Synthesis and Biological Evaluation of Novel Millepachine Derivatives As a New Class of Tubulin Polymerization Inhibitors

Abstract

Twenty-one novel derivatives of millepachine were synthesized and evaluated for their in vitro antiproliferative activity. Among them, 8 exhibited the most potent activity, with IC50 values of 8-27 nM against panel of cancer cell lines and retained full activity in multidrug resistant cancer cells. Treated cells were arrested in G2/M phase and resulted in cellular apoptosis. Microtubule dynamics confirmed 8 was a novel tubulin polymerization inhibitor by binding at the colchicine site. 8 also exhibited antivascular activity because it concentration dependently reduced the cell migration and disrupted capillary like tube formation in HUVEC cells. Furthermore, the hydrochloride salt of 8 (8·HCl) significantly improved the bioavailability up to 47% while retaining the antiproliferative activity. Importantly, 8·HCl significantly inhibited tumor growths in four xenograft models including resistance tumor-cell-bearing mice models without causing significant loss of body weight, suggesting that 8 is a promising new orally anticancer agent to be developed.

Chalcone: A Privileged Structure in Medicinal Chemistry

“…Several studies using microtubule dynamics and competitive assays have provided support that this compound inhibits tubulin polymerization by binding at the colchicine site. 293–295 In addition to simple chalcones, chalcones with fused structures ( 71 – 73 , 76 ) have also exhibited antimicrotubule and cytotoxicity effects. Bu et al synthesized a novel o -aryl chalcone ( 74 ) by the Suzuki–Claisen–Schmidt reaction.…”

Characterization of in vitro primary metabolic profile of SKLB-M8, a novel antitumor compound, using liquid chromatography coupled with triple quadrupole tandem mass spectrometry and quadrupole time-of-flight tandem mass spectrometry

“…1) showed the most promising antitumor activity in four xenografts models including resistance tumor-cell bearing mice models [2,3]. Meanwhile, microtubule dynamics also confirmed that SKLB-M8 was a novel tubulin de-polymerization agent by binding at the colchicine site and exhibited excellent anti-vascular activity [3]. To comprehensively evaluate the mechanisms of its antitumor activity, further metabolic research on SKLB-M8 was necessary.…”

“…Among these analogs, (E)-3-(3-amino-4-methoxyphenyl)-1-(5-methoxy-2,2-dimethyl-2H-chromen-8-yl)prop-2-en-1-one hydrochloride (SKLB-M8) (Fig. 1) showed the most promising antitumor activity in four xenografts models including resistance tumor-cell bearing mice models [2,3]. Meanwhile, microtubule dynamics also confirmed that SKLB-M8 was a novel tubulin de-polymerization agent by binding at the colchicine site and exhibited excellent anti-vascular activity [3].…”

Synthesis, biological evaluation and mechanism study of chalcone analogues as novel anti-cancer agents

“…14 Some chalcon derivatives also exhibited potent activity as microtubule polymerization inhibitor. 17 Indanones and their derivatives are important bioactive molecules that have been studied to determine their biological activities for the treatment of disease including Alzheimer' s disease 18 and cancer. 15 Bu reported the synthesis and evaluation of a series of cytotoxic ortho-aryl chalcones as new scaffold targeting tubulin and mitosis.…”