D609-A novel cytoprotectant & selective antitumor agent

D609-一种新型细胞保护剂

• 批准号: 7034494
• 负责人: DAOHONG ZHOU
• 金额: $ 25.16万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7034494
• 关键词: B cell lymphoma; antineoplastics; biomarker; ceramides; cytoprotection; cytotoxicity; drug design /synthesis /production; drug screening /evaluation; enzyme activity; fibrosarcoma; high performance liquid chromatography; hydrolysis; ionizing radiation; laboratory mouse; molecular site; neoplasm /cancer chemotherapy; neoplastic growth; nonhuman therapy evaluation; nuclear magnetic resonance spectroscopy; pharmacokinetics; prodrugs; radiation protection; radioprotective agents; reversed phase chromatography; sphingomyelin phosphodiesterase; B cell lymphoma; antineoplastics; biomarker; ceramides; cytoprotection; cytotoxicity; drug design /synthesis /production; drug screening /evaluation; enzyme activity; fibrosarcoma; high performance liquid chromatography; hydrolysis; ionizing radiation; laboratory mouse; molecular site; neoplasm /cancer chemotherapy; neoplastic growth; nonhuman therapy evaluation; nuclear magnetic resonance spectroscopy; pharmacokinetics; prodrugs; radiation protection; radioprotective agents; reversed phase chromatography; sphingomyelin phosphodiesterase

DESCRIPTION (provided by applicant): Tricyclodecan-9-yl-xanthogenate (D609) was originally developed as an antitumor and antiviral agent. Recently, we have discovered that D609 is a novel and potent antioxidant and cytoprotectant that has the ability to protect mice from ionizing radiation (IR)-induced lethality. Similar to the other known nucleophilic sulfur antioxidants, D609 has a -SH group presented as a xanthate (-C [=S] S-/-C [=S] SH) moiety that scavenges free radicals in a manner similar to that of the sulfhydryl (-SH) moiety of glutathione (GSH) and WR1065 (the active compound of amifostine). However, unlike all other known nucleophilic sulfur antioxidants, D609 is unique because it is also a selective tumor cytotoxic agent, possibly by inhibition of sphingomyelin synthase (SMS). Inhibition of SMS by D609 increases the intracellular level of ceramide and decreases that of diacylglycerol (DAG) thus favoring the induction of cell cycle arrest, senescence, and apoptosis in tumor cells in a cell type dependent manner. The xanthate group of D609 appears to be part of the SMS inhibitory pharmacophore, since blocking this group by S-alkylation abolishes that activity. However, this moiety is oxidatively unstable and is thought to undergo facile oxidation in biological systems, contributing to the poor antitumor activity of D609 observed in vivo. We hypothesize that S-modification of D609 through a metabolically labile linkage (alkoxyphosphoryl or alkoxylacyl) will protect the pharmacophore (-C [=S] SH) and lead to prodrugs with increased oxidative stability, improved pharmacokinetics and enhanced therapeutic efficacy. To test this hypothesis, we will pursue the following specific aims: 1). To rationally design, synthesize and select lead D609 prodrugs with optimal oxidative stability, appropriate hydrolytic properties and superior pharmacokinetics for in vivo therapeutic evaluation; 2). To assess the therapeutic efficacy of select D609 prodrugs for radiation protection and for tumor therapy with or without IR in a mouse model. We believe that D609 prodrugs have the potential to be developed as a unique double agent for cancer therapy. When used as an adjuvant with IR and/or chemotherapy, D609 prodrugs may provide dual therapeutic benefits against cancer, e.g. protection of normal tissues and enhanced tumor cell killing.

描述（由申请人提供）：三环-9-基-Xanthogenate（D609）最初是作为抗肿瘤和抗病毒剂开发的。 最近，我们发现D609是一种新型且有效的抗氧化剂和细胞保护剂，具有保护小鼠免受电离辐射（IR）诱导的致死性的能力。与其他已知的亲核硫抗氧化剂相似，D609具有一个-SH组为Xanthate（-c [= S] S - / - C [= S] SH）部分，该部分以类似于硫酸（-sh）glutathione（-sh）的（gsh）和wrif的方式（-sh）和wers1065（Amf）（-sh）的一部分。然而，与所有其他已知的亲核硫抗氧化剂不同，D609是独一无二的，因为它也是一种选择性肿瘤细胞毒性剂，可能是通过抑制鞘磷脂合酶（SMS）的抑制。 D609对SMS的抑制会增加神经酰胺的细胞内水平，并降低二酰基甘油（DAG）的细胞内水平，从而有利于以细胞类型的方式诱导细胞周期停滞，衰老和肿瘤细胞中的凋亡。 D609的黄盐组似乎是SMS抑制性药效团的一部分，因为通过S-烷基化阻止了该组的活性。 但是，该部分在氧化上是不稳定的，并且被认为在生物系统中会容易氧化，这有助于在体内观察到的D609的抗肿瘤活性不良。我们假设通过代谢不稳定的连锁（烷氧基磷酸或烷氧基酰基）对D609进行S型验证将保护药理（-c [= S] SH），并导致氧化稳定性增加，改善药代动力学和增强的药物治疗效率的前药。为了检验这一假设，我们将追求以下特定目标：1）。合理设计，合成和选择具有最佳氧化稳定性，适当的水解特性和优质药代动力学的铅D609前药，用于体内治疗评估； 2）。评估精选D609前药的治疗疗效，用于辐射保护和小鼠模型中有或没有IR的肿瘤治疗。我们认为，D609前药有可能作为癌症治疗的独特双重药物开发。当用作IR和/或化学疗法的辅助药物时，D609前药可能会为癌症提供双重治疗益处，例如保护正常组织和增强的肿瘤细胞杀伤。