Dual inhibition of topoisomerase II and tubulin polymerization by azatoxin, a novel cytotoxic agent

1993 ◽  
Vol 45 (12) ◽  
pp. 2449-2456 ◽  
Author(s):  
Eric Solary ◽  
François Leteurtre ◽  
Kenneth D. Paull ◽  
Dominic Scudiero ◽  
Ernest Hamel ◽  
...  
Keyword(s):  
Topoisomerase Ii ◽  
Cytotoxic Agent ◽  
Tubulin Polymerization ◽  
Dual Inhibition

scholarly journals Indole C6 Functionalization of Tryprostatin B Using Prenyltransferase CdpNPT

Catalysts ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1247
Author(s):  
Eric D. Gardner ◽  
Dustin A. Dimas ◽  
Matthew C. Finneran ◽  
Sara M. Brown ◽  
Anthony W. Burgett ◽  
...  
Keyword(s):  
Natural Products ◽  
Late Stage ◽  
Topoisomerase Ii ◽  
High Selectivity ◽  
Direct Access ◽  
Tubulin Polymerization ◽  
Cyclic Dipeptide ◽  
Structure Activity ◽  
Methoxy Substituent ◽  
Dual Inhibition

Tryprostatin A and B are prenylated, tryptophan-containing, diketopiperazine natural products, displaying cytotoxic activity through different mechanisms of action. The presence of the 6-methoxy substituent on the indole moiety of tryprostatin A was shown to be essential for the dual inhibition of topoisomerase II and tubulin polymerization. However, the inability to perform late-stage modification of the indole ring has limited the structure–activity relationship studies of this class of natural products. Herein, we describe an efficient chemoenzymatic approach for the late-stage modification of tryprostatin B using a cyclic dipeptide N-prenyltransferase (CdpNPT) from Aspergillus fumigatus, which generates novel analogs functionalized with allylic, benzylic, heterocyclic, and diene moieties. Notably, this biocatalytic functionalizational study revealed high selectivity for the indole C6 position. Seven of the 11 structurally characterized analogs were exclusively C6-alkylated, and the remaining four contained predominant C6-regioisomers. Of the 24 accepted substrates, 10 provided >50% conversion and eight provided 20–50% conversion, with the remaining six giving <20% conversion under standard conditions. This study demonstrates that prenyltransferase-based late-stage diversification enables direct access to previously inaccessible natural product analogs.

Dual inhibition of topoisomerase I and tubulin polymerization by BPR0Y007, a novel cytotoxic agent

2003 ◽  
Vol 65 (12) ◽  
pp. 2009-2019 ◽  
Author(s):  
Jang-Yang Chang ◽  
Hsing-Pang Hsieh ◽  
Wen-Yu Pan ◽  
Jing-Ping Liou ◽  
Shian-Jy Bey ◽  
...  
Keyword(s):  
Topoisomerase I ◽  
Cytotoxic Agent ◽  
Tubulin Polymerization ◽  
Dual Inhibition

Benzothienoquinazolinones as new multi-target scaffolds: Dual inhibition of human Topoisomerase I and tubulin polymerization

2019 ◽  
Vol 181 ◽  
pp. 111583 ◽  
Author(s):  
Jessica Ceramella ◽  
Anna Caruso ◽  
Maria Antonietta Occhiuzzi ◽  
Domenico Iacopetta ◽  
Alexia Barbarossa ◽  
...  
Keyword(s):  
Topoisomerase I ◽  
Tubulin Polymerization ◽  
Dual Inhibition

Isoindolo[2,1-a]quinoxaline Derivatives, Novel Potent Antitumor Agents with Dual Inhibition of Tubulin Polymerization and Topoisomerase I

2008 ◽  
Vol 51 (8) ◽  
pp. 2387-2399 ◽  
Author(s):  
Patrizia Diana ◽  
Annamaria Martorana ◽  
Paola Barraja ◽  
Alessandra Montalbano ◽  
Gaetano Dattolo ◽  
...  
Keyword(s):  
Topoisomerase I ◽  
Antitumor Agents ◽  
Tubulin Polymerization ◽  
Quinoxaline Derivatives ◽  
Dual Inhibition

scholarly journals A Novel Cytotoxic Conjugate Derived from the Natural Product Podophyllotoxin as a Direct-Target Protein Dual Inhibitor

