These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: Tubulin structure-based drug design for the development of novel 4β-sulfur-substituted podophyllum tubulin inhibitors with anti-tumor activity.
    Author: Zhao W, Bai JK, Li HM, Chen T, Tang YJ.
    Journal: Sci Rep; 2015 May 11; 5():10172. PubMed ID: 25959922.
    Abstract:
    The well-characterized anti-tubulin agent, podophyllotoxin (PTOX), with the 4'-position methoxyl group, targets the colchicines domain located between α- and β-tubulin. Two guanosine triphosphate (GTP) analogs of the tubulin-binding region were synthesized from PTOX, where a hydroxyl group was substituted with a carbon-sulfur bond. These compounds, 4-MP-PTOX and 4-TG-PTOX, reduce the dosage and greatly improve the therapeutic effect for microtubule damage in cancer cells. Here we characterize the anti-tubulin properties of these compounds. We found the stronger inhibition of tubulin polymerization (the concentration of 50% growth inhibition, GI50<2 μM) for compounds 4-TG-PTOX and 4-MP-PTOX, which were better than that of PTOX or colchicine. The cytotoxicity of two designed compounds on tumor cells was also significantly enhanced by comparing to those of PTOX and colchicines. The ΔH value of 4-MP-PTOX and 4-TG-PTOX binding to tubulin by isothermal titration calorimetry (ITC) was found to be -7.4 and -5.3 kcal·mol(-1), respectively. The wide range of enthalpy values across the series may reflect entropy/enthalpy compensation effects. Fragments 6-mercaptopurine (MP) and 6-thioguanine (TG) likely enhance the affinity of 4-MP-PTOX and 4-TG-PTOX binding to tubulin by increasing the number of binding sites. The correctness of rational drug design was strictly demonstrated by a bioactivity test.
    [Abstract] [Full Text] [Related] [New Search]