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Identification and Synthesis of DDI-6, a Quinolinol Analog Capable of Activating Both Caenorhabditis elegans and Mouse Spermatozoa
Chemical & Pharmaceutical Bulletin ( IF 1.5 ) Pub Date : 2021-06-01 , DOI: 10.1248/cpb.c21-00127
Yukiko Karuo 1 , Riona Shiraki 2 , Ayaka Yoshida 2 , Ryo Tsunokawa 1 , Mayuko Nakahara-Yamada 2 , Atsushi Tarui 1 , Kazuyuki Sato 1 , Kentaro Kawai 1 , Masaaki Omote 1 , Hitoshi Nishimura 2
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Sperm activation is an essential process by which the male gametes become capable of fertilization. Because the process in Caenorhabditis elegans is readily reproducible in vitro, this organism serves as an excellent model to investigate it. C. elegans sperm activation in vivo occurs during spermiogenesis. Membranous organelles (MOs) contained within spermatids fuse with the plasma membrane, resulting in extracellular release of their contents and relocation of some proteins indispensable for fertilization from the MO membrane onto the sperm surface. Intriguingly, these cytological alternations are exhibited similarly in mouse spermatozoa during the acrosome reaction, which also represents a form of sperm activation, prompting us to hypothesize that C. elegans and mice share a common mechanism for sperm activation. To explore this, we first screened a chemical library to identify compounds that activate C. elegans spermatozoa. Because a quinolinol analog named DDI-6 seemed to be a candidate sperm activator, we synthesized it to use for further analyses. This involved direct dechlorination and hydrogenolysis of commercially available 5-chloro-8-quinolinol, both of which are key steps to yield 1,2,3,4-tetrahydro-8-quinolinol, and we subsequently introduced the sulfonamide group to the compound. When C. elegans spermatids were stimulated with solvent alone or the newly synthesized DDI-6, approx. 3% and approx. 28% of spermatids became MO-fused spermatozoa, respectively. Moreover, DDI-6 triggered the acrosome reaction in approx. 20% of mouse spermatozoa, while approx. 12% became acrosome-reacted after mock stimulation. Thus, DDI-6 serves as a moderately effective activator for both C. elegans and mouse spermatozoa.

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中文翻译:

DDI-6 的鉴定和合成,一种能够激活秀丽隐杆线虫和小鼠精子的喹啉类似物

精子激活是雄配子能够受精的重要过程。由于秀丽隐杆线虫的过程在体外很容易重现,因此该生物体可作为研究它的极好模型。C. 线虫体内精子激活发生在精子发生过程中。包含在精子细胞内的膜细胞器 (MO) 与质膜融合,导致其内容物的细胞外释放和一些对受精必不可少的蛋白质从 MO 膜重新定位到精子表面。有趣的是,这些细胞学变化在顶体反应期间在小鼠精子中表现出类似的表现,这也代表了精子激活的一种形式,促使我们假设秀丽隐杆线虫和小鼠共享一个共同的精子激活机制。为了探索这一点,我们首先筛选了一个化学库来识别激活秀丽隐杆线虫的化合物精子。因为一种名为 DDI-6 的喹啉类似物似乎是一种候选精子激活剂,我们合成了它以用于进一步分析。这涉及市售的 5-氯-8-羟基喹啉的直接脱氯和氢解,这两个步骤都是产生 1,2,3,4-四氢-8-羟基喹啉的关键步骤,我们随后将磺酰胺基团引入到该化合物中。当线虫精子细胞单独用溶剂或新合成的 DDI-6 刺激时,大约。3% 和大约 分别有 28% 的精子细胞变成了 MO 融合的精子。此外,DDI-6 触发了顶体反应。小鼠精子的 20%,而大约。12% 在模拟刺激后发生顶体反应。因此,DDI-6 可作为两种秀丽隐杆线虫的中等有效激活剂 和小鼠精子。

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更新日期:2021-05-31
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