Synthesis of Novel 3,19-Dihydroxyjolkinolides and Related Derivatives Starting from Andrographolide

Abstract

The jolkinolides are a series of naturally occurring ent-abietane diterpenes with potent antitumor activity, which have been isolated from the genus Euphorbia. We describe the first method for the total synthesis of 3,19-dihydroxyjolkinolide and its derivatives. The strategy for the synthesis of 3,19-dihydroxyjolkinolide A has 12 steps with an overall yield of 4.3%. The synthesized compounds were evaluated for their antitumor activity in nine kinds of tumor cell lines.

19-(Benzyloxy)-19-oxojolkinolide B (19-BJB), an ent-abietane diterpene diepoxide, inhibits the growth of bladder cancer T24 cells through DNA damage

“…Recently, our research group reported a protocol for synthesizing jolkinolide A and jolkinolide B [21]. We also reported the first synthesis of jolkinolide derivatives [22,23]. 19-(Benzyloxy)-19-oxojolkinolide B , one of derivatives we synthesized, showed potential inhibitory effect in different kinds of cancer cell lines.…”

“…After jolkinolide derivatives synthesized, comparative molecular field analysis (CoMFA) was employed to establish the 3D-QSAR model to further explain the structure-activity relationships (SAR) of jolkinolide derivatives. For the evaluation of functional groups introduced into the ring A of jolkinolide, we evaluated the 33 derivatives we had synthesized to analyze the impact on the design of jolkinolide derivatives [22,23]. The structures of 33 jolkinolide derivatives were displayed in the S1 Fig.…”

“…Additionally, the 3D-QSAR models of jolkinolides were established and the bulky groups on C-19 of ring A maybe the key moiet of DNA damage. All of the compounds described above are shown in Fig 1 [11,[18][19][20][21][22][23].…”

Asymmetric syntheses of ent-pimarane diterpenoids

“…The second cyclization is mediated by ent -pimaradiene synthase OsKSL5, which yields ent -pimaradiene that is further diversified into various ent -pimarane diterpenes. 6 Although several elegant protocols have been established to prepare pimarane diterpenoids 7 and their structurally similar natural products, 8–10 the total synthesis of ent -pimarane diterpenoids remains far less explored. In 2022, Magauer et al .…”