Drugs that target DNA topoisomerase II isoforms and alkylate DNA represent two mechanistically distinct and clinically important classes of anticancer drugs. Guided by molecular modeling and docking a series of etoposide analog epipodophyllotoxin-N-mustard hybrid compounds were designed, synthesized and biologically characterized. These hybrids were designed to alkylate nucleophilic protein residues on topoisomerase II and thus produce inactive covalent adducts and to also alkylate DNA. The most potent hybrid had a mean GI(50) in the NCI-60 cell screen 17-fold lower than etoposide. Using a variety of in vitro and cell-based assays all of the hybrids tested were shown to target topoisomerase II. A COMPARE analysis indicated that the hybrids had NCI 60-cell growth inhibition profiles matching both etoposide and the N-mustard compounds from which they were derived. These results supported the conclusion that the hybrids displayed characteristics that were consistent with having targeted both topoisomerase II and DNA.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254203 | PMC |
| http://dx.doi.org/10.1016/j.bmc.2014.09.014 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Insights into podophyllotoxin lactone features: New cyclolignans as potential dual tubulin-topoisomerase II inhibitors.
Arch Pharm (Weinheim)
November 2024
Department of Medicine and General Cytometry Service-Nucleus, CIBERONC CB16/12/00400, Cancer Research Centre (IBMCC/CSIC/USAL/IBSAL), IBSAL, Campus Miguel de Unamuno, Universidad de Salamanca-CSIC, Salamanca, Spain.
Chemomodulation of natural cyclolignans as podophyllotoxin has been a successful approach to obtain semisynthetic bioactive derivates. One example of this approach is the FDA-approved drug etoposide for solid and hematological tumors. It differs from the antimitotic activity of the natural product in its mechanism of action, this drug being a topoisomerase II inhibitor instead of a tubulin antimitotic.
View Article and Find Full Text PDFMetastatic insulinoma-outcomes in the current era.
Oncologist
October 2024
Department of Medicine, University of California, San Francisco, CA 94143, United States.
Article Synopsis
- Multimodal treatments for metastatic insulinoma have shown improved survival rates, with some patients living significantly longer than the previously reported median of 2 years.* -
- A study of 14 patients from 2006 to 2023 revealed that 7 patients survived between 1.2 to 12.3 years post-diagnosis, and their hypoglycemia was effectively managed.* -
- The results suggest that combining various treatment methods can lead to better clinical outcomes, challenging earlier beliefs about the prognosis of patients with metastatic insulinoma.*
ALKBH5 regulates etoposide-induced cellular senescence and osteogenic differentiation in osteoporosis through mediating the mA modification of VDAC3.
Sci Rep
October 2024
Department of Hand Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710000, Shaanxi, China.
Osteoporosis, a common bone disease in older individuals, involves the progression influenced by N6-methyladenosine (m6A) modification. This study aimed to elucidate the effects of VDAC3 m6A modification on human bone mesenchymal stromal cell (BMSC) senescence and osteogenic differentiation. BMSCs were treated with etoposide to induce senescence.
View Article and Find Full Text PDFLow to intermediate grade lung neuroendocrine tumours. A single centre real world experience.
Cancer Treat Res Commun
December 2024
University of Ottawa Division of Medical Oncology, Ottawa, Ontario, Canada; The Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada; The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Article Synopsis
- - Lung neuroendocrine tumors (LNETs) are rare and increasingly diagnosed tumors, and this study examines their diagnosis, treatment, and survival trends among patients with low to intermediate grades.
- - A review of 59 patients revealed that surgical treatment led to significantly better five-year overall survival (83%) compared to non-surgical options (44%), although metastatic disease had a poor prognosis (39% survival for stage IV).
- - The study emphasizes that while there are multiple treatment options, the lack of established guidelines for treatment sequencing indicates a need for improved evidence-based practices in managing LNETs.
C-4 analogues of podophyllotoxin as tubulin inhibitors: synthesis, biological evaluation, and structure-activity relationship.
Nat Prod Res
October 2024
Department of Chemistry, Biochemistry & Physics, Aspiring Scholars Directed Research Program (ASDRP), Fremont, CA, USA.
The diversity of lignan small molecules derived from podophyllotoxin, a non-covalent tubulin inhibitor isolated from the Podophyllum family, has led to the clinical development of FDA-approved anticancer agents etoposide and teniposide. While these two compounds share the same tetracyclic core as podophyllotoxin, two subtle structural changes-4' demethylation on the aromatic ring and stereospecific glycosylation at the C-4 hydroxyl-result in an alternate biological mechanism. Given the immense pharmacological importance of altering the C-4 position, we synthesised and evaluated a systematic library of diversified esters to establish a structure-activity relationship regarding modification at C-4 on the properties of podophyllotoxin.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!