Abstract 2534: Novel and stable water-soluble N-mustards with potent therapeutic efficacy against human tumor xenografts in nude mice

Abstract The bioavailability of drugs is one of the important factors to determine whether a drug can be successfully developed for clinical application. Consequently, the physicochemical properties, including solubility, permeability, stability pKa, and lipophilicity/hydrophilicity balance, are key factors that influence the bioavailability of drugs. Compounds with poor solubility usually have a higher risk of difficulties to overcome during the period of new drug discovery and development because these properties may affect antitumor evaluations in animal models as well as pharmacokinetic and pharmacodynamic properties of the compound. In the present studies, we have synthesized a series of novel water-soluble N-mustard-benzene conjugates bearing a urea linker were synthesized. The benzene moiety contains a variety of hydrophilic side chains. These side chains are linked to the meta- or para-position of the urea linker via a carboxamide or an ether linkage. Compounds having a carboxamide hydrophilic side-chain can be converted into water-soluble hydrochloride or mesylate. The preliminary antitumor studies revealed that these conjugates exhibited potent cytotoxicity in vitro and antitumor therapeutic efficacy against human tumor xenografts in vivo. Furthermore, these derivatives have little or no cross-resistance to either Taxol or Vinblastine. Among these conjugates, compound WS-1707, which bearing a N,N-dimethylaminoethylcarboxamide hydrochloride water-soluble side-chain possessed potent therapeutic efficacy in nude mice bearing human breast carcinoma MX-1 (Remarkably, complete tumor remission in nude mice bearing human breast carcinoma MX-1 xenograft (complete tumor remission), prostate adenocarcinoma PC-3 xenograft (>99% suppression), and human colon cancer HCT-116 xenograft (>95% suppression) at the maximal tolerable dose 30 mg/kg, Q2D×5, intravenous injection. We also compared the therapeutic potency of WS-1707 with Carbopltin, and Doxetaxol in nude mice bearing prostate cancer HL2 xenograft (orthotopic implantation). It reveals that WS-1707 is as potent as Doxetaxol (>82% tumor suppression), but significantly more potent than Carboplatin. Study on the mechanism of action that this agent is able to induce DNA cross-linking through alkaline agarose gel shift assay. Early pharmacokinetic study shows that this conjugates has acceptable profile in rats with a half-life of 0.56 h. These results suggest that this agent is a promising candidate for preclinical studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2534. doi:10.1158/1538-7445.AM2011-2534