Synthesis and SQAR of DNA-Cleaving Propargylic Sulfones

DNA 切割炔丙砜的合成和 SQAR

• 批准号: 08044141
• 负责人: NISHIMOTO Sei-ichi
• 金额: $ 1.79万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08044141/
• 关键词: DNA Cleavage; Propargylic Sulfones; Anti-tumor Compounds; Prodrug; Intercalation; Molecular Recognization; Cytotoxicity; Structure-Activity Relationship

New class of propargylic sulfones, that are activated to possess alkylating reactivity toward a specific DNA-base sequence and thereby result in DNA-strand breaks, were designed and synthesized. The following results were obtained through the joint research for 2 years.(1) The head investigator or the investigator of Kyoto University visited the Hong Kong University of Science and Technology, 2 times in 1996 and 3 times in 1997, investigating the molecular design and synthesis of propargylic sulfone compounds, and the structure-reactivity relationship of DNA-cleaving compounds including natural products.(2) The investigator of the Hong Kong University of Science and Technology was invited once every year to investigate the research trends on the mechanism by which propargylic sulfones are activated to possess anti-tumor activity and cytotoxicity.(3) 45 kinds of cis-enediyne type propargylic sulfones, mono-propargylic sulfones and bis-propargylic sulfones were synthesized to quantify th … More e structure-activity relationship on DNA cleavage and cytotoxicity. 1,5-Diyne compounds were identified to generate cis-enediyne structure by rearrangement of an allylic double bond.(4) For a series of propargylic sulfone compounds, the DNA-cleaving activity was correlated to the intercalating ability to DNA double strand, indicating a trend that mono-propargylic sulfones cause DNA double-strand breaks more readily than bis-analogs. While napthalene and anthracene moieties are efficient function for DNA intercalation, effective DNA cleavage can not be achieved unless the active allenic sulfone moiety is located at the right sites for DNA base alkylation.(5) A model reaction of propargylic sulfone with guanosine in aqueous solution demonstrated that the active allenic slufone moiety formed in situ alkylates the N7 position of guanosine, followed by hydrolytic release of ribose to give an adduct with guanine. This reaction pathway accounts for the DNA-cleaving activity of propargylic sulfones. Less

设计并合成了一类新的炔丙基砜，它们被活化以具有对特定DNA碱基序列的烷基化反应性，从而导致DNA链断裂。通过两年的共同研究，取得了以下成果。(1)京都大学的首席研究员或研究员于1996年2次和1997年3次访问香港科技大学，研究炔丙基砜化合物的分子设计和合成，以及包括天然产物在内的DNA裂解化合物的结构-反应性关系。(2)香港科技大学的研究员每年获邀一次，就炔丙基砜被活化而具有抗肿瘤活性及细胞毒性的机制的研究趋势进行调查。(3)合成了45种顺烯二炔型炔丙基砜、单炔丙基砜和双炔丙基砜， ...更多信息 e对DNA切割和细胞毒性的构效关系。1，5-二炔类化合物通过烯丙基双键重排生成顺式烯二炔结构。(4)一系列炔丙基砜类化合物的DNA切割活性与插入DNA双链的能力相关，表明单炔丙基砜类化合物比双炔丙基砜类化合物更容易引起DNA双链断裂。虽然萘和蒽部分是DNA嵌入的有效功能，但除非活性丙二烯砜部分位于DNA碱基烷基化的正确位点，否则不能实现有效的DNA切割。(5)炔丙基砜与鸟苷在水溶液中的模型反应表明，在原位形成的活性丙二烯砜部分烷基化鸟苷的N7位，然后水解释放核糖，得到与鸟嘌呤的加合物。该反应途径解释了炔丙基砜的DNA裂解活性。少

项目成果

戴 偉民: "First Synthesis of cis-Enediynes from 1,5-Diynes by Rearrangement of an Allylic Double Bond." Tetrahedron Letters. 37. 8413-8416 (1996)

戴伟民：“通过烯丙基双键重排首次从 1,5-二炔合成顺式烯二炔。” 37. 8413-8416 (1996)

西本清一: "Hydroxyl Radical-Induced Cross-Linking of Thymine and Lysine : Identification of the Orimary Structure and Mechanism" Bioorganic & Medicinal Chemistry Letter. 8. 印刷中 (1998)

Seiichi Nishimoto：“羟基自由基诱导的胸腺嘧啶和赖氨酸交联：原始结构和机制的鉴定”《生物有机与药物化学通讯》8。出版中（1998 年）。

戴 偉民: "Remarkable Tethering Effect on DNA Cleavage of Propargylic Sulfone Conjugates with Intercalating Moieties" Bioorganic & Medicinal Chemistry Letter. 8・2. 169-174 (1998)

戴伟民：“具有嵌入部分的丙炔砜缀合物对 DNA 裂解的显着束缚效应”《生物有机与药物化学通讯》169-174。

Dai, W.-M. ; Fong, K.C. ; Danjo, H. ; Nishimoto, S.: "Synthesis of cis-Enediynes from 1,5-Diynes by Rearrangement of an Allylic Double Bond" Angew.Chem.Int.Ed.Engl.35(7). 779-781 (1996)

戴，W.-M。

戴偉民: "DNA Cleavage of Novel Propargylic Sulfones.Enhancement of Potency via Intercalating Interaction" Bioorganic & Medicinal Chemistry Letters. 6・10. 1093-1098 (1996)

戴伟民：“新型丙炔磺酮的 DNA 裂解。通过插入相互作用增强效力”《生物有机与药物化学快报》6・10（1996 年）。