Ombrabulin Hydrochloride

A new series of CA4P analogs (5a-g, 6a-g) has been designed and effectively synthesized via a one-pot reaction from Combretastatin A-4/Erianin, com. available amino acid esters and Ph dichlorophosphate.To establish new candidates with anticancer activity, the in vitro antiproliferative effect of these compounds was measured by the CCK8 method on different cancer cell lines such as human liver carcinoma (HepG2), cervical cancer (HeLa) and colorectal carcinoma (HCT-116).The structure-activity relationships between CA4P outgrowth-promoting activity and its analogs suggested that the biaryl structure linked with double bond in Part A and the steric effect at the position α-carbon atom in the amino acid ester moiety (Part B) are essential for affecting the in vitro proliferation inhibitory activity of CA4P analogs.Addnl., the results of biol. activity and mol. docking simulation showed that the vast majority of these novel Phosphoramidate derivatives exhibited potent anti-cancer activities. [graphic not available: see fulltext].

Tumor-specific prodrug treatment renders the exclusive delivery of antitumor agents with the lowest untoward effects. In this work, we reported the synthesis and biological assessment of four NQO1-activatable combretastatin A-4 prodrugs constituted by active drug CA-4, different self-immolating linkers, and NQO1-responsive trigger groups. The in vitro antiproliferative activities showed that prodrug 4 displayed greater selective toxicity toward the tumor cells that overexpressed NQO1, taxol-resistant A549 cells, hypoxia-exposed A549 and HepG2 cells, and incurred lower damage to normal cells in comparison with combretastatin A-4, prodrugs 1, 2, and 3. Moreover, based on a mechanistic study, NQO1 triggered prodrug 4 to effectively liberate the parent drug combretastatin A-4 and kill tumor cells. Furthermore, we also demonstrated that prodrug 4 exerted a stronger anticancer effect and greater safety than combretastatin A-4 under in vivo conditions. Hence, from the above results, NQO1 can be used as a specific delivery system for releasing anticancer agents; besides, prodrug 4 can serve as a candidate lead for developing specific anticancer agents.