Abstract 3517: Complete remission of xenograft tumor in nude mice induced by N-mustard-quinoline conjugates bearing hydrazinecarboxamide linker

Abstract

Abstract Designing DNA-directed alkylating agents is a promising strategy to overcome the drawbacks of alkylating agents by enhancing DNA specific cross-linking and reducing the chemical reactivity of N-mustard. These compounds are generally synthesized by linking the alkylating warhead (such as alkyl or phenyl N-mustard pharmacophore) to the DNA-affinic carrier (such as DNA intercalating or groove binding agents). Recently, we reported that N-mustard-9-anilinoacridine conjugates via a urea, carbamate, or carbonate linker exhibited potent cytotoxicity and therapeutic efficacy against various human tumor xenografts indicating that these linkers are able to stabilize the reactive alkylating war head. Thus, these derivatives have a long half-life in plasma. Some of these conjugates are able to induce complete tumor remission (CR) in inhibiting human tumor xenograft model with low toxicity. To continue our research in finding potent DNA-directed alkylating agents, we have recently synthesized a series of N-mustard-quinoline conjugates bearing a hydrazinecarboxamide linker. These conjugates were prepared in good yield by the condensation of appropriate 4-hydrazinoquinolines with 4-bis(2-chloroethyl)- aminophenyl isocynate. The results showed that these conjugates possessed significant cytotoxicity against human lymphoblastic leukemia (CCRF-CEM) and various solid tumor xenografts (such as MX-1, HCT-116, H1299, CL 1-0, CL 1-5, PC3 and MCF-7) cell growth in vitro. Among these agents, BO-1392 and BO-1393 were able to induce CR against human breast carcinoma MX-1 xenograft and significantly suppress against human ovarian SK-OV3 xenograft in animal model with relative low toxicity. Interestingly, we found that BO-1393 (iv. injection) can significantly prolong the life span of nude mice bearing human glioma SK-NA-S xenograft (orthotropic implanted in brain). The experiment was compared with Temozolomide (oral administration). The modified comet assay and alkaline agarose gel shift assay showed that these conjugates are capable of inducing DNA interstrand cross-linking in human non-small lung cancer H1299 cells. In conclusion, the present studies demonstrated that the newly synthesized N-mustard-quinoline conjugates having a hydrazinecarboxamide linker exhibited a broad spectrum of antitumor activity and are chemically stable. The remarkable therapeutic efficacy of BO-1393 demonstrated that this agent has high potential for clinical development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3517.