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Cited by 70Microbial Natural Products and BiosynthesisSynthesis and Biological ActivityMarine Sponges and Natural Products

Chlorizidine, a Cytotoxic 5 H-Pyrrolo[2,1-a]isoindol-5-one-Containing Alkaloid from a Marine Streptomyces sp.

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Alvarez-Mico, Xavier, Jensen, Paul R., Fenical, William, Hughes, Chambers C.·2013·Organic Letters
DOI 10.1021/ol303374ePMC PMC3702164
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Abstract

Cultivation of an obligate marine Streptomyces strain has provided the cytotoxic natural product chlorizidine A. X-ray crystallographic analysis revealed that the metabolite is composed of a chlorinated 2,3-dihydropyrrolizine ring attached to a chlorinated 5H-pyrrolo[2,1-a]isoindol-5-one. The carbon stereocenter in the dihydropyrrolizine is S-configured. Remarkably, the 5H-pyrrolo[2,1-a]isoindol-5-one moiety has no precedence in the field of natural products. The presence of this ring system, which was demonstrated to undergo facile nucleophilic substitution reactions at the activated carbonyl group, is essential to the molecule's cytotoxicity against HCT-116 human colon cancer cells.

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  • The use of acetic anhydride aided in the discovery of chlorizidine A, a cytotoxic alkaloid obtained from a marine Streptomyces sp.

    “For instance, the use of acetic anhydride aided in the discovery of chlorizidine A, a cytotoxic alkaloid obtained from a marine Streptomyces sp.”

    From Connecting metabolome and phenotype: recent advances in functional metabolomics tools for the identification of bioactive natural products (2024) · cites this paper as [110]

    The paper reports that chlorizidine A is a cytotoxic natural product isolated from a marine Streptomyces strain. In the passage on phenolic functionalization (section labeled Abstract; page unavailable), acetic anhydride is used to make a more stable diacetate from chlorizidine A, not to discover chlorizidine A. The claimed role of acetic anhydride in its discovery is therefore unsupported. (LLM, conf=0.88)

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  • The diacetyl derivative of chlorizidine A has better stability, facilitating convenient isolation.

    “The diacetyl derivative of chlorizidine A has better stability, facilitating convenient isolation.110”

    From Connecting metabolome and phenotype: recent advances in functional metabolomics tools for the identification of bioactive natural products (2024) · cites this paper as [110]

    The passage on phenolic functionalization (page not provided) identifies compound 2 as chlorizidine A diacetate and says it is much less prone to degradation than chlorizidine A. Other passages say that obtaining pure chlorizidine A was difficult, but the paper does not say that the diacetate’s stability made its isolation convenient. (LLM, conf=0.82)

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Cites

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Research works printed but not linked: 3

  1. [7]For the synthesis of 5H-pyrrolo[2, 1-a]isoindol-5-ones, see: Marsili A Scartoni V Morelli I Pierangeli P J Chem Soc, Perkin Trans 1 1977 959 965. Itahara T J Chem Soc Chem Comm 1981 254 255. Maruyama K Kubo Y J Org Chem 1981 46 3612 3622. Crabb TA Patel A Newton RF Price BJ Tucker MJ J Chem Soc, Perkin Trans 1 1982 2783 2786. Danheiser RL Kwasigroch CA Tsai Y-M J Am Chem Soc 1985 107 7233 7235. Grigg R Sridharan V Stevenson P Sukirthalingam S Worakun T Tetrahedron 1990 46 4003 4018. Yavari I Islami MR J Chem Research (S) 1998 166 167. Kaden S Reissig H-U Brüdgam I Hartl H Synthesis 2006 1351 1359. McNab H Tyas RG J Org Chem 2007 72 8760 8769 17949040
  2. [12]The therapeutic properties of other 5H-pyrrolo[2, 1-a]isoindol-5-one-containing compounds have been described. For dihydropyridine-substituted 5H-pyrrolo[2, 1-a]isoindol-5-ones and their use, see: Kuhl A D E Patent 10,034,265 2005. For 5H-pyrrolo[2, 1-a]isoindol-5-ones that function as Cdk4 inhibitors, see: Honma T Hayashi K Aoyama T Hashimoto N Machida T Fukasawa K Iwama T Ikeura C Ikuta M Suzuki-Takahashi I Iwasawa Y Hayama T Nishimura S Morishima H J Med Chem 2001 44 4615 4627 11741479
  3. [13]Brattain MG Fine WD Khaled FM Thompson J Brittain DE Cancer Res 1981 41 1751 1756 7214343

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Authors
Alvarez-Mico, X., Jensen, P. R., Fenical, W., & Hughes, C. C.
Affiliations
  • Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California—San Diego, La Jolla, California 92093-0204, United States
  • Scripps Institution of Oceanography (US)
Corresponding author
Hughes, Chambers C.
ORCID
Venue
Organic Letters
Publisher
American Chemical Society (ACS)
Published
2013-02-13
Volume
15
Issue
5
Pages
988-991
ISSN
  • 1523-7052 (ISSN-L)
  • 1523-7060
DOI
10.1021/ol303374e
PMC
PMC3702164
OpenAlex
W2006232662
Cited by
69
References
42
Citations by year
2026: 2 · 2025: 6 · 2024: 5 · 2023: 5 · 2022: 5 · 2021: 8 · 2020: 4 · 2019: 8 · 2018: 3 · 2017: 5 · 2016: 4 · 2015: 8 · 2014: 2 · 2013: 4
FWCI
4.41
Type
journal article
Language
en
Open access
Locations
  • Organic Letters (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • University of California, San Diego
  • National Cancer Institute (R37CA044848)
Topics
  • Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Synthesis and Biological Activity
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Marine Sponges and Natural Products
Keywords
Streptomyces, marine natural products, cytotoxic alkaloids, crystal structure, nucleophilic substitution, HCT-116 colon cancer cells
MeSH terms
Antineoplastic Agents, Drug Screening Assays, Antitumor, Humans, Marine Biology, Molecular Conformation, Stereoisomerism, Streptomyces, Molecular Structure, Crystallography, X-Ray, Indole Alkaloids, HCT116 Cells

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