as a potent chemotherapeutic agent against human cervical cancer.

Cyclizine induces cytotoxicity and apoptosis in macrophages through the extrinsic and intrinsic apoptotic pathways

“…In patients with nausea associated with panenteric dysmotility syndrome, the intramuscular administration of cyclizine thrice a day for 3 years may result in hip osteonecrosis, inflammatory myopathy, and mixed connective tissue disease 28 . N ‐benzhydryl‐4‐((5‐(4‐aminophenyl)‐1,3,4‐oxadiazol‐2‐yl)methyl) piperazine (NBAOMP; N ‐benzhydrylpiperazine derivative) and 2‐ N , N ‐diethylaminocarbonyloxymethyl‐1‐diphenylmethyl‐4‐(3,4,5‐trimethoxybenzoyl) piperazine hydrochloride (benzhydrylpiperazine derivative) have been demonstrated to induce apoptosis in a human cervical cancer cell line (HeLa) and human Burkitt lymphoma cell line (Raji), respectively 29,30 . Cinnarizine, a compound with a structure similar to that of cyclizine, can induce apoptosis in various myeloma cell lines (MPC‐11, RAW264.7, KMS‐18, OPM‐2, RPMI‐8226, and U‐266), lymphoma cell lines (OCI‐Ly 8 Lam‐53, Raji, and SUDHL‐4), and Leishmania major 31,32 .…”

“…In macrophages exposed to various hazardous materials, apoptosis is induced by activated caspase‐3, resulting from the activation of caspase‐9 38 . In HeLa cells, NBAOMP induces mitochondrial dysfunction and caspase‐3 expression 29 . Cinnarizine (concentration, >50 μM) induces mitochondrial permeability transition in rat liver cells 39 .…”

“…27 In patients with nausea associated with panenteric dysmotility syndrome, the intramuscular administration of cyclizine thrice a day for 3 years may result in hip osteonecrosis, inflammatory myopathy, and mixed connective tissue disease. 28 29,30 Cinnarizine, a compound with a structure similar to that of cyclizine, can induce apoptosis in various myeloma cell lines (MPC-11, RAW264.7, KMS-18, OPM-2, RPMI-8226, and U-266), lymphoma cell lines (OCI-Ly 8 Lam-53, Raji, and SUDHL-4), and Leishmania major. 31,32 Our investigation revealed that cyclizineinduced apoptosis and necrosis in RAW264.7 macrophages, and this effect was dependent on the concentration of cyclizine applied.…”

Novel oxadiazole- and triazole-based calixarene derivatives: synthesis and extraction properties

“…1,3,4-oxadiazole and 1,2,4-triazole derivatives are known to exhibit biological activities such as anticancer, antimicrobial, antifungal and antiviral [28][29][30][31][32]. In addition to biological properties, 1,3,4-oxadiazole has a great advantage in material science due to its various electronic properties [33][34][35].…”

Spiropyrrolizidine and piperazine derivatives: Synthesis and evaluation on kras expression levels in human colon cancer cells

“…Results within cells. [101][102][103] can potentially generate ROS sufficient enough to cause DNA damage leading to G2/M arrest. 103 Regardless of the mechanism, G2/M inhibition by SPOPP (8) could be beneficial as a therapy.…”