Stereodivergent Synthesis of Bispyrrolidinoindoline Alkaloidal Scaffolds and Generation of a Lead Candidate with Stereospecific Antiproliferative Activity

Q4 · BIOLOGY

Article

Author: Oikawa, Hideaki ; Kato, Mitsuyasu ; Suzuki, Hiroyuki ; Oguri, Hiroki ; Tsubouchi, Akira ; Wada, Mitsuhiro

AbstractThe fungal secondary metabolites (+)‐WIN 64821 and (−)‐ditryptophenaline are biosynthesized through condensation of l‐tryptophan and l‐phenylalanine, followed by reductive dimerization with generation of stereochemical variations. Inspired by the stereodivergent biogenetic process, we designed and synthesized a collection of bispyrrolidinoindoline diketopiperazine alkaloids and their analogues with systematic diversification of the stereochemistry of the privileged structural motif of the fungal alkaloids. Not only the stereochemical modifications of (+)‐WIN 64821 at the 3‐/3′‐, 11‐/11′‐, and 15‐/15′‐positions, but also ring cleavage of the diketopiperazine moieties, allowed the generation of a lead compound exhibiting potent growth inhibitory activity (IC50=3.03 μm) toward human colon cancer cells. Structure–activity relationship studies revealed that all six stereogenic centers were essential for the pharmacophore. High cell densities dramatically intensified the cytotoxic activities of the lead compound.

01 Jan 2019·Magnetic Resonance in ChemistryQ3 · CHEMISTRY

A new asymmetric diketopiperazine dimer from the sponge‐associated fungus Aspergillus versicolor 16F‐11

Q3 · CHEMISTRY

Letter

Author: Lin, Hou‐Wen ; Gu, Bin‐Bin ; Jiao, Wei‐hua ; Wang, Shu‐Ping ; Li, Lei ; Su, Zhi‐You ; Yang, Fan ; Sun, Fan ; Gui, Yu‐Han ; Liu, Li

Prior investigation of the fungus Aspergillus versicolor 16F-11 isolated from the marine sponge Phakellia fusca in our group has resulted in the isolation of several new and biol. active natural products.Continuing investigation of the remaining subfractions of its EtOAc extract afforded a new asym. diketopiperazine dimer as perflocin(1 )as well as a known compound WIN 64821 (2).

03 Apr 2018·Natural Product ResearchQ3 · CHEMISTRY

New asymmetrical bispyrrolidinoindoline diketopiperazines from the marine fungus Aspergillus sp. DX4H

Q3 · CHEMISTRY

Article

Author: Wang, Pinmei ; Xu, Jinzhong ; Di, Yanan ; Ding, Wanjing ; Hu, Qian

Known diketopiperazine WIN 64821 and its asymmetric stereoisomers (1-3) had been isolated from the culture broth of a marine gut fungus Aspergillus sp. DX4H. The planar and stereochemistry for new compounds were determined by a suite of techniques including mass, NMR and CD spectra together with Marfey's method. Their inhibitory activity against PC3 cell line had been tested.

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Discovery	US	Sterling Winthrop Products, Inc.	-
Inflammatory Bowel Diseases	Discovery	US	Sterling Winthrop Products, Inc.	-
Rheumatoid Arthritis	Discovery	US	Sterling Winthrop Products, Inc.	-

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