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Shishjimicin A edit
Background edit
Shishjimicin A is a natural complex enediyne molecule, that is derived from the rare marine sea squirt Didemnum proliferum. Isolated in 2003[1], it is part of the family of 10 membered rind enediyne antitumor antibiotic agents, which includes: namenamicin, esperamicin and, calicheamicin. Due to its high potency from cytotoxicity, Shishjimicin A is currently undergoing testing as a possible Antibody-antibiotic Conjugate (ADCs) cancer treatment. Laboratory tests indicate it to be “more than 1,000 times as toxic to cancer cells as the anticancer drug taxol”[2], also known as Paclitaxel, a prevalent chemotherapy medication. As such, theoretically, only an administration of a miniscule dose of the molecule would be necessary per each treatment. As shishjimicin A supply is scarce and the full extent of its side effects is not yet established, there is still a need for further biological and clinical studies.
Prior and ongoing research edit
The total synthesis of shishjimicin A was published by scientists at Rice University in 2015[3], led by K. C. Nicolaou. Using methodology from the previous isolation of calicheamicin[4], where 21 total steps were conducted for the synthesis[5][6], briefly outlined below:
- Shishijimicin A undergoes deprotection
- Trisulfide formation with glycosidation
- Carboline disaccharide coupling
The total synthesis includes:
- Reduction with ethylene glycol and diisobutylaluminium hydride
- Asymmetric addition of anion with selective protection
- Aldehyde oxidation via Swern oxidation and oxime formation
- Intramolecular dipolar cycloaddition
- Selective control of diastereoisomer formation
- Removal of protection and completed oxidation
- Coupling with lithium (3Z)-3-Hexene-1,5-diyne triisopropylsilyl chloride with Knochel's salt (LaCl3·2LiCl)
- Acetylation
- Deprotection
The goal is to create two complex intermediate compounds, trichloroacetimidate and hydroxy enediye. These will be coupled to produce shishjiimicin A. Though this organic synthesis is challenging, its mapping allows for further contribution to research efforts. Further improvements of the coupling reaction are currently being studied. Practicality and synthesis variations of the complex molecule are essential to working alongside pharmaceutical companies to develop clinical trials and treatment options.
In addition to its total synthesis, there is research regarding the DNA-cleaving mechanism that shishijimicin A undergoes published in 2019. According to the same research team at Rice University, "[shishijimicin A] binds to the minor groove of double-stranded DNA (dsDNA) and that its β-carboline moiety plays a role in the binding through intercalation"[7]. The conclusion of the research the unbound linker regions of DNA in the process of interphase and metaphase are open to binding by binders such as shishijimicin A. These regions lack protective histone proteins throughout the eukaryotic cell cycle. This dsDNA cleavage visualized and low selection probability for sequences by shishijimicin A may attribute to its cytotoxic properties[7].
The cytotoxicity that shishijimicin A exhibits is towards HeLa cells, specifically in the IC50 values that range between 1.8-6.9 pM[8].
References edit
- ^ Zhang, Hao; Li, Ruofan; Ba, Sai; Lu, Zhaoyong; Pitsinos, Emmanuel N.; Li, Tianhu; Nicolaou, K. C. (2019-05-15). "DNA Binding and Cleavage Modes of Shishijimicin A". Journal of the American Chemical Society. 141 (19): 7842–7852. doi:10.1021/jacs.9b01800. ISSN 0002-7863.
- ^ "Rice lab synthesizes cancer-killing compound". TMC News. 2015-07-13. Retrieved 2021-11-29.
- ^ Nicolaou, K. C.; Lu, Zhaoyong; Li, Ruofan; Woods, James R.; Sohn, Te-ik (2015-07-15). "Total Synthesis of Shishijimicin A". Journal of the American Chemical Society. 137 (27): 8716–8719. doi:10.1021/jacs.5b05575. ISSN 0002-7863.
- ^ Smith, A. L.; Pitsinos, E. N.; Hwang, C. K.; Mizuno, Y.; Saimoto, H.; Scarlato, G. R.; Suzuki, T.; Nicolaou, K. C. (1993-08-01). "Total synthesis of calicheamicin .gamma.1I. 2. Development of an enantioselective route to (-)-calicheamicinone". Journal of the American Chemical Society. 115 (17): 7612–7624. doi:10.1021/ja00070a005. ISSN 0002-7863.
- ^ "The Nicolaou Synthesis of Shishijimicin A". www.organic-chemistry.org. Retrieved 2021-11-29.
- ^ Nicolaou, K. C.; Lu, Zhaoyong; Li, Ruofan; Woods, James R.; Sohn, Te-ik (2015-07-15). "Total Synthesis of Shishijimicin A". Journal of the American Chemical Society. 137 (27): 8716–8719. doi:10.1021/jacs.5b05575. ISSN 0002-7863.
- ^ a b Zhang, Hao; Li, Ruofan; Ba, Sai; Lu, Zhaoyong; Pitsinos, Emmanuel N.; Li, Tianhu; Nicolaou, K. C. (2019-05-15). "DNA Binding and Cleavage Modes of Shishijimicin A". Journal of the American Chemical Society. 141 (19): 7842–7852. doi:10.1021/jacs.9b01800. ISSN 0002-7863.
- ^ Oku, Naoya; Matsunaga, Shigeki; Fusetani, Nobuhiro (2003-02-01). "Shishijimicins A−C, Novel Enediyne Antitumor Antibiotics from the Ascidian Didemnum proliferum". Journal of the American Chemical Society. 125 (8): 2044–2045. doi:10.1021/ja0296780. ISSN 0002-7863.