Ajoene

History and syntheses

The structure of ajoene was determined and it was synthesized based on biosynthetic considerations in 1984, correcting an incorrect structure published in 1983. A short, scalable total synthesis of ajoene was reported in 2018 by Wirth and coworkers while a biosynthetically modeled synthesis of trifluoroajoene from difluoroallicin was published in 2017. Syntheses of various ajoene analogues have also been reported. The chemistry of ajoene has been extensively investigated.

When a garlic clove is crushed or finely chopped, allicin is released, with subsequent formation of ajoene when the material is dissolved in various solvents including edible oils. Ajoene is also found in garlic extract. Ajoene is most stable and most abundant in macerate of garlic (chopped garlic in edible oil).

The reaction sequence that forms ajoene (2 in the diagram) involves two molecules of allicin. First, one allicin molecule (1 in the diagram) fragments to form 2-propenesulfenic acid and thioacrolein. These two react in separate stages with another allicin molecule by way of a conjugated thiocationic intermediate.

Medicinal properties

Ajoene has multiple medicinal uses. It functions as an antioxidant by inhibiting the release of superoxide. Ajoene also has antithrombotic (anti-clotting) properties, which helps prevent platelets in the blood from forming blood clots, potentially reducing the risk of heart disease and stroke in humans. Ajoene has shown potential virucidal properties against a number of viruses including vesicular stomatitis, vaccinia, human rhinovirus parainfluenza, and herpes simplex. In the infected cell system of a human immunodeficiency virus (HIV), it is shown to block the integrin-dependent processes.

Ajoene has broad-spectrum antimicrobial (antibacterial and antifungal) properties. For example, Ajoene has been shown to have activity against the human dermatophyte Trichophyton rubrum, the most common cause of tinea pedis, commonly known as Athlete's Foot. The specific mechanism of action is unclear, but is thought to be related to the inhibition of phosphatidylcholine biosynthesis in human dermatophytes. In a randomized study by Ledezma et al. (2000), 70 soldiers from the Venezuelan Armed Forces with KOH or culture proven tinea pedis interdigitalis were randomly distributed into 3 treatment groups: 0.6% ajoene, 1% ajoene, and 1% terbinafine (commercially available as Lamisil AT) applied twice daily for 1 week. At the 60 day follow up, 72%, 100%, and 94% of the patients treated with 0.6% and 1% ajoene, and 1% terbinafine, respectively, had maintained culture-proven mycologic cure suggesting that short-term topical treatment with ajoene is at least as effective as topical terbinafine for treating tinea pedis.

Ajoene has been investigated as a chemotherapeutic agent for treatment of cancer stem cells in glioblastoma multiforme, of lung adenocarcinoma and as an anti-leukemia agent for acute myeloid leukemia therapy. Ajoene has been found to decrease basal-cell carcinoma tumor size by inducing apoptosis while it has also been shown effective in inhibiting tumor cell growth by targeting the microtubule cytoskeleton of such cells and by other mechanisms. Ajoene inhibits genes controlled by quorum sensing, through binding to the RNA chaperone Hfq, then hindering its interaction with the small RNAs that, ultimately, control the production of quorum sensing autoinducers. Since this interaction occurs at the proximal Hfq binding site (the first site that small RNAs bind to), the subsequent pairing with messenger RNAs never occurs and the expression of virulence factors in Gram-negatives is impaired.

References

References

1. (1984). "(''E'',''Z'')-Ajoene: A potent antithrombotic agent from garlic". [[Journal of the American Chemical Society]].
2. Apitz-Cȧstro, R.. (1983). "Effects of garlic extract and of three pure components isolated from it on human platelet aggregation, arachidonate metabolism, release reaction and platelet ultrastructure". [[Thrombosis Research]].
3. Silva, F.. (2018). "Short total synthesis of ajoene". [[Angewandte Chemie International Edition]].
4. Block, E.. (2017). "Fluorinated analogs of organosulfur compounds from garlic (''Allium sativum''). Synthesis, chemistry and anti-angiogenesis and antithrombotic studies.". [[Molecules]].
5. Kaschula CH. (2012). "Structure-activity studies on the anti-proliferation activity of ajoene analogues in WHCO1 oesophageal cancer cells". European Journal of Medicinal Chemistry.
6. Block, E. (1985). "The chemistry of garlic and onions". [[Scientific American]].
7. Apitz-Castro, R. (1986). "Ajoene, the antiplatelet principle of garlic, synergistically potentiates the antiaggregatory action of prostacyclin, forskolin, indomethacin and dypiridamole on human platelets.". Thrombosis Research.
8. (1986). "The chemistry of alkyl thiosulfinate esters. 9. Antithrombotic organosulfur compounds from garlic: structural, mechanistic, and synthetic studies". Journal of the American Chemical Society.
9. Block, E. (2010). "Garlic and Other Alliums: The Lore and the Science". [[Royal Society of Chemistry]].
10. (1992). "In vitro virucidal effects of ''Allium sativum'' (garlic) extract and compounds". Planta Med.
11. (1992). "The ajoene blockade of integrin-dependent processes in an HIV-infected cell system". Vestn Ross Akad Med Nauk.
12. (2012). "In vitro antifungal activity of ajoene on five clinical isolates of ''Histoplasma capsulatum'' var. capsulatum". Revista Iberoamericana de Micologia.
13. (2006). "Ajoene the main active compound of garlic (''Allium sativum''): a new antifungal agent". Revista Iberoamericana de Micologia.
14. Choi JA. (2018). "Enhancement of the antimycobacterial activity of macrophages by ajoene.". Innate Immunity.
15. (2000). "Efficacy of ajoene in the treatment of tinea pedis: a double-blind and comparative study with terbinafine". Journal of the American Academy of Dermatology.
16. (2014). "Systemic approaches identify a garlic-derived chemical, Z-ajoene, as a glioblastoma multiforme cancer stem cell-specific targeting agent". Molecules and Cells.
17. (2016). "ROS-mediated activation of JNK/p38 contributes partially to the pro-apoptotic effect of ajoene on cells of lung adenocarcinoma". Tumour Biology.
18. Hassan HT. (2004). "Ajoene (natural garlic compound): a new anti-leukaemia agent for AML therapy". Leukemia Research.
19. (2003). "The garlic-derived organosulfur component ajoene decreases basal cell carcinoma tumor size by inducing apoptosis". Archives of Dermatological Research.
20. (2007). "Activities of ''Z''-ajoene against tumour and viral spreading in vitro". Fundamental & Clinical Pharmacology.
21. Givskov M. (2012). "Ajoene, a sulfur rich molecule from garlic, inhibits genes controlled by quorum sensing". [[Antimicrobial Agents and Chemotherapy]].
22. Jakobsen TH. (2017). "A broad range quorum sensing inhibitor working through sRNA inhibition". [[Scientific Reports]].
23. (2010). "Ajoene, a sulfur-rich molecule from garlic, inhibits genes controlled by Quorum Sensing". [[Antimicrobial Agents and Chemotherapy]].
24. (2023). "Modulation of Pseudomonas aeruginosa quorum sensing by ajoene through direct competition with small RNAs for binding at the proximal site of Hfq – A structure-based perspective". [[Gene]].