Indene Compounds Synthetically Derived from Vitamin D Have Selective Antibacterial Action on Helicobacter pylori

Abstract

Helicobacter pylori infects the human stomach and is closely linked with the development of gastric cancer. When detected, this pathogen can be eradicated from the human stomach using wide-spectrum antibiotics. However, year by year, H. pylori strains resistant to the antibacterial action of antibiotics have been increasing. The development of new antibacterial substances effective against drug-resistant H. pylori is urgently required. Our group has recently identified extremely selective bactericidal effects against H. pylori in (1R,3aR,7aR)-1-[(1R)-1,5-dimethylhexyl]octahydro-7a-methyl-4H-inden-4-one (VDP1) (otherwise known as Grundmann's ketone), an indene compound derived from the decomposition of vitamin D and proposed the antibacterial mechanism whereby VDP1 induces the bacteriolysis by interacting at least with PtdEtn (dimyristoyl-phosphatidylethanolamine [di-14:0 PtdEtn]) retaining two 14:0 fatty acids of the membrane lipid constituents. In this study, we synthesized new indene compounds ((1R,3aR,7aR)-1-((2R,E)-5,6-dimethylhept-3-en-2-yl)-7a-methyloctahydro-4H-inden-4-one [VD2-1], (1R,3aR,7aR)-1-((S)-1-hydroxypropan-2-yl)-7a-methyloctahydro-1H-inden-4-ol [VD2-2], and (1R,3aR,7aR)-7a-methyl-1-((R)-6-methylheptan-2-yl)octahydro-1H-inden-4-ol [VD3-1]) using either vitamin D or vitamin D as materials. VD2-1 and VD3-1 selectively disrupted the di-14:0 PtdEtn vesicles without destructing the vesicles of PtdEtn (dipalmitoyl-phosphatidylethanolamine) retaining two 16:0 fatty acids. In contrast, VD2-2, an indene compound lacking an alkyl group, had no influence on the structural stability of both PtdEtn vesicles. In addition, VD2-1 and VD3-1 exerted extremely selective bactericidal action against H. pylori without affecting the viability of commonplace bacteria. Meanwhile, VD2-2 almost forfeited the bactericidal effects on H. pylori. These results suggest that the alkyl group of the indene compounds has a crucial conformation to interact with di-14:0 PtdEtn of H. pylori membrane lipid constituents whereby the bacteriolysis is ultimately induced.

Influence of serum vitamin D level on Helicobacter pylori eradication: A multi‐center, observational, prospective and cohort study

“…Several clinical studies have illustrated that vitamin D analogs may have anti‐ H. pylori antimicrobial effects . Cytological research has also found that vitamin D 3 decomposition product 1 (VDP1) can lyse H. pylori bacterial cells by inducing the collapse of the cell membrane …”

“…[4][5][6][7][8][9][10] Cytological research has also found that vitamin D 3 decomposition product 1 (VDP1) can lyse H. pylori bacterial cells by inducing the collapse of the cell membrane. 11,12 However, the correlation between vitamin D levels and H. pylori has not been fully illustrated, and studies on the impact of serum vitamin D levels on H. pylori eradication were mostly of small sample sizes. Therefore, we conducted a multicenter prospective cohort study with a relatively large sample size to determine whether serum vitamin D levels had an impact on H. pylori infection and eradication, and whether its low level was an independent risk factor affecting H. pylori eradication.…”

Effect of vitamin D on Helicobacter pylori infection and eradication: A meta‐analysis

“…The most important reason may be its antibacterial action against H pylori . Previous study reported that infected macrophages upregulate the production of β‐defensin to kill H pylori strains by VDR . β‐defensins are secreted in the gastric mucosa, playing a pivotal role in the immune response of the gastrointestinal epithelium to H pylori infection .…”

The application of copolymer‐coated graphene oxide‐Fe3O4 in the highly efficient synthesis of 2′‐aminospiro[indeno[1,2‐b]quinoxaline‐11,4′‐[4'H] pyran]‐3′‐carbonitrile and 2′‐aminospiro[indeno‐2,4′‐[4'H]pyran]‐3′‐carbonitrile

“…Several methods have been reported for the preparation of these two biologically active moieties . In addition, indene derivatives have attracted much interest due to their anti‐inflammatory, analgesic, and antibacterial properties . Therefore, the synthesis of compounds having various pharmacophores, such as pyran, quinoxaline, and indole, is very important and they can exhibit unique pharmaceutical properties.…”