Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
J Med Chem. 2012 Sep 27;55(18):8128-36. doi: 10.1021/jm301040s. Epub 2012 Sep 14.
In a continuing study of bevirimat (2), the anti-HIV-maturation clinical trials agent, 28 new betulinic acid (BA, 1) derivatives were designed and synthesized. Among these compounds, 17, with a C-28 MEM ester moiety, and 22, with a C-28 ethyl hexanoate, increased the anti-HIV replication activity compared with 2 by 2-fold while compounds 40, 41, 48, and 49, with C-28 piperazine or piperidine amide substitutions, increased the activity by 3- to 15-fold. The best new compound, 41, exhibited an anti-HIV IC(50) of 0.0059 μM compared with 0.087 μM for 2. All of the active compounds showed only antimaturation effects, as confirmed by TZM-bl assay, in blocking the HIV replication. The results suggest that proper C-28 substitutions can further enhance the antimaturation activity of 2 without any antientry effects. Thus, 41 may serve as a promising new lead for development of anti-AIDS clinical trial candidates.
在对艾滋病毒成熟抑制剂 bevirimat（2）的持续研究中，设计并合成了 28 种新型桦木酸（BA，1）衍生物。这些化合物中，17 位带有 C-28 MEM 酯基，22 位带有 C-28 乙酯，与 2 相比，抗 HIV 复制活性提高了 2 倍，而 40、41、48 和 49 位带有 C-28 哌嗪或哌啶酰胺取代基，活性提高了 3 到 15 倍。最好的新化合物 41 的抗 HIV IC（50）为 0.0059 μM，而 2 的抗 HIV IC（50）为 0.087 μM。所有具有活性的化合物都仅显示出成熟阻断作用，这通过 TZM-bl 试验得到证实，可阻断 HIV 复制。结果表明，适当的 C-28 取代可以进一步提高 2 的成熟阻断活性，而不会产生任何进入抑制作用。因此，41 可能成为开发抗艾滋病临床试验候选药物的有前途的新先导化合物。
