Synthesis and SQAR of DNA-Cleaving Propargylic Sulfones

设计并合成了一类新的丙基砜，它们被激活后对特定的dna碱基序列具有烷基化反应活性，从而导致dna链断裂。通过2年的共同研究，得出以下结论：(1)京都大学首席研究员或研究员分别于1996年2次、1997年3次访问香港科技大学，研究丙炔砜类化合物的分子设计与合成，以及包括天然产物在内的dna切割化合物的构效关系。(2)每年一次邀请香港科技大学研究员对丙炔砜活化机制具有抗肿瘤活性和细胞毒性的研究动态进行调研。(3)合成了45种顺式烯二炔型丙炔砜、单丙炔砜和双丙炔砜，定量测定了它们在DNA切割和细胞毒性方面的构效关系。1,5-二炔化合物通过烯丙基双键重排生成顺式烯二炔结构。(4)对于一系列丙炔砜类化合物，其DNA切割活性与插入DNA双链的能力相关，表明单丙炔砜类化合物比双丙炔砜类化合物更容易导致DNA双链断裂。虽然萘和蒽基团是DNA插入的有效功能，但除非活性异位砜基团位于DNA碱基烷基化的正确位置，否则无法实现有效的DNA切割。(5)水溶液中丙炔砜与鸟嘌呤的模型反应表明，原位形成的活性异位酮部分使鸟嘌呤的N7位烷基化，随后核糖水解释放，与鸟嘌呤形成加合物。这一反应途径解释了丙炔砜的dna切割活性。少

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