Pagani Alberto, Gaeta Simone, Savchenko Andrei I, Williams Craig M, Appendino Giovanni
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy.
School of Chemistry and Molecular Biosciences, University of Queensland, 4072, Brisbane, Australia.
Beilstein J Org Chem. 2017 Jul 11;13:1361-1367. doi: 10.3762/bjoc.13.133. eCollection 2017.
Croton oil is the only commercial source of the diterpenoid phorbol (), the starting material for the semi-synthesis of various diesters extensively used in biomedical research to investigate cell function and to evaluate in vivo anti-inflammatory activity. While efficient chemoselective esterification protocols have been developed for phorbol, its isolation from croton oil is technically complicated, and involves extensive manipulation of very toxic materials like the oil or its native diterpenoid fraction. The preparation of a crude non-irritant phorboid mixture from croton oil was telescoped to only five operational steps, and phorbol could then be purified by gravity column chromatography and crystallization. Evidence is provided that two distinct phorboid chemotypes of croton oil exist, differing in the relative proportion of type-A and type-B esters and showing different stability to deacylation. The isolation of phorbol from croton oil is dangerous because of the toxic properties of the oil, poorly reproducible because of differences in its phorboid profile, and time-consuming because of the capricious final crystallization step. A solution for these issues is provided, suggesting that the poor-reproducibility of croton oil-based anti-inflammatory assays are the result of poor quality and/or inconsistent composition of croton oil.
巴豆油是二萜类佛波醇（）的唯一商业来源，是广泛用于生物医学研究以研究细胞功能和评估体内抗炎活性的各种二酯半合成的起始原料。虽然已经开发出了用于佛波醇的高效化学选择性酯化方案，但其从巴豆油中的分离在技术上很复杂，并且涉及对像巴豆油或其天然二萜馏分这样的剧毒物质进行大量操作。从巴豆油制备粗制的无刺激性佛波醇混合物被简化为仅五个操作步骤，然后可以通过重力柱色谱法和结晶法纯化佛波醇。有证据表明存在两种不同化学类型的巴豆油佛波醇，其A 型和B 型酯的相对比例不同，并且对脱酰作用表现出不同的稳定性。由于巴豆油的毒性，从巴豆油中分离佛波醇很危险；由于其佛波醇谱的差异，重现性差；并且由于最终结晶步骤变幻莫测，耗时很长。针对这些问题提供了一种解决方案，表明基于巴豆油的抗炎试验重现性差是巴豆油质量差和/或成分不一致的结果。
