Abstract 4475: New water-soluble and stable N-mustard-benzeneconjugates with potent antitumor activity, BO-2094, generated via leadoptimization by bioisostere approach.

Abstract

Abstract The water solubility of drug candidate plays an important determinant of the bioavailability and supports whether a drug candidate can be successfully developed for clinical application. Previously, we have synthesized a series of water-soluble N-mustards, in which the phenyl N-mustard pharmacophore is linked to a benzamide moiety containing a hydrophilic side-chain at the meta- or para-position of the carboxamide function via a urea spacer. Of these derivatives, the water-soluble BO-1055 HCl exhibits a broad spectrum of antitumor activity and potent therapeutic efficacy against various human solid tumor (such as breast MX-1, colon HCT-116, and prostate PC-3) xenografts. To optimize the antitumor activity of BO-1055 via structural modification by bioisostere approach, we synthesized a series of new N-mustard-benzene conjugates, in which the phenyl N-mustard pharmacophore is linked to a benzene moiety via a urea linker, which can reduce the reactivity of the reactive N-mustard moiety. The benzene ring contains a variety of ω-N,N-dialkylaminoalkylamide or ω-cyclicaminoalkylamide side-chains at the meta- or para-position of the ureido linker. The tertiary amino function on the side-chain can be converted into a variety of water-soluble salts with inorganic or organic acids. The newly synthesized conjugates were subject to antitumor studies both in vitro and in tumor xenograft model. The results showed that these water-soluble conjugates exhibit a broad spectrum of antitumor activity against a panel of human leukemia and solid tumor cell growth in culture. Among these derivatives, BO-2094 [N-(4-(3-(4-(bis(2-chloroethyl)amino)phenyl)ureido)phenyl)-2-(diethylamino)acetamide], was revealed to be more cytotoxic than BO-1055 in inhibiting various tumor cell growth in vitro. It also showed that this agent is more potent than BO-1055 against human colon HCT-116, prostate PC3, and lung cancer H460 xenografts in mice. Studies on the mechanism of action revealed that BO-2094 is able to induce DNA cross-linking and cell arrest at G2/M phase. The present investigations conclude that BO-2094, a new water-soluble N-mustard-benzene conjugated with more potent therapeutic effect than BO-1055, has high potential to be selected as a candidate for preclinical antitumor studies. Citation Format: Tsann-Long Su, Satishkumar Tala, Tai-Hsin Ou, Kiranben Tala, Rajesh Kakadiya, Yi-wen Lin, Chi-Wei Chen, Te-Chang Lee. New water-soluble and stable N-mustard-benzeneconjugates with potent antitumor activity, BO-2094, generated via leadoptimization by bioisostere approach. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4475. doi:10.1158/1538-7445.AM2013-4475