Bismuth antiulcer drugs

Bismuth compounds have been used for treating gastrointestinal disorders for more than two centuries (451). These include bicarbonate, nitrate and salicylate salts, and colloidal bismuth subcitrate. These are all Bi(III) compounds Bi(V) is usually a strong oxidant. Their structures are largely unknown and often contain a mixture of anionic ligands. This reflects the strong tendency of Bi(III) to hydrolyze and form stable hydroxo and oxo complexes. The first pKa of Bi(III) in water is ca. 1.5. Bismuth(III) has a variable coordination number, from 3 to 10. 

The best understood in structural terms are the citrate complexes for which about seven X-ray structures have been determined (452), none of which has exactly the same composition as the drugs themselves (453). The dominant feature is the dimeric [(cit)BiBi(cit)]2-unit, where citric acid is H4cit, which contains bridging citrate anions (Fig. 20). The Bi-O(alkoxide) bond is very short (2.2 A) and strong, 

The antimicrobial activity of Bi(III) against the bacterium Helicobacter pylori appears to be important for its antiulcer activity (458). This organism may be involved in other conditions such as cancer. The mechanism of antimicrobial activity may involve interference in Fe(III) or Zn(II) biochemical pathways. Bismuth(III) is not known to bind to DNA. Attempts to synthesize new Bi(III) complexes with activity against H. pylori include those of Keppler et al. (459), who have found that Bi(III)-tropolonato complexes such as 98 are highly active 

The tripeptide glutathione (y-L-Glu-L-Cys-Gly) may play a role in the transport of Bi(III) in the body. The complex [Bi(SG)3] is very stable (log K 29.6) over a wide pH range (2-10) with binding via the S atom only (465). Exchange of GSH between free and bound forms is relatively rapid at physiological pH (ca. 1500 s 1). 

Inhibition of the dinuclear Ni(II) enzyme urease by Bi(III) thiolates may be important for its antibacterial activity. Helicobacter pylori relies on urease for the production of ammonia which allows survival under the highly acidic conditions of the gastric lumen and mucosa. Bismuth(III) mercaptoethanol complexes are ca. 103 more active inhibitors than mercaptoethanol alone (466). The thiol can bind directly to Ni(II) in the active site and also form a disulfide with a Cys residue in the active site cavity (467). 

---

Bismuth antiulcer drugs—the sugars used to produce the usually polymeric structures are shown... 

The goal of HP drug therapy is eradication of the organism. Treatment shonld be effective, well-tolerated, easy to comply with, and cost-effective. HP regimens should have eradication (cure) rates of at least 80% based on intention-to-treat analysis, or at least 90% based on per protocol analysis, and should minimize the potential for antimicrobial resistance. The use of a single antibiotic, bismuth salt, or antiulcer drug does not achieve this goal. However,... 

Scheme 5.7 The basic BP citrate dimer found in the antiulcer drugs, colloidal bismuth subcitrate (CBS, DE-Nol ) and possibly ranitidine bismuth citrate. Assembly of these building block leads to the formation of polymeric anion.

The in vitro interactions of the cysteine-rich intracellular protein Zn7-metal-lothionein with cisplatin and transplatin and the histidine-rich proteins Hpni32,i33 HspA with a bismuth antiulcer compound were investigated, respectively. These kinds of interactions may play a crucial role in the metabolism of various metallodrugs. Notably, drug binding to plasma proteins has a strong influence on their biodistribution, biotransformation, and pharmacokinetics, and therefore merits further characterizations. 

---