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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.
Highlights
Reduce the toxicity of the lead compound[6]
The phenyl ring of the compounds was located at the α/β interface of tubulin
Analysis of the docking studies revealed that the trimethoxyphenyl (TMP) group of 4β-S-(6-mercaptopurine-yl)sulfanyl-4-deoxy-podophyllotoxin (4-MP-PTOX), 4β-S-(6-thioguanine-yl)sulfanyl-4-deoxy-podophyllotoxin (4-TG-PTOX), and colchicine could bind via hydrophobic interactions with the β-unit of tubulin at residues Gln 472 and Thr 353, respectively
Summary
We utilized a tubulin stathmin-like domain complex (Brookhaven Protein Data Bank; PDB code 1SA110) as the target structure in molecular docking. These results indicate that 4-TG-PTOX causes a complete depolymerization of the microtubule cytoskeleton This is in line with previous reports that PTOX with the para-position methoxyl group (4′ -MeO) is a mitotic spindle agent that inhibits the polymerization of tubulin and stops cell division at the G2/M phase[13]. They were approximately 1.7 times and 2 times higher than that of colchicines (6.42 ± 1.03 μM) and approximately 1.3 times and 1.6 times higher than that of nocodazole (8.51 ± 1.73 μM), respectively These results indicate that the substitution of the sulfur-containing heterocyclic compounds with a 4β-configuration at position 4 of PTOX is a very useful modification, resulting in enhanced anti-tumor activity and reduced toxic side-effects. We show that the two resultant compounds, 4-MP-PTOX and 4-TG-PTOX, greatly improve the therapeutic effect for microtubule damage in cancer cells by inhibiting tubulin polymerization, arresting mitosis, and inducing apoptosis. This study is a key step in the ongoing effort to develop better anti-tubulin compounds with enhanced anti-tumor capacities
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