Synthesis of podophyllotoxin linked β-carboline congeners as potential anticancer agents and DNA topoisomerase II inhibitors

Sathish, Manda; Kavitha, Botla; Nayak, V. Lakshma; Tangella, Yellaiah; Ajitha, Ayyappan; Nekkanti, Shalini; Alarifi, Abdullah; Shankaraiah, Nagula; Nagesh, Narayana; Kamal, Ähmed

doi:10.1016/j.ejmech.2017.12.055

Cited by 63 publications

(45 citation statements)

References 44 publications

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“…This may suggest that these two genes are potential anticancer drug targets in CC. The enzyme encoded by TOP2A has been designed as the target for several anticancer agents and a variety of mutations in this gene have been associated with the development of drug resistance [52]. Small molecule compounds targeting CENPF have not been reported, possibly attributed by the difficulty to target a non-enzyme target.…”

Section: Discussionmentioning

confidence: 99%

TOP2A and CENPF are synergistic master regulators activated in cervical cancer

Yu¹,

Chen

Zhang

et al. 2020

BMC Med Genomics

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Background Identification of master regulators (MRs) using transcriptome data in cervical cancer (CC) could help us to develop biomarkers and find novel drug targets to fight this disease. Methods We performed differential expression (DE) analyses of public microarray and RNA-seq transcriptome data of CC and normal cervical tissues (N). Virtual Inference of Protein activity by Enriched Regulon analysis (VIPER) was used to convert the DE outcomes to differential activity (DA) signature for MRs. Synergy analysis was conducted to study synergistic effect of MR-pairs. TCGA and microarray data were used to test the association of expression of a MR and a clinical feature or a molecular feature (e.g. somatic mutations). Various bioinformatic tools/websites (DAVID, GEPIA2, Oncomine, cBioPortal) were used to analyze the expression of the top MRs and their regulons. Results Ten DE and 10 DA signatures were generated for CC. Two MRs, DNA topoisomerase II alpha (TOP2A) and centromere protein F (CENPF) were found to be up-regulated, activated and synergistic in CC compared to N across the 10 datasets. The two MRs activate a common set of genes (regulons) with functions in cell cycle, chromosome, DNA damage etc. Higher expression of CENPF was associated with metastasis. High expression of both MRs is associated with somatic mutation of a set of genes including tumor suppressors (TP53, MSH2, RB1) and genes involved in cancer pathways, cell cycle, DNA damage and repair. The magnitude of up-regulation and the absolute expression level of both MRs in CC are significantly higher compared to many other cancer types. Conclusion TOP2A and CENPF are a synergistic pair of MRs that are overexpressed and activated in CC. Their high expression is correlated with some prognosis features (e.g. metastasis) and molecular features (e.g. somatic mutations) and distinctly high in CC vs. many other cancer types. They may be good biomarkers and anticancer drug targets for CC.

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Section: Discussionmentioning

confidence: 99%

TOP2A and CENPF are synergistic master regulators activated in cervical cancer

Yu¹,

Chen

Zhang

et al. 2020

BMC Med Genomics

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“…β -carboline alkaloids are a class of natural and synthetic indole alkaloids with a wide range of pharmacological activities, including antitumor, antiviral, antiparasitic, and antibacterial activities [ 5 , 6 ]. Particularly, previous studies have shown that β -carboline alkaloids exerted antitumor activity through insertion into DNA [ 10 , 11 , 12 ], inducing apoptosis [ 13 , 45 ], inhibiting CDKs [ 16 ], and topoisomerase I and II activity [ 13 , 15 ]. The substitution at the C 3 and N 9 positions of β -carbolines could significantly increase their DNA insertion ability [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

