Phenylboronate Amino Acid Building Blocks

Boric acid and boronates can act as Lewis acids and form reversible covalent complexes with sugars, amines, hydroxamic acids etc. An interesting feature of boronic acids (BA) is that they can covalently pair with electron rich vicinal functions like, e.g., catechols (CA) and salicylhydroxamates (SHA), i.e., with Lewis-donors.

By incorporating BA and CA into linear structures (like, e.g., synthetic peptide backbones), you may obtain highly affine complementary strands with low spatial requirements. They can be used to encode binary information, to release payloads or to reversibly immobilize tagged structures, as this interaction depends on pH. While the bonds between BA and CA readily form at neutral pH, they will break when the surroundings become acidic, like it is the case in the microenvironments of many tumors, in the lysosomal compartment of cells, or simply by adjusting pH.

Illustration of the pH-dependent reversible reaction between a boronic acid-modified phenylalanine and a catechol-bearing residue (e.g., dihydroxy-L-phenylalanine).

In conjunction with salicylhydroxamates, boronate derivatives have been investigated for the controlled release of cytostatic drugs like, e.g., a boronate-modified Camptothecin.

A complex formed between the phenylboronate side chain of a synthetic peptide and the salicylhydroxamate moiety of an effector molecule. The latter may be released at weakly acidic conditions, e.g., in the lysosomal compartment.

Naturally, boron occurs as two isotopes: ¹⁰B (19.6%) and ¹²B (80.3%). When it is irradiated with thermal (= low energy) neutrons, ¹⁰B absorbs one neutron and becomes activated ¹¹B, which is unstable and quickly decomposes into an alpha particle and a lithium ion. Concomitantly, a huge amount of energy (2.31 MeV) is released within a very narrow space: The corpuscular radiation is reaching only as far as 5-9 µm, which corresponds to the size of just a single cell, and thus makes it ideal for destroying tumors, while the surrounding healthy tissue is spared.

This phenomenon is exploited in an experimental medical technique named BNCT (boron neutron capture therapy) by first enriching boron containing molecules at the tumor site, followed by irradiation with thermal neutrons (which may be generated with an accelerator device). The accumulation of about 10 µg (1 µmol) of ¹⁰B per gram tissue is required. The selective uptake of boron by the targeted cells is of course essential and requires the precise delivery of boron containing probes.

To enable the convenient incorporation of boronates into peptides by solid phase synthesis, we have added three differently protected building blocks to our portfolio (see related products). The purpose of the pinanediol protection in FAA0010 is to prevent aggregation of the peptide during synthesis when several boronates are introduced. The pinanediol protection is conveniently removed during the release of the finished peptide with TFA. TentaGel® resins are recommended as solid support for SPPS. To adjust the solubility of the boronate containing peptide in aqueous media, charged amino acids like lysine may be added during SPPS.

→ You are interested in other linker technologies for drug delivery? Browse our brochure “Linkerology®”!

→ Discover TentaGel® and other available resins as well as application guidelines in our booklet! 

References:

Boron-Carbohydrate Interactions; B. Pappin, M. Kiefel, T. Houston; In book: Carbohydrates - Comprehensive Studies on Glycobiology and Glycotechnology; C. Chang (ed.). InTech 2012; http://dx.doi.org/10.5772/50630

Sequence Programming with Dynamic Boronic Acid/Catechol Binary Codes; M. Hebel, A. Riegger, M. Zegota, G. Kizilsavas, J. Gačanin, M. Pieszka, T. Lückerath, J. Coelho, M. Wagner, P. Gois, D. Ng, T. Weil; J Am Chem Soc. 2019; 141: 14026-14031. https://doi.org/10.1021%2Fjacs.9b03107

Dual Stimuli-Responsive Dynamic Covalent Peptide Tags: Toward Sequence-Controlled Release in Tumor-like Microenvironments; M. Zegota, M. Müller, B. Lantzberg, G. Kizilsavas, J. Coelho, P. Moscariello, M. Martínez-Negro, S. Morsbach, P. Gois, M. Wagner, D. Ng, S. Kuan, T. Weil; J Am Chem Soc. 2021; 143: 17047-17058. https://doi.org/10.1021/jacs.1c06559

Macrocyclic Dual-Locked “Turn-On” Drug for Selective and Traceless Release in Cancer Cells; D. Schauenburg, B. Gao, L. Rochet, D. Schüler, J. Coelho, D. Ng, V. Chudasama, S. Kuan, T. Weil; Angew. Chem. Int. Ed. 2024; e202314143. https://doi.org/10.1002/anie.202314143

Construction of targeted ¹⁰B delivery agents and their uptake in gastric and pancreatic cancer cells; S. Wang, Z. Zhang, L. Miao, J. Zhang, F. Tang, M. Teng, Y. Li; Front. Oncol. 2023; 13: 1105472. https://doi.org/10.3389/fonc.2023.1105472

Boron phenyl alanine targeted chitosan–PNIPAAm core–shell thermo-responsive nanoparticles: boosting drug delivery to glioblastoma in BNCT; M. Soleimanbeigi, F. Dousti, F. Hassanzadeh, M. Mirian, J. Varshosaz, Y. Kasesaz, M. Rostami; Drug Dev Ind Pharm. 2021; 47: 1607-1623. https://doi.org/10.1080/03639045.2022.2032132