Hejchman E, Haugwitz R D, Cushman M
Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
J Med Chem. 1995 Aug 18;38(17):3407-10. doi: 10.1021/jm00017a025.
The potential therapeutic application of the naturally occurring, cytotoxic pseudoguaianolide sesquiterpene lactone ambrosin is limited by its aqueous insolubility. A number of water-soluble ambrosin derivatives have therefore been prepared for potential use as prodrugs. Michael addition of several secondary amines to both the alpha,beta-unsaturated ketone and alpha-methylene lactone moieties of ambrosin afforded tertiary amine diadducts that were converted to water-soluble hydrochloride salts. The salt of the bis-piperidine adduct proved to be the most potent, producing cytotoxic activity only slightly less potent than that of ambrosin itself in a variety of human cancer cell cultures. The sodium salt of the bis-sulfonic acid derivative of ambrosin was inactive, while the sodium salt of the bis-sulfinic acid analog had low activity. Biological evaluation of several ambrosin analogs with reduced and/or isomerized alpha,beta-unsaturated ketone and alpha-methylene lactone moieties demonstrated the importance of both of these functional groups for biological activity.
天然存在的具有细胞毒性的伪愈创木烷型倍半萜内酯青蒿素的潜在治疗应用受到其水不溶性的限制。因此，人们制备了多种水溶性青蒿素衍生物，以期用作前药。通过将几种仲胺对青蒿素的α,β-不饱和酮和α-亚甲基内酯部分进行迈克尔加成反应，得到叔胺双加合物，并将其转化为水溶性盐酸盐。双哌啶加合物的盐被证明是最有效的，在多种人类癌细胞培养物中产生的细胞毒性活性仅略低于青蒿素本身。青蒿素双磺酸衍生物的钠盐无活性，而双亚磺酸类似物的钠盐活性较低。对几种α,β-不饱和酮和α-亚甲基内酯部分经过还原和/或异构化的青蒿素类似物进行生物学评价，结果表明这两个官能团对生物活性都很重要。