“…β -carbolines have multiple biological and pharmacological properties [ 2 , 3 , 4 ], of which antitumor activity is the most widely studied [ 5 , 6 , 7 , 8 ]. Previous studies have shown that β -carbolines exerted their antitumor activity mainly through intercalating into DNA [ 7 , 9 , 10 , 11 , 12 , 13 ], inducing apoptosis, and inhibiting topoisomerase I and II (Top I and II) [ 13 , 14 , 15 ], cyclin-dependent kinases (CDKs) [ 16 , 17 ], mitogen-activated protein kinase (MAPK) [ 18 ], and I-Kappa-B kinase (IKK) [ 19 ]. Particularly, parent carbolines can be inserted into DNA, which can further cause cell apoptosis [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and In Vitro Antitumor Activity of Novel Bivalent β-Carboline-3-carboxylic Acid Derivatives with DNA as a Potential Target

Dai

et al. 2018

IJMS

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A series of novel bivalent β-carboline derivatives were designed and synthesized, and in vitro cytotoxicity, cell apoptosis, and DNA-binding affinity were evaluated. The cytotoxic results demonstrated that most bivalent β-carboline derivatives exhibited stronger cytotoxicity than the corresponding monomer against the five selected tumor cell lines (A549, SGC-7901, Hela, SMMC-7721, and MCF-7), indicating that the dimerization at the C3 position could enhance the antitumor activity of β-carbolines. Among the derivatives tested, 4B, 6i, 4D, and 6u displayed considerable cytotoxicity against A549 cell line. Furthermore, 4B, 6i, 4D, and 6u induced cell apoptosis in a dose-dependent manner, and caused cell cycle arrest at the S and G2/M phases. Moreover, the levels of cytochrome C in mitochondria, and the expressions of bcl-2 protein, decreased after treatment with β-carbolines, which indicated that 6i and 6u could induce mitochondria-mediated apoptosis. In addition, the results of UV-visible spectral, thermal denaturation, and molecular docking studies revealed that 4B, 6i, 4D, and 6u could bind to DNA mainly by intercalation.

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“…These compounds are reported to possess topoisomerase II inhibitory activity with a non-intercalative catalytic inhibitory mechanism. Sathish and coworkers 110 have reported the synthesis of a series of podophyllotoxins linked to beta-carbolines with demonstrated anticancer activity against the A549 (lung cancer), DU-145 (prostate cancer), MDAMB-231 (breast cancer), HT-29 (colon cancer), and HeLa (cervical cancer) cell lines. Their investigations to date suggest a topoisomerase II inhibitory mechanism.…”

Section: Pre-clinical Topoisomerase Inhibitors Under Investigationmentioning

confidence: 99%

Recent developments in topoisomerase-targeted cancer chemotherapy

Hevener

Verstak

Lutat

et al. 2018

Acta Pharmaceutica Sinica B

192

131

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The DNA topoisomerase enzymes are essential to cell function and are found ubiquitously in all domains of life. The various topoisomerase enzymes perform a wide range of functions related to the maintenance of DNA topology during DNA replication, and transcription are the targets of a wide range of antimicrobial and cancer chemotherapeutic agents. Natural product-derived agents, such as the camptothecin, anthracycline, and podophyllotoxin drugs, have seen broad use in the treatment of many types of cancer. Selective targeting of the topoisomerase enzymes for cancer treatment continues to be a highly active area of basic and clinical research. The focus of this review will be to summarize the current state of the art with respect to clinically used topoisomerase inhibitors for targeted cancer treatment and to discuss the pharmacology and chemistry of promising new topoisomerase inhibitors in clinical and pre-clinical development.

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Synthesis of podophyllotoxin linked β-carboline congeners as potential anticancer agents and DNA topoisomerase II inhibitors

Cited by 63 publications

References 44 publications

TOP2A and CENPF are synergistic master regulators activated in cervical cancer

TOP2A and CENPF are synergistic master regulators activated in cervical cancer

Synthesis and In Vitro Antitumor Activity of Novel Bivalent β-Carboline-3-carboxylic Acid Derivatives with DNA as a Potential Target

Recent developments in topoisomerase-targeted cancer chemotherapy

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