Medicinal chemistry of group 15 : anticancer mechanism of arsenic and antimicrobial bismuth combination therapy

Abstract

Metals play crucial roles in biological systems, serving as essential components of enzymes, cofactors and signaling molecules. Arsenic and bismuth, two distinct Group 15 elements, exhibit unique chemical properties and potential applications in medicine. Arsenic, despite its toxicity, has garnered attention due to its intriguing antileukemia feature and potential applications. Conversely, bismuth is relatively nontoxic and offers appealing properties for biomedical and material sciences. While both interact with thiolate-containing biomolecules, they have distinct effects and toxicity profiles. It is therefore crucial to investigate the chemical and biological aspects of arsenic and bismuth. In this thesis, the properties and potential applications of arsenic and bismuth in medicine are examined.

The anticancer mechanism of arsenic (e.g arsenic trioxide (ATO)) has been investigated through bioinformatics analysis of arsenic-associated proteins and proteomes in leukemia cells. A total of 250 arsenic-associated proteins were identified, and 10 hub proteins were discovered, with heat shock protein 60 (Hsp60) being the most up-regulated. The binding of arsenic trioxide to Hsp60, resulted in the disruption of its refolding and ATPase activity. ATO treatment further disrupts complexes involving Hsp60, such as Hsp60-p53 and Hsp60-survivin, leading to the degradation of p53 and survivin. The integrative approach provides a comprehensive platform for understanding the therapeutic and toxicological effects of arsenic and guiding rational design of other metallodrugs.

Bismuth drugs, used in combination with antibiotics, have been used in medicine for H. pylori infection. However, their limited bioavailability in vivo hinders their effectiveness. To enhance the bioavailability of bismuth(III), a combinatorial treatment of bismuth with hinokitiol has been explored. This combination significantly improves cellular bismuth uptake by 4-fold and reduces Fe(III) levels accordingly. As a result, synergistic effects against methicillin-resistant S. aureus (MRSA) are observed, with the MIC dropping by 32-fold. Animal studies further validate the efficacy of the co-therapy, showcasing reduced bacterial loads in multiple organs and the successful healing of skin infection, with minimal toxicity. This approach holds promise in combating antimicrobial resistance and offers potential treatment options for drug-resistant bacterial infections, addressing the critical issue of MRSA.

Colloidal bismuth subcitrate (CBS), originally an antiulcer agent, holds great promise as a platform for drug delivery systems with its versatile structures and channels. The discovery of MOF-type structure of CBS as a drug delivery tool, achieved through co-crystallization with spermidine (and relevant molecules), resulted in a structure with a maximum channel size of 28.5×14.5 Å. CBS demonstrates efficient loading capabilities for low mass drugs and exhibits a pH-responsive feature, releasing more drug under acidic environments. When utilized as a delivery system for cisplatin, CBS showcases controlled drug release while preserving the anticancer activity of cisplatin. The versatile structure and controlled drug release properties of CBS highlight its potential as a drug delivery system, offering opportunities for further development and exploration of its applications in various fields.