Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Department of Environmental and Molecular Health Sciences, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
J Am Chem Soc. 2024 Mar 27;146(12):8746-8756. doi: 10.1021/jacs.4c01589. Epub 2024 Mar 14.
Tigliane diterpenoids possess exceptionally complex structures comprising common 5/7/6/3-membered ABCD-rings and disparate oxygen functionalities. While tiglianes display a wide range of biological activities, compounds with HIV latency-reversing activity can eliminate viral reservoirs, thereby serving as promising leads for new anti-HIV agents. Herein, we report collective total syntheses of phorbol () and 11 tiglianes - with various acylation patterns and oxidation states, and their evaluation as HIV latency-reversing agents. The syntheses were strategically divided into five stages to increase the structural complexity. First, our previously established sequence enabled the expeditious preparation of ABC-tricycle in 15 steps. Second, hydroxylation of and ring-contractive D-ring formation furnished phorbol (). Third, site-selective attachment of two acyl groups to produced four phorbol diesters -. Fourth, the oxygen functionalities were regio- and stereoselectively installed to yield five tiglianes -. Fifth, further oxidation to the most densely oxygenated acerifolin A () and tigilanol tiglate () was realized through organizing a 3D shape of the B-ring. Assessment of the HIV latency-reversing activities of the 12 tiglianes revealed seven tiglianes (- and -) with 20- to 300-fold improved efficacy compared with prostratin (), a representative latency-reversing agent. Therefore, the robust synthetic routes to a variety of tiglianes with promising activities devised in this study provide opportunities for advancing HIV eradication strategies.
雷公藤二萜具有异常复杂的结构，包含常见的 5/7/6/3 元 ABCD-环和不同的氧官能团。虽然雷公藤二萜显示出广泛的生物活性，但具有 HIV 潜伏逆转活性的化合物可以消除病毒库，因此作为新型抗 HIV 药物的有前途的先导化合物。在此，我们报告了对佛波醇（）和 11 种雷公藤二萜的集体全合成 - 具有各种酰化模式和氧化态，并对其作为 HIV 潜伏逆转剂进行了评估。合成策略性地分为五个阶段，以增加结构复杂性。首先，我们之前建立的序列使 ABC-三萜 能够快速制备，共 15 步。其次，和的环收缩 D-环形成使佛波醇（）羟化。第三，在 上选择性地连接两个酰基基团产生四种佛波醇二酯 - 。第四，通过组织 B 环的 3D 形状，对氧官能团进行区域和立体选择性的安装，得到了五种雷公藤二萜 - 。第五，通过进一步氧化得到最高度氧合的 acerifolin A () 和 tigilanol tiglate ()。对 12 种雷公藤二萜的 HIV 潜伏逆转活性评估表明，与代表性的潜伏逆转剂 prostratin（）相比，有 7 种雷公藤二萜（- 和 -）的功效提高了 20-300 倍。因此，本研究设计的各种具有潜在活性的雷公藤二萜的稳健合成路线为推进 HIV 根除策略提供了机会。
