The solubility of compound is one of the important factors for determining the success of the agent during drug development. We have previously reported a series of water-soluble N-mustards-benzamide conjugates having hydrophilic side-chain at the meta- or para-position of the carboxamide group via a urea spacer. Of these derivatives, BO-1055 HCl exhibits a broad spectrum of antitumor activity and potent therapeutic efficacy against various human solid tumor xenografts. Recently, we have synthesized a series of novel water soluble N-mustard-benzene conjugates prepared by linking phenyl N-mustard pharmacophore with benzene moiety through urea linker. The benzene ring bears a variety of ?-N,N-dialkylaminoalkylamide or ?-cyclicaminoalkylamide side-chains located to the meta- or para-position of the urea linker. The tertiary amino function on the side-chain can be converted into a variety of water-soluble salts with various acids. The newly synthesized derivatives were subject to evaluate their antitumor activities both in vitro and in tumor xenograft model. The results showed that these conjugates exhibit a broad spectrum of antitumor activity against variety of human leukemia and solid tumor cell growth in culture. Among these derivatives, BO-2094  was selected for further antitumor evaluation. The results revealed that this agent exhibited potent antitumor activity several human tumor xenografts in animal model. Studies on the mechanism of action revealed that BO-2094  is able to induce DNA cross-linking and arrest cell cycle at G2/M phase. The present studies suggest that BO-2094  is a promising candidate for preclinical antitumor studies.

Novel water soluble N-mustard-benzene conjugates with potent antitumor activity, synthesis, and biological activity

246th National Meeting (2013)

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