Synthesis and Biological Evaluation of (2S,2′S)‑Lomaiviticin A

(−)-Lomaiviticin A (1) is a genotoxic C 2-symmetric metabolite that arises from the formal dimerization of two bis­(glycosylated) diazotetrahydrobenzo­[b]­fluorenes. Here we present a synthesis of the monomer 17 and its coupling to form (2S,2′S)-lomaiviticin A (4), an unnatural diastereomer of 1. (2...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2021-01, Vol.143 (2), p.1126-1132
Main Authors: Kaneko, Miho, Li, Zhenwu, Burk, Matthew, Colis, Laureen, Herzon, Seth B
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Cell Proliferation - drug effects
Cell Survival - drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Fluorenes - chemical synthesis
Fluorenes - chemistry
Fluorenes - pharmacology
Humans
K562 Cells
Models, Molecular
Molecular Conformation
Stereoisomerism
Structure-Activity Relationship
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Description
Summary:(−)-Lomaiviticin A (1) is a genotoxic C 2-symmetric metabolite that arises from the formal dimerization of two bis­(glycosylated) diazotetrahydrobenzo­[b]­fluorenes. Here we present a synthesis of the monomer 17 and its coupling to form (2S,2′S)-lomaiviticin A (4), an unnatural diastereomer of 1. (2S,2′S)-Lomaiviticin A (4) is significantly less genotoxic, a result we attribute to changes in the orientation of the diazofluorene and carbohydrate residues, relative to 1. These data bring the importance of the configuration of the conjoining bond to light and place the total synthesis of 1 itself within reach.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.0c11960