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4258
Author(s):  
Ángela-Patricia Hernández ◽  
Paula Díez ◽  
Pablo A. García ◽  
Martín Pérez-Andrés ◽  
Pablo Ortega ◽  
...  
Keyword(s):  
Natural Product ◽  
Single Molecule ◽  
Topoisomerase Ii ◽  
Biological Activities ◽  
Point Of View ◽  
Tubulin Polymerization ◽  
The Novel ◽  
Dual Inhibitor ◽  
Structural Modifications ◽  
Dual Functional

Natural products are the ideal basis for the design of novel efficient molecular entities. Podophyllotoxin, a naturally occurring cyclolignan, is an example of natural product which displays a high versatility from a biological activity point of view. Based on its unique chemical structure, different derivatives have been synthesized presenting the original antitumoral properties associated with the compound, i.e., the tubulin polymerization inhibition and arising anti-topoisomerase II activity from structural modifications on the cyclolignan skeleton. In this report, we present a novel conjugate or hybrid which chemically combines both biological activities in one single molecule. Chemical design has been planned based in our lead compound, podophyllic aldehyde, as an inhibitor of tubulin polymerization, and in etoposide, an approved antitumoral drug targeting topoisomerase II. The cytotoxicity and selectivity of the novel synthetized hybrid has been evaluated in several cell lines of different solid tumors. In addition, these dual functional effects of the novel compound have been also evaluated by molecular docking approaches.

scholarly journals Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells

2021 ◽  
Vol 14 (11) ◽  
pp. 1126
Author(s):  
Joelle C. Boulos ◽  
Mohamed E. M. Saeed ◽  
Manik Chatterjee ◽  
Yagmur Bülbül ◽  
Francesco Crudo ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Cancer Cells ◽  
Cell Lines ◽  
Topoisomerase Ii ◽  
Tubulin Polymerization ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Cell Lung Carcinoma ◽  
Myeloma Cells

Crizotinib was a first generation of ALK tyrosine kinase inhibitor approved for the treatment of ALK-positive non-small-cell lung carcinoma (NSCLC) patients. COMPARE and cluster analyses of transcriptomic data of the NCI cell line panel indicated that genes with different cellular functions regulated the sensitivity or resistance of cancer cells to crizotinib. Transcription factor binding motif analyses in gene promoters divulged two transcription factors possibly regulating the expression of these genes, i.e., RXRA and GATA1, which are important for leukemia and erythroid development, respectively. COMPARE analyses also implied that cell lines of various cancer types displayed varying degrees of sensitivity to crizotinib. Unexpectedly, leukemia but not lung cancer cells were the most sensitive cells among the different types of NCI cancer cell lines. Re-examining this result in another panel of cell lines indeed revealed that crizotinib exhibited potent cytotoxicity towards acute myeloid leukemia and multiple myeloma cells. P-glycoprotein-overexpressing CEM/ADR5000 leukemia cells were cross-resistant to crizotinib. NCI-H929 multiple myeloma cells were the most sensitive cells. Hence, we evaluated the mode of action of crizotinib on these cells. Although crizotinib is a TKI, it showed highest correlation rates with DNA topoisomerase II inhibitors and tubulin inhibitors. The altered gene expression profiles after crizotinib treatment predicted several networks, where TOP2A and genes related to cell cycle were downregulated. Cell cycle analyses showed that cells incubated with crizotinib for 24 h accumulated in the G2M phase. Crizotinib also increased the number of p-H3(Ser10)-positive NCI-H929 cells illustrating crizotinib’s ability to prevent mitotic exit. However, cells accumulated in the sub-G0G1 fraction with longer incubation periods, indicating apoptosis induction. Additionally, crizotinib disassembled the tubulin network of U2OS cells expressing an α-tubulin-GFP fusion protein, preventing migration of cancer cells. This result was verified by in vitro tubulin polymerization assays. In silico molecular docking also revealed a strong binding affinity of crizotinib to the colchicine and Vinca alkaloid binding sites. Taken together, these results demonstrate that crizotinib destabilized microtubules. Additionally, the decatenation assay showed that crizotinib partwise inhibited the catalytic activity of DNA topoisomerase II. In conclusion, crizotinib exerted kinase-independent cytotoxic effects through the dual inhibition of tubulin polymerization and topoisomerase II and might be used to treat not only NSCLC but also multiple myeloma.

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