L-Carboranylalanine (LCba) was the first polyhedral borane amino acid derivative synthesized in 1976 along with the development of Boron Neutron Capture Therapy (BNCT). Its design purpose was to mimic the structure of the essential amino acid phenylalanine in the human body(As shown in the figure below). By replacing the benzene ring with a carbon-boron cage, it could participate in the biological metabolic process as a phenylalanine analogue. At the same time, the introduction of carbon-boron also endowed the molecule with unique properties such as three-dimensional aromaticity, hydrophobicity, chemical inertness, and high boron content. This made it not only a direct candidate boron drug for BNCT but also a molecular tool to improve drug activity.
In earlier studies, L-Carboranylalanine demonstrated excellent safety. Animal experiments showed that when injected intraperitoneally at a dose of 25mg per mouse (or 85mg/kg), no toxic effects were observed within three weeks (J. Labelled Compd. Radiopharm. 1977, 14, 487). In experiments with mouse melanoma cells, the intracellular binding ability of L-carbonborane-alanine was superior to the commonly used clinical boron drug BPA. After neutron irradiation, the cell survival rate significantly decreased (Acta. Oncologica. 1994, 33, 685).
What is exciting is that L-Carboranylalanine, after being chloroacetylated and modified, was successfully transformed into a translation initiation factor (As shown in the figure below), successfully integrating L-Carboranylalanine into the macrocyclic peptide. This macrocyclic peptide has high affinity and specificity for human epidermal growth factor receptor and can directly participate in the binding to the hydrophobic site of the receptor, and its function cannot be replaced by phenylalanine; at the same time, the introduction of L-Carboranylalanine enhances the stability of the peptide. The macrocyclic peptide labeled with fluorescein can also be used for fluorescence imaging (J. Am. Chem. Soc. 2019, 141, 19193), and is a highly promising candidate compound for BNCT boron drugs.
Not only is boron-based drug, but it is also a "magic helper" in drug development. By using L-Carboranylalanine as the amino acid unit to replace the phenylalanine in the peptide chain of the pancreatic trypsin inhibitor analog (As shown in the figure below), it can effectively bind to the hydrophobic recognition site of the enzyme's phenylalanine and has a good inhibitory effect on trypsin, with a better effect than the phenylalanine peptide chain (Helv. Chim. Acta. 1977, 60, 959). Moreover, after replacing the phenylalanine at the 4th position of [Leu5]-enkephalin with L-Carboranylalanine (As shown in the figure below), the [Car4, Leu5]-enkephalin has a 3-fold increase in binding affinity to the opioid receptor and is comparable to the naturally strongest [Met5]-enkephalin (FEBS Lett. 1977, 82, 325).
The above research indicates that L-Carboranylalanine possesses unique scientific value and broad application prospects. With the breakthrough in the preparation process, L-Carboranylalanine and its derivatives have been commercially available in our company. We believe that in the future, chiral carborane-alanine and its derivatives will play an increasingly important role in the design of precise drug molecules.