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  • br Conclusions These results demonstrate that N nitrosation

    2020-07-31


    Conclusions These results demonstrate that N-nitrosation of BMAA results in an alkylating agent that damages DNA in vitro, generating single strand breaks, and is toxic to neuroblastoma cells. Our results suggest a novel INK 128 in which in situ nitrosation of BMAA, and potentially other amines, likely catalysed by the microbiome leads to the formation of a variety of alkylating agents that may contribute to the aetiology of ALS and other neurodegenerative diseases.
    Conflict of interest
    Author’s contributions
    Acknowledgement
    Introduction DNA-alkylating agents were the first chemotherapeutic drugs developed for the treatment of cancer [1]. Although the classic, highly reactive DNA-alkylating agents (e.g., melphalan, chlorambucil, and platinum-based agents) are potent chemotherapeutic agents, they have limited clinical benefits mainly because of their toxicity, which results in severe adverse side effects [2]. The toxicity associated with DNA-alkylating agents highlights the need to develop anticancer agents with greater selectivity. To overcome the drawbacks of alkylating agents, which lack intrinsic DNA-binding affinity and thus are genotoxic and carcinogenic [3], DNA-directed alkylating agents with increased DNA-binding selectivity were designed to avoid “off-target” effects on cellular components and hence reduce adverse side effects [4]. Accordingly, we and many other scientists have previously synthesized a series of DNA-directed alkylating agents by coupling various DNA-affinic carriers (a DNA-intercalating agent or a DNA minor groove binder) that directly target DNA with the N-mustard pharmacophore [5], [6], [7], [8], [9], [10]. These DNA-directed alkylating agents were shown to have increased chemical stability and improved anticancer activity. Based on structural-activity relationship studies, selecting the appropriate DNA-affinic carrier and the spacer, which links to the alkylating warhead, is critical for improving the antitumor activity of DNA-directed alkylating agents [11], [12] In 1991, Denny and coworkers first synthesized N-mustard-quinoline conjugates that exerted potent cytotoxicity by forming DNA cross-links and bulky monoadducts [4]. Additionally, N-mustard-quinoline derivatives were found to overcome the poor solubility and low DNA-binding selectivity of some DNA intercalators, such as acridine mustard conjugates [9]. To improve the antitumor activity and increase the chemical stability of DNA-affinic N-mustards, we previously designed and synthesized a series of conjugates by coupling the N-mustard residue to quinoline moieties via a urea or hydrazinecarboxamide linker [13]. We found that these N-mustard-quinoline conjugates were chemically stable in serum and possessed strong growth inhibitory activity against human lymphoblastic leukemia and a panel of solid tumor cell lines [13]. These compounds also displayed limited systemic toxicity in animals. Among them, we noted that compound 18c, redesignated SL-1 (Figure 1A), was the most potent suppressor of the growth of breast carcinoma MX-1 xenografts, even achieving complete tumor remission [13]. These results indicate that SL-1 is a potential lead and warrants further investigation.