Expeditious Total Synthesis of Hemiasterlin Through a Convergent Multicomponent Strategy and Its Use in Targeted Cancer Therapeutics

Overview

Journal Angew Chem Int Ed Engl

Specialty Chemistry

Date 2020 Sep 7

PMID 32894646

Citations 6

Authors

Jiraborrirak Charoenpattarapreeda

Stephen J Walsh

Jason S Carroll

David R Spring

Affiliations

Soon will be listed here.

Abstract

Hemiasterlin is an antimitotic marine natural product with reported sub-nanomolar potency against several cancer cell lines. Herein, we describe an expeditious total synthesis of hemiasterlin featuring a four-component Ugi reaction (Ugi-4CR) as the key step. The convergent synthetic strategy enabled rapid access to taltobulin (HTI-286), a similarly potent synthetic analogue. This short synthetic sequence enabled investigation of both hemiasterlin and taltobulin as cytotoxic payloads in antibody-drug conjugates (ADCs). These novel ADCs displayed sub-nanomolar cytotoxicity against HER2-expressing cancer cells, while showing no activity against antigen-negative cells. This study demonstrates an improved synthetic route to a highly valuable natural product, facilitating further investigation of hemiasterlin and its analogues as potential payloads in targeted therapeutics.

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References

Abdollahpour-Alitappeh M, Lotfinia M, Gharibi T, Mardaneh J, Farhadihosseinabadi B, Larki P . Antibody-drug conjugates (ADCs) for cancer therapy: Strategies, challenges, and successes. J Cell Physiol. 2018; 234(5):5628-5642. DOI: 10.1002/jcp.27419. View

Toure B, Hall D . Natural product synthesis using multicomponent reaction strategies. Chem Rev. 2009; 109(9):4439-86. DOI: 10.1021/cr800296p. View

Ogitani Y, Aida T, Hagihara K, Yamaguchi J, Ishii C, Harada N . DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1. Clin Cancer Res. 2016; 22(20):5097-5108. DOI: 10.1158/1078-0432.CCR-15-2822. View

Kaplon H, Muralidharan M, Schneider Z, Reichert J . Antibodies to watch in 2020. MAbs. 2019; 12(1):1703531. PMC: 6973335. DOI: 10.1080/19420862.2019.1703531. View

Poruchynsky M, Kim J, Nogales E, Annable T, Loganzo F, Greenberger L . Tumor cells resistant to a microtubule-depolymerizing hemiasterlin analogue, HTI-286, have mutations in alpha- or beta-tubulin and increased microtubule stability. Biochemistry. 2004; 43(44):13944-54. DOI: 10.1021/bi049300+. View

Shaabani S, Domling A . The Catalytic Enantioselective Ugi Four-Component Reactions. Angew Chem Int Ed Engl. 2018; 57(50):16266-16268. PMC: 6346735. DOI: 10.1002/anie.201811129. View

Lang J, Jones P, Lindel T . Total Synthesis of the Marine Natural Product Hemiasterlin by Organocatalyzed α-Hydrazination. Chemistry. 2017; 23(52):12714-12717. DOI: 10.1002/chem.201702812. View

Bargh J, Walsh S, Isidro-Llobet A, Omarjee S, Carroll J, Spring D . Sulfatase-cleavable linkers for antibody-drug conjugates. Chem Sci. 2021; 11(9):2375-2380. PMC: 8157321. DOI: 10.1039/c9sc06410a. View

Lambert J, Chari R . Ado-trastuzumab Emtansine (T-DM1): an antibody-drug conjugate (ADC) for HER2-positive breast cancer. J Med Chem. 2014; 57(16):6949-64. DOI: 10.1021/jm500766w. View

10.

Wang Y, Benz F, Wu Y, Wang Q, Chen Y, Chen X . Structural Insights into the Pharmacophore of Vinca Domain Inhibitors of Microtubules. Mol Pharmacol. 2015; 89(2):233-42. DOI: 10.1124/mol.115.100149. View

11.

Zask A, Birnberg G, Cheung K, Kaplan J, Niu C, Norton E . Synthesis and biological activity of analogues of the antimicrotubule agent N,beta,beta-trimethyl-L-phenylalanyl-N(1)-[(1S,2E)-3-carboxy-1-isopropylbut-2-enyl]- N(1),3-dimethyl-L-valinamide (HTI-286). J Med Chem. 2004; 47(19):4774-86. DOI: 10.1021/jm040056u. View

12.

Gamble W, Durso N, Fuller R, Westergaard C, Johnson T, Sackett D . Cytotoxic and tubulin-interactive hemiasterlins from Auletta sp. and Siphonochalina spp. sponges. Bioorg Med Chem. 1999; 7(8):1611-5. DOI: 10.1016/s0968-0896(99)00089-9. View

13.

Ravi M, Zask A, Rush 3rd T . Structure-based identification of the binding site for the hemiasterlin analogue HTI-286 on tubulin. Biochemistry. 2005; 44(48):15871-9. DOI: 10.1021/bi051268b. View

14.

Beck A, Goetsch L, Dumontet C, Corvaia N . Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017; 16(5):315-337. DOI: 10.1038/nrd.2016.268. View

15.

Vishwanatha T, Giepmans B, Goda S, Domling A . Tubulysin Synthesis Featuring Stereoselective Catalysis and Highly Convergent Multicomponent Assembly. Org Lett. 2020; 22(14):5396-5400. PMC: 7372561. DOI: 10.1021/acs.orglett.0c01718. View

16.

Walsh S, Omarjee S, Galloway W, Kwan T, Sore H, Parker J . A general approach for the site-selective modification of native proteins, enabling the generation of stable and functional antibody-drug conjugates. Chem Sci. 2019; 10(3):694-700. PMC: 6349026. DOI: 10.1039/c8sc04645j. View

17.

Zhu J, Wu X, Danishefsky S . On the Preparation of Enantiomerically Pure Isonitriles from Amino Acid Esters and Peptides. Tetrahedron Lett. 2011; 50(5):577-579. PMC: 3159893. DOI: 10.1016/j.tetlet.2008.11.069. View

18.

Znabet A, Polak M, Janssen E, de Kanter F, Turner N, Orru R . A highly efficient synthesis of telaprevir by strategic use of biocatalysis and multicomponent reactions. Chem Commun (Camb). 2010; 46(42):7918-20. DOI: 10.1039/c0cc02823a. View

19.

Walsh S, Iegre J, Seki H, Bargh J, Sore H, Parker J . General dual functionalisation of biomacromolecules via a cysteine bridging strategy. Org Biomol Chem. 2020; 18(22):4224-4230. DOI: 10.1039/d0ob00907e. View

20.

Zhang Y, Ao Y, Huang Z, Wang D, Wang M, Zhu J . Chiral Phosphoric Acid Catalyzed Asymmetric Ugi Reaction by Dynamic Kinetic Resolution of the Primary Multicomponent Adduct. Angew Chem Int Ed Engl. 2016; 55(17):5282-5. DOI: 10.1002/anie.201600751. View