Skip to main content
SpringerLink
Log in

Design, synthesis and bioactivity evaluation of novel monomethyl auristatin F analogues

  • Original Article
  • Published:
Molecular Diversity Aims and scope Submit manuscript

Abstract

Monomethyl auristatin F (MMAF), a synthetic analogue of the natural compound dolastatin 10, has garnered significant attention in cancer research due to its high potency in vitro. While previous studies have focused on modifying the N-terminal extension of the amino group and the C-terminal modification of the carboxyl group, there has been limited exploration into modifying the P1 and P5 side chains. In this study, we substituted the valine residue at the P1 position with various natural or unnatural amino acids and introduced triazole functional groups at the P5 side chain. Compounds 11k and 18d exhibited excellent inhibition on tubulin. Additionally, compound 18d demonstrated enhanced cytotoxicity against HCT116 cells compared to the parent compound MMAF, suggesting its potential as a cytotoxic payload for further antibody–drug conjugates (ADCs) development.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Scheme 1
Scheme 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Jin Y, Schladetsch MA, Huang X et al (2021) Stepping forward in antibody-drug conjugate development. Pharmacol Ther 229:107917. https://doi.org/10.1016/j.pharmthera.2021.107917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Abdolvahab MH, Karimi P, Mohajeri N et al (2024) Targeted drug delivery using nanobodies to deliver effective molecules to breast cancer cells: the most attractive application of nanobodies. Cancer Cell Int 24:67. https://doi.org/10.1186/s12935-024-03259-8

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sun T, Niu X, He Q et al (2023) Development, efficacy and side effects of antibody-drug conjugates for cancer therapy (Review). Mol Clin Oncol 18:47. https://doi.org/10.3892/mco.2023.2643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wang Z, Li H, Gou L et al (2023) Antibody–drug conjugates: recent advances in payloads. Acta Pharm Sin B 13:4025. https://doi.org/10.1016/j.apsb.2023.06.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wainberg ZA, Hochster HS, Kim EJ et al (2020) Open-label, phase I study of nivolumab combined with nab-paclitaxel plus gemcitabine in advanced pancreatic cancer. Clin Cancer Res 26:4814. https://doi.org/10.1158/1078-0432.CCR-20-0099

    Article  CAS  PubMed  Google Scholar 

  6. Philip PA, Lacy J, Portales F et al (2020) Nab-paclitaxel plus gemcitabine in patients with locally advanced pancreatic cancer (LAPACT): a multicentre, open-label phase 2 study. Lancet Gastroenterol Hepatol 3:285. https://doi.org/10.1016/s2468-1253(19)30327-9

    Article  Google Scholar 

  7. Ko AH, Truong T-G, Kantoff E et al (2012) A phase I trial of nab-paclitaxel, gemcitabine, and capecitabine for metastatic pancreatic cancer. Cancer Chemother Pharmacol 70:875. https://doi.org/10.1007/s00280-012-1979-7

    Article  CAS  PubMed  Google Scholar 

  8. Zhang D, Benedikt Westphalen C, Quante M et al (2024) Gemcitabine and nab-paclitaxel combined with afatinib in metastatic pancreatic cancer—results of a phase 1b clinical trial. Eur J Cancer 201:113926. https://doi.org/10.1016/j.ejca.2024.113926

    Article  CAS  PubMed  Google Scholar 

  9. Rittmeyer A, Barlesi F, Waterkamp DA et al (2017) Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389:255. https://doi.org/10.1016/s0140-6736(16)32517-x

    Article  PubMed  Google Scholar 

  10. Herbst RS, Baas P, Kim D-W et al (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387:1540. https://doi.org/10.1016/s0140-6736(15)01281-7

    Article  CAS  PubMed  Google Scholar 

  11. Borghaei H, Paz-Ares LG, Horn L et al (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373:1627. https://doi.org/10.1056/nejmoa1507643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Qu Y, Safonova OV, De Luca V (2018) Completion of the canonical pathway for assembly of anticancer drugs vincristine/vinblastine in Catharanthus roseus. Plant J 97:257. https://doi.org/10.1111/tpj.14111

    Article  CAS  PubMed  Google Scholar 

  13. Geisler SM, Doan RA, Cheng GC et al (2019) Vincristine and bortezomib use distinct upstream mechanisms to activate a common SARM1-dependent axon degeneration program. JCI insight 4:129920. https://doi.org/10.1172/jci.insight.129920

    Article  PubMed  Google Scholar 

  14. Škubník J, Pavlíčková VS, Ruml T et al (2021) Vincristine in combination therapy of cancer: emerging trends in clinics. Biology 10:849. https://doi.org/10.3390/biology10090849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bai R, Petit GR, Hamel E (1941) Dolastatin 10, a powerful cytostatic peptide derived from a marine animal: inhibition of tubulin polymerization mediated through the vinca alkaloid binding domain. Biochem Pharmacol 1990:39. https://doi.org/10.1016/0006-2952(90)90613-p

    Article  Google Scholar 

  16. Pettit GR, Kamano Y, Herald CL et al (1987) The isolation and structure of a remarkable marine animal antineoplastic constituent: dolastatin 10. J Am Chem Soc 109:6883. https://doi.org/10.1021/ja00256a070

    Article  CAS  Google Scholar 

  17. Hamel E (1992) Natural products which interact with tubulin in the vinca domain: maytansine, rhizoxin, phomopsin a, dolastatins 10 and 15 and halichondrin B. Pharmacol Ther 55:31. https://doi.org/10.1016/0163-7258(92)90028-x

    Article  CAS  PubMed  Google Scholar 

  18. Lonial S, Lee HC, Badros A et al (2020) Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol 21:207. https://doi.org/10.1016/S1470-2045(19)30788-0

    Article  CAS  PubMed  Google Scholar 

  19. Markham A (2020) Belantamab Mafodotin: first approval. Drugs 80:1607. https://doi.org/10.1007/s40265-020-01404-x

    Article  CAS  PubMed  Google Scholar 

  20. Chang HL, Schwettmann B, McArthur HL et al (2023) Antibody-drug conjugates in breast cancer: overcoming resistance and boosting immune response. J Clin Investig 133:172156. https://doi.org/10.1172/jci172156

    Article  CAS  Google Scholar 

  21. Yamazaki CM, Yamaguchi A, Anami Y et al (2020) Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance. Nat Commun 12:3528. https://doi.org/10.1038/s41467-021-23793-7

    Article  CAS  Google Scholar 

  22. Abelman RO, Wu B, Spring LM et al (2023) Mechanisms of resistance to antibody-drug conjugates. Cancers 24:9674. https://doi.org/10.3390/ijms24119674

    Article  CAS  Google Scholar 

  23. Tsuchikama K, Anami Y, Ha SYY et al (2024) Exploring the next generation of antibody-drug conjugates. Nat Rev Clin Oncol 21:203. https://doi.org/10.1038/s41571-023-00850-2

    Article  CAS  PubMed  Google Scholar 

  24. Mendelsohn BA et al (2017) Investigation of hydrophilic auristatin derivatives for use in antibody drug conjugates. Bioconjug Chem 28:371. https://doi.org/10.1021/acs.bioconjchem.6b00530

    Article  CAS  PubMed  Google Scholar 

  25. Yan Q, Wang Y, Zhang W, Li Y (2016) Novel azetidine-containing TZT-1027 analogues as antitumor agents. Mar Drugs 14:85. https://doi.org/10.3390/md14050085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dugal-Tessier J, Barnscher SD, Kanai A, Mendelsohn BA (2017) Synthesis and evaluation of dolastatin 10 analogues containing heteroatoms on the amino acid side chains. J Nat Prod 80:2484. https://doi.org/10.1021/acs.jnatprod.7b00359

    Article  CAS  PubMed  Google Scholar 

  27. Doronina SO et al (2006) Enhanced activity of monomethylauristatin F through monoclonal antibody delivery: effects of linker technology on efficacy and toxicity. Bioconjug Chem 17:114–124. https://doi.org/10.1021/bc0502917

    Article  CAS  PubMed  Google Scholar 

  28. Moquist PN et al (2024) Abstract 4476: Novel auristatins with improved tolerability and unique bystander activity profile. Can Res 84:4476–4476. https://doi.org/10.1158/1538-7445.AM2024-4476

    Article  Google Scholar 

  29. Komarova Y, Waight AB, Bargsten K et al (2016) Structural basis of microtubule destabilization by potent auristatin anti-mitotics. PLoS ONE 11:160890. https://doi.org/10.1371/journal.pone.0160890

    Article  CAS  Google Scholar 

  30. Maderna A, Doroski M, Subramanyam C et al (2014) Discovery of cytotoxic dolastatin 10 analogues with N-terminal modifications. J Med Chem 57:10527. https://doi.org/10.1021/jm501649k

    Article  CAS  PubMed  Google Scholar 

  31. Tomioka K, Kanai M, Koga K (1991) An expeditious synthesis of dolastatin 10. Tetrahedron Lett 32:2395. https://doi.org/10.1186/s12934-018-1036-2

    Article  CAS  Google Scholar 

  32. Shioiri T, Hayashi K, Hamada Y (1913) Stereoselective synthesis of dolastatin 10 and its congeners. Tetrahedron 1993:49. https://doi.org/10.1016/S0040-4020(01)80547-0

    Article  Google Scholar 

  33. Zhou W, Nie X-D, Zhang Y et al (2017) A practical approach to asymmetric synthesis of dolastatin 10. Org Biomol Chem 15:6119. https://doi.org/10.1039/C7OB01395G

    Article  CAS  PubMed  Google Scholar 

  34. Mordant C, Reymond S, Tone H et al (2007) Total synthesis of dolastatin 10 through ruthenium-catalyzed asymmetric hydrogenations. Tetrahedron 63:6115. https://doi.org/10.1016/j.tet.2007.03.036

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Support for this research from the National Natural Science Foundation of China (92056201), the National Key Research and Development Program of China (2023YFC3404500), Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery (2023B1212060022), Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai) (SML2003SP236), Natural Science Foundation of Guangdong Province (2023A1515011486) and Key-Area Research and Development Program of Guangdong Province (2022B1111050003) is greatly acknowledged.

Author information

Authors and Affiliations

  1. State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China

    Lisheng Yang, Xinglin Li, Lei Zhao, Wenhao Hu & Yu Qian

Authors
  1. Lisheng Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xinglin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lei Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wenhao Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yu Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LSY and LZ performed experiments on synthesis, LSY analyzed the data and performed cell viability evaluation of the target compounds, XLL carried out experiments on Tubulin polymerization assay, WHH and YQ designed the study, supervised the study and revised the manuscript.

Corresponding authors

Correspondence to Wenhao Hu or Yu Qian.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 3832 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, L., Li, X., Zhao, L. et al. Design, synthesis and bioactivity evaluation of novel monomethyl auristatin F analogues. Mol Divers (2024). https://doi.org/10.1007/s11030-024-10873-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11030-024-10873-1

Keywords

Search

Navigation