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Planta Med 2022; 88(08): 678-684
DOI: 10.1055/a-1530-1128
Biological and Pharmacological Activity
Original Papers

Two New Cytotoxic Maytansinoids Targeting Tubulin from Trewia nudiflora

Chun Lei
1   School of Pharmacy, Fudan University, Shanghai, China
,
Ya-Nan Li
1   School of Pharmacy, Fudan University, Shanghai, China
,
Jia-Nan Li
2   National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
4   University of Chinese Academy of Sciences, Beijing, China
5   School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
,
Yu-Bo Zhou
2   National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
4   University of Chinese Academy of Sciences, Beijing, China
5   School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
,
Ming-Jun Cui
3   Puer Institute of Traditional Ethnomedicine, Yunnan, China
,
Kai-Cong Fu
3   Puer Institute of Traditional Ethnomedicine, Yunnan, China
,
Jia Li
2   National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
4   University of Chinese Academy of Sciences, Beijing, China
5   School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
,
Ai-Jun Hou
1   School of Pharmacy, Fudan University, Shanghai, China
› Author AffiliationsSupported by: Shanghai Commission of Science and Technology 19495800800
Supported by: National Natural Science Foundation of China 21672040
Supported by: National Natural Science Foundation of China 82073717
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Abstract

Two new maytansinoids, N-methyltreflorine (1) and methyltrewiasine (2), were isolated from the dried fruits of Trewia nudiflora, together with three known congeners (3 – 5). Their structures were elucidated by spectroscopic methods, and the absolute configuration of 1 and 2 was determined by X-ray crystallographic analysis. Compounds 1 – 5 exhibited strong cytotoxicity against human tumor cell lines, including HeLa, MV-4 – 11, and MCF-7, with IC50 values ranging from 0.12 to 11 nM. Compounds 1 and 4 also showed inhibitory activity against the MCF-7/ADR cell line with IC50 values of 13 and 28 nM, respectively. Compounds 1 and 2 significantly inhibited tubulin polymerization in vitro with IC50 values of 3.6 and 3.2 µM, respectively.

Key words

Trewia nudiflora - Euphorbiaceae - maytansinoids - cytotoxicity - tubulin polymerization

Supporting Information

    Detailed X-ray crystallographic data, IR, HRESIMS, and NMR spectra of 1 and 2, and the cytotoxicity and tubulin polymerization data are available as Supporting Information.

  • Supporting Information


Publication History

Received: 21 February 2021

Accepted after revision: 02 June 2021

Article published online:
29 October 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 Kirschning A, Harmrolfs K, Knobloch T. The chemistry and biology of the maytansinoid antitumor agents. C R Chimie 2008; 11: 1523-1543
    CrossrefPubMedSearch in Google Scholar
  • 2 Oroudjev E, Lopus M, Wilson L, Audette C, Provenzano C, Erickson H, Kovtun Y, Chari R, Jordan MA. Maytansinoid-antibody conjugates induce mitotic arrest by suppressing microtubule dynamic instability. Mol Cancer Ther 2010; 9: 2700-2713
    CrossrefPubMedSearch in Google Scholar
  • 3 Kupchan SM, Komoda Y, Court WA, Thomas GJ, Smith RM, Karim A, Gilmore CJ, Haltiwanger RC, Bryan RF. Maytansine, a novel antileukemic ansa macrolide from Maytenus ovatus . J Am Chem Soc 1972; 94: 1354-1356
    CrossrefPubMedSearch in Google Scholar
  • 4 Taplin S, Vashisht K, Walles M, Calise D, Kluwe W, Bouchard P, Johnson R. Hepatotoxicity with antibody maytansinoid conjugates: A review of preclinical and clinical findings. J Appl Toxicol 2018; 38: 600-615
    CrossrefPubMedSearch in Google Scholar
  • 5 Lambert JM, Chari RVJ. Ado-trastuzumab emtansine (T-DM1): an antibody-drug conjugate (ADC) for HER2-positive breast cancer. J Med Chem 2014; 57: 6949-6964
    CrossrefPubMedSearch in Google Scholar
  • 6 Qiu H, Gilbert MG. Flora of China. Beijing: Science Press; 2008: 224
    Search in Google Scholar
  • 7 Powell RG, Weisleder D, Smith CR. Novel maytansinoid tumor inhibitors from Trewia nudiflora: trewiasine, dehydrotrewiasine, and demethyltrewiasine. J Org Chem 1981; 46: 4398-4403
    CrossrefPubMedSearch in Google Scholar
  • 8 Powell RG, Weisleder D, Smith CR, Kozlowski JJ, Rohwedder WK. Treflorine, trenudine, and N-methyltrenudone: novel maytansinoid tumor inhibitors containing two fused macrocyclic rings. J Am Chem Soc 1982; 104: 4929-4934
    CrossrefPubMedSearch in Google Scholar
  • 9 Powell RG, Smith CR, Plattner JRD, Jones BE. Additional new maytansinoids from Trewia nudiflora: 10-epitrewiasine and nortrewiasine. J Nat Prod 1983; 46: 660-666
    CrossrefPubMedSearch in Google Scholar
  • 10 Li BJ, Wang C, Xu XK, Yue XF, Sheng ZM, Han JX, Lu LJ, Xu CH, Yang WY. Maytansinoids from the seeds of Trewia nudiflora . Acta Botanica Yunnanica 1991; 13: 432-439
    PubMedSearch in Google Scholar
  • 11 Wani MC, Taylor HL, Wall ME. Plant antitumour agents: colubrinol acetate and colubrinol, antileukaemic ansa macrolides from Colubrina texensis . J C S Chem Comm 1973; 13: 390
    CrossrefPubMedSearch in Google Scholar
  • 12 Guo Y, Wang Y, Li H, Wang K, Wan Q, Li J, Zhou Y, Chen Y. Novel nitric oxide donors of phenylsulfonylfuroxan and 3-benzyl coumarin derivatives as potent antitumor agents. ACS Med Chem Lett 2018; 9: 502-506
    CrossrefPubMedSearch in Google Scholar