Stephacidin A and its congeners are a collection of secondary metabolites that possess intriguing structural motifs. They stem from unusual biosynthetic sequences that lead to the incorporation of a prenyl or reverse-prenyl group into a bicyclo[2.2.2]diazaoctane framework, a chromene unit or the vestige thereof. To complement biosynthetic studies, which normally play a significant role in unveiling the biosynthetic pathways of natural products, here we demonstrate that chemical synthesis can provide important insights into biosynthesis. We identify a short total synthesis of congeners in the reverse-prenylated indole alkaloid family related to stephacidin A by taking advantage of a direct indole C6 halogenation of the related ketopremalbrancheamide. This novel strategic approach has now made possible the syntheses of several natural products, including malbrancheamides B and C, notoamides F, I and R, aspergamide B, and waikialoid A, which is a heterodimer of avrainvillamide and aspergamide B. Our approach to the preparation of these prenylated and reverse-prenylated indole alkaloids is bioinspired, and may also inform the as-yet undetermined biosynthesis of several congeners.
Lysophosphatidic
acid (LPA) is a bioactive lipid mediator that
elicits a number of biological functions, including smooth muscle
contraction, cell motility, proliferation, and morphological change.
LPA is endogenously produced by autotaxin (ATX) from extracellular
lysophosphatidylcholine (LPC) in plasma. Herein, we report our medicinal
chemistry effort to identify a novel and highly potent ATX inhibitor,
ONO-8430506 (20), with good oral availability. To enhance
the enzymatic ATX inhibitory activity, we designed several compounds
by structurally comparing our hit compound with the endogenous ligand
LPC. Further optimization to improve the pharmacokinetic profile and
enhance the ATX inhibitory activity in human plasma resulted in the
identification of ONO-8430506 (20), which enhanced the
antitumor effect of paclitaxel in a breast cancer model.
Arcutinidine and other arcutinidine-type diterpenoid alkaloids feature an intricate polycyclic, bridged framework with unusual connectivity. A chemical network analysis approach to the arcutane skeleton enabled the identification of highly simplifying retrosynthetic disconnections, which indicated that the caged structure could arise from a simpler fused ring system. On this basis, a total synthesis of arcutinidine is reported herein, featuring an unprecedented oxopyrrolium Diels− Alder cycloaddition which furnishes a key tetracyclic intermediate. In addition, the synthesis utilizes a diastereoselective oxidative dearomatization/cycloaddition sequence and a SmI 2 -mediated C−C coupling to forge the bridged framework of the natural products. This synthetic plan may also enable future investigations into the biosynthetic relationships between the arcutanes, the related diterpenoid atropurpuran, and other diterpenoid alkaloids.Communication pubs.acs.org/JACS
A concise synthesis of APDOEGCg (3) was accomplished. Due to the reactivity of its amine group, the compound could be easily converted to the fluorescein probe 21 and immunogen probe 22 efficiently. We then demonstrated the usefulness of the probes for imaging studies and the generation of antibodies.
